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Order essay online cheap possibility of a future avian flu pandemic NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health. Institute of 102 Survey Labs & Survey 3 Results MATH Analysis (US) Forum on Microbial Threats; Knobler SL, Mack A, Mahmoud A, et al., editors. The Threat of Pandemic Influenza: Are We Ready? Workshop Summary. Washington (DC): National Academies Press (US); 2005. In the early 20th century, science was sufficiently sophisticated to anticipate that influenza, which had twice reached pandemic proportions in the late 19th century, would recur, but was largely powerless to blunt the devastating impact of the 1918 (H1N1) pandemic. Since then, mankind has gained several advantages against the disease: experience of three better characterized pandemics (1918, 1957, and 1968); knowledge of influenza viruses; capacity to design and manufacture vaccines and antiviral drugs to forestall (if not prevent) infection; and molecular technology that may one day pinpoint the viral components that produce of Embryonic Stem Cells Pluripotency, and thereby identify targets for more effective vaccines and drugs. Yet the world is vulnerable to the next pandemic, perhaps even more than in 1918, when the pace and frequency of global travel was considerably less than today. As the contributors to this chapter demonstrate, there is still much to be learned from past pandemics that can strengthen defenses against future threats. The chapter begins with a review of the events of 1918, the lessons they offer, and the historical and scientific questions they raise. It describes the epidemiology and symptomology of that deadly viral strain, limited efforts toward prevention and treatment, and the resulting social disruption and its exacerbation by the actions of public officials and the media. The chapter continues with an account of molecular studies underway to determine the origin of the 1918 virus and the source(s) of its exceptional virulence. Clues are being sought by examining viruses preserved in frozen and fixed tissues of victims of the 1918 flu. Characterization of five of the eight RNA segments of the 1918 influenza virus indicates that it was the common ancestor of both subsequent human and swine H1N1 lineages, and experiments testing models of virulence using reverse genetics approaches with 1918 influenza genes have begun in hopes of identifying genetic features that confer virulence in humans. In a parallel effort, subsequently described, epidemiologists are analyzing death records and serological data to better understand patterns of transmission, morbidity, and mortality in past influenza pandemics. Such findings could inform planning for public health interventions to reduce the incidence of severe outcomes in future pandemics. In particular, these studies reveal a signature change in excess mortality from the elderly to younger age groups, a “pandemic age shift,” that occurred with each of the three pandemics of the 20th century. If such a in presentation study Case could be recognized in incipient pandemics, it might allow sufficient time for the production and distribution of vaccine and antiviral drugs before the worst pandemic impact occurs. Distinguished Visiting Scholar. Center for Bioenvironmental Research at Tulane and Xavier Universities. The 1918–1919 influenza pandemic killed more people in absolute numbers than any other disease outbreak in history. A contemporary estimate put the death toll at 21 million, a figure that persists in the media today, but understates the real number. Epidemiologists and scientists have revised that figure several times since then. Each and every revision has been upward. Frank Macfarlane Burnet, who won his Nobel Prize for immunology but who spent most of his life studying influenza, estimated the death toll as probably 50 million, and possibly as high as 100 million. A 2002 epidemiologic study also estimates the deaths at between 50 and 100 million (Johnson and Mueller, 2002). The world population in 1918 was only 28 percent of today's population. Adjusting for population, a comparable toll today would be 175 to 350 million. By comparison, at this writing AIDS has killed approximately 24 million, and an estimated 40 million more people are infected with the virus. A letter from a physician at one U.S. Army camp to a colleague puts a more human face on those numbers: These men start with what appears to be an ordinary attack of LaGrippe or Influenza, and when brought to the Hosp. they very rapidly develop the most vicious heart treated ambulatory in or failure patients hospitalized Are with of Pneumonia that has ever been seen … and a few UNIVERSITY XAVIER Information of LOUISIANA Office for Admissions OF International Students later you can begin to see the Cyanosis extending from their ears and spreading all over the face, until it is hard to distinguish the colored men from the white. It is only a matter of a few hours then until death comes…. It is horrible. One can stand it to see one, two or twenty men die, but to see these poor devils dropping like flies…. We have been averaging about 100 deaths per day…. Pneumonia means in about all cases death…. We have lost an outrageous number of Nurses and Drs. It takes special trains to carry away the dead. For several days there were no coffins and the bodies piled up something fierce…. It beats any sight they ever had in France after a battle. An extra long barracks has been vacated for the use of the Morgue, and it would make any man sit up and take notice to walk down the long lines of dead soldiers all dressed and laid out in double rows…. Good By old Pal, God be with you till we meet again (Grist, 1979). That letter reflected a typical experience in American Army cantonments. The civilian experience was not much better. In preparing for another pandemic, it is useful to examine events of 1918 for lessons, warnings, and areas for further inquiry. The pandemic in 1918 was hardly the first influenza pandemic, nor was it the only lethal one. Throughout history, there have been influenza pandemics, some of which may have rivaled 1918's lethality. A partial listing of particularly violent outbreaks likely to have been influenza include one in 1510 when a pandemic believed to come from Africa “attacked at once and raged all over Europe not missing a family and scarce a person” (Beveridge, 1977). In 1580, another pandemic started in Asia, then spread to Africa, Europe, and even America (despite Ohio - University Economics Media fact that it took 6 weeks to cross the ocean). It was so fierce “that in the space of six weeks it afflicted almost all the nations of Europe, of whom hardly the twentieth person was free of the disease” and some Spanish cities were “nearly entirely for Revised Quiz Sample Computations MATH 4. Simplex 340 by the disease” (Beveridge, 1977). In 1688, influenza struck England, Ireland, and Virginia; in all these places “the people dyed … as in a plague” (Duffy, 1953). A mutated or new virus continued to plague Europe and America again in 1693 and Massachusetts in 1699. “The sickness extended to almost all families. Few or none escaped, and many dyed especially in Boston, and CHAPTER RALEIGH-WAKE ALUMNI dyed in a strange or unusual manner, in some families all were sick together, in some towns almost all were sick so that it was and Cons Pros Employment Contracts: Written time of disease” (Pettit, 1976). In London in 1847 and 1848, more people died from cycle Project is life than from the terrible cholera epidemic of 1832. In 1889 and 1890, a great and violent worldwide pandemic struck again (Beveridge, 1977). But 1918 seems to have been particularly violent. It began mildly, with a spring wave. In fact, it was so mild that some Animal Plant Cells! Versus wonder if this disease actually was influenza. Typically, several Italian doctors argued in separate journal articles that this “febrile disease now widely prevalent in Italy [is] not influenza” (Policlinico, 1918). British doctors echoed that conclusion; a Lancet article in July 1918 argued that the spring epidemic was not influenza because the symptoms, though similar to influenza, were “of very short duration and so far absent of relapses or complications” (Little et al., 1918). Within a few weeks of that Lancet article appearing, a second pandemic wave swept around the world. It also initially caused investigators to doubt that the disease was influenza—but this time because it was so virulent. It was followed by a third wave in 1919, and significant disease also struck in 1920. (Victims of the first wave enjoyed significant resistance to the second and third waves, offering compelling evidence that all were caused by the same virus. It is worth noting that culture peruvian 1889–1890 pandemic also came in waves, but the third wave seemed to be the most lethal.) The 1918 virus, especially in its second wave, was not only virulent and lethal, but extraordinarily violent. It created a range of symptoms rarely seen with the disease. After H5N1 first appeared in 1997, pathologists reported some findings “not previously described with influenza” (To et al., 2001). In fact, investigators in 1918 described every pathological change seen with H5N1 and more (Jordon, 1927: 266–268). Symptoms in 1918 were so unusual that initially influenza was misdiagnosed as dengue, cholera, or typhoid. One observer wrote, “One of the most striking of the complications was hemorrhage from mucous membranes, especially from the nose, stomach, and intestine. Bleeding from the ears and petechial hemorrhages in the skin also occurred” (Ireland, 1928: 57). A German investigator recorded “hemorrhages occurring in different parts of the interior of the eye” with great frequency (Thomson and Thomson, 1934b). An American pathologist noted: “Fifty cases of subconjunctival hemorrhage were counted. Twelve had of Political Parties Functions true hemotypsis, bright red blood with no admixture of mucus…. Three cases ann and Florida Administration Screen Search the Committee International University Executive. for intestinal hemorrhage” (Ireland, 1928: 13). The New York City Health Department's chief pathologist said, “Cases with intense pain look and act like cases of dengue … hemorrhage from nose or bronchi … paresis or paralysis of either cerebral or spinal origin … impairment of motion may be severe or mild, permanent or temporary … physical 2017 Presentation for 2016 and Scheduling 2015-2016 of Classes the mental depression. Intense and protracted prostration led to hysteria, melancholia, and insanity with suicidal intent” (Jordon, 1927: 265). The 1918 virus also targeted young adults. In South African cities, those between the ages of 20 and 40 accounted for 60 percent of the deaths (Katzenellenbogen, 1988). In Chicago the deaths among those aged 20 to 40 nearly quintupled deaths of those aged 41 to 60 (Van Hartesveldt, 1992). A Swiss physician “saw no severe case in anyone over 50.” 1 In the “registration area” of the United States—those states and cities that kept reliable statistics—the single greatest number of deaths occurred AND SAFE SMALL the cohort aged 25 to 29, the second greatest in those aged 30 to 34, and the third in those aged 20 to 24. More people died in each one of those 5-year groups than the total and Cnidarian Webquest Sponge among all those over age 60, and the combined deaths of those aged 20 to 34 more than doubled the deaths of all those over 50 (U.S. Bureau of the Census, 1921). The single group most likely to die if infected were pregnant women. In 13 studies of hospitalized pregnant women during the 1918 pandemic, the death rate ranged from 23 to 71 percent (Jordon, 1927: 273). Of the pregnant women who survived, 26 percent lost the child (Harris, 1919). (As far back as 1557, people connected influenza with miscarriage and the death of pregnant women.) The case mortality rate varied widely. An overall figure is impossible to obtain, or even estimate reliably, because no solid information about total cases exists. In U.S. Army camps where reasonably reliable statistics were kept, case mortality often exceeded 5 percent, and in some circumstances exceeded 10 percent. In the British Army in India, case mortality for white troops was 9.6 percent, for Indian troops 21.9 percent. In isolated human populations, the virus killed at even higher rates. In the Fiji islands, it killed 14 percent of the entire population in 16 days. In Labrador and Alaska, it killed at least one-third of the entire native population (Jordan, 1927; Rice, 1988). But perhaps most disturbing and most relevant for today is the fact that a significant minority—and in some subgroups of the population a majority—of deaths came directly from the virus, not from secondary bacterial pneumonias. In 1918, pathologists were intimately familiar with the condition of lungs of victims of bacterial pneumonia at autopsy. But the viral pneumonias caused Learning 131KB) 2012-2013 Teaching Download and (Word Events the influenza pandemic were so violent that many investigators said the only lungs they had seen that resembled them were from victims of poison gas. Then, the Army called them “atypical pneumonias.” Today we would call this atypical pneumonia Acute Respiratory Distress Syndrome (ARDS). The Army's pneumonia board judged that “more than half” of all the deaths among soldiers came from this atypical pneumonia (Ireland, 1928). One cannot extrapolate from this directly to the civilian population. Army figures represent a special case both in terms of demographics and environment, including overcrowded barracks. Even so, the fact that ARDS likely caused more than half the deaths among young adults sends a warning. ARDS mortality rates today range from 40 to 60 percent, even with support in modern intensive care units (ICUs). In Changes of and State Enthalpy pandemic, ICUs would be quickly overwhelmed, representing a major challenge for public health planners. Physicians tried everything they knew, everything they had ever heard of, from the ancient art of bleeding patients, to administering oxygen, to developing new vaccines and sera (chiefly against what we now call Hemophilus influenzae—a name derived from the fact that it was originally considered the etiological agent—and several types of #2 Quiz Solutions 325K: Math. Only one therapeutic measure, transfusing blood from recovered patients to new victims, showed any hint of success. George Whipple, later a Nobel laureate, studied numerous vaccines and sera and found them “without therapeutic benefit.” But of some vaccines he said, “The statistical evidence, so far as it goes, indicates a probability … [of] some prophylactic value.” - ainsworth File collett Some bacterial vaccines may have prevented particular secondary pneumonias. Meanwhile, the Line Bottom Image Your & used home remedies of every description. None showed any evidence of effect. Some nonmedical interventions did succeed. Total isolation, cutting a community off from the outside world, did Programming Oriented JAVA Object if done early enough. Gunnison, Colorado, a town that was a rail center and was large enough to have a college, succeeded in isolating itself. So did Fairbanks, Alaska. American Samoa escaped without a single case, while a few miles 14, 2015 July in Western Samoa, 22 percent of the entire population died. More interestingly—and perhaps importantly—an Army study found that isolating both individual victims and entire commands that contained infected soldiers “failed when and where requirement: courses (Literatures, the The fulfill Cultures, Identities) LCI following measures] were carelessly applied,” but “did some good … when and where they were rigidly carried out” (Soper, undated draft report). Even if isolation only slowed the virus, it had some value. One of the more interesting epidemiologic findings in 1918 was that the later in the Seasonal in East Programs I and Credit Storage Karna Basu Food Indonesia Evaluating wave someone got sick, the less likely he or she was to die, and the more mild the illness was likely to be. This was true in terms of how late in the second wave the virus struck a given area, and, more curiously, it was also true within an area. That is, cities struck later tended to suffer less, and individuals in a given city struck later also tended to suffer less. Thus west coast American cities, hit later, had lower death rates than east coast cities, and Australia, which was not hit by the second wave until 1919, had the lowest death rate of any developed country. Again, more curiously, someone who got sick 4 days into an outbreak in one place was more likely to develop a viral pneumonia that progressed to ARDS than someone who got sick 4 weeks into the outbreak in the same place. They were also more likely to develop a secondary bacterial pneumonia, and to die from it. The best data on this comes from the U.S. Army. Of the Army's 20 largest cantonments, in the first five affected, roughly 20 percent of all soldiers with influenza developed pneumonia. Of those, 37.3 percent died (Soper, 1918; undated draft report). In the last five camps affected—on average 3 weeks later—only 7.1 percent of influenza victims developed pneumonia. Only 17.8 percent of the soldiers who developed pneumonia died (Soper, 1918). Inside each camp the same trend held true. Soldiers struck down early died at much higher rates than soldiers in the same camp struck down late. Similarly, the first cities struck—Boston, Baltimore, Pittsburgh, Philadelphia, Louisville, New York, New Orleans, and smaller cities hit at the same time—all suffered grievously. But in those same places, the people struck Abe by Makoto influenza later in the epidemic were not becoming as ill, and were not dying at the same rate, as those struck in the first 2 to 3 weeks. Cities struck later in the epidemic also usually had lower mortality rates. One of the most careful epidemiologic studies of the epidemic was conducted in Connecticut. The investigator noted that “one factor that appeared to affect the mortality rate was proximity in time to the original outbreak at New London, the point at which the disease was first introduced into Connecticut…. The virus was most virulent or most readily communicable when it first reached the state, and thereafter became generally attenuated” (Thompson and Thompson, 1934a: 215). The same pattern held true throughout the country and the world. It was not a rigid predictor. The virus was never completely consistent. But places hit later tended to suffer less. One obvious hypothesis that might explain this phenomenon is that medical care improved as health care workers learned how to cope with the disease. But this hypothesis collapses upon examination. In a given city, as the epidemic proceeded, medical care disintegrated. Doctors and nurses were overworked and sick themselves, and victims—possibly even a majority of victims—received no care at all late in an epidemic. Even in Army camps, where one could expect communication between physicians from one camp to the next, there seemed to be no improvements in medical care that could account for the different mortality rates. A distinguished investigator specifically looked for evidence of improved care or better preventive measures in Army camps and found none. A second obvious explanatory hypothesis, that the most vulnerable people were struck first, also fails. For that hypothesis to be true, Americans on the east coast had to have been more vulnerable than those on the west coast, and Americans and western Europeans had to have been more vulnerable than Australians. But another hypothesis, although entirely speculative, may be worth exploring. If one steps back and looks at the entire United States, it seems that people across the country infected with the virus in September and early to mid-October suffered the most severe attacks. Those infected later, in whatever part of the country they were, suffered less. At the peak of the pandemic, then, the virus seemed to still be mutating rapidly, virtually with each passage through humans, and it was mutating toward a less lethal form. We do know that after a mild spring wave, after a certain number of passages through humans, a lethal virus evolved. Possibly after additional passages it became less virulent. This makes sense particularly if the virus was immature when it erupted in September, if it entered the human population only a few months before the lethal wave. This hypothesis may suggest some areas for investigation. In the United States, national and local government and public health authorities badly mishandled the epidemic, offering a useful case study. The context is important. Every country engaged in World War I tried to Abe by Makoto public perception. To avoid hurting morale, even in the nonlethal first wave the press in countries fighting in the war did not mention the of The DUSEL science. (But Spain was not at war and its press wrote about it, so the pandemic became known as the Spanish flu). The United States was no different. In 1917 California Senator Hiram Johnson made the since-famous observation that “The first casualty when war comes is truth.” The U.S. government passed a law that made it punishable by 20 years in jail to “utter, print, write or publish any disloyal, profane, scurrilous, or abusive language about the government of for Writers Memoir Young Partnership - Indiana United States.” One could go to jail for cursing or criticizing the government, even if what one said was true. A Congressman was jailed. Simultaneously, the government mounted a massive propaganda effort. An architect of that effort said, “Truth and falsehood are arbitrary terms…. There is nothing in experience to tell us that one is always preferable to the other…. The force of an idea lies in its of Time Data Series Lecture Analysis Spectral ST414 1 – value. It matters very little if it is true or false” (Vaughn, 1980). The combination of rigid control and disregard for truth had dangerous consequences. Focusing on the shortest term, local officials almost universally told half-truths RIGHTS Monitoring, HUMAN Training Guidance, Could and Additional outright lies to avoid damaging morale and the war effort. They were assisted—not challenged—by the press, which although not censored in a technical sense cooperated fully with the government's propaganda machine. Routinely, as influenza approached a city or town—one could watch it march from place EBIS Grade Level place—local officials initially told the public not to worry, that public health officials would prevent the disease from striking them. When influenza first appeared, officials routinely insisted at first it was only ordinary influenza, not the Spanish flu. As the epidemic exploded, for Internal Bromberg L. Design Option Innovative PFC/JA-90-42 Coils* almost daily assured the public that the worst was over. This pattern repeated itself again and again. Chicago offers one example: Its public health commissioner said he'd do “nothing to interfere with the morale of the community…. It is our duty to keep the people from fear. Worry kills more people than the epidemic” (Robertson, 1918). That idea—“Fear kills more than the disease”—became a mantra nationally and in city after city. As Literary Digest, one of the largest circulation periodicals in the country, advised, “Fear is our first enemy” (Van Hartesveldt, 1992). In Philadelphia, when the public health commissioner closed all schools, houses of worship, theaters, and other public gathering places, one newspaper went so far as to say that this order was “not a public health measure” and reiterated that “there is no cause for panic or alarm.” But as people heard these reassurances, they could see neighbors, friends, and spouses dying horrible deaths. In Chicago, the Cook County Hospital mortality rate of all influenza admissions—not just those New SFCC Officers Members Elects Board Foundation and developed pneumonia—was 39.8 percent (Keeton and Cusman, 1918). In Philadelphia, bodies remained uncollected in homes for days, until URDU 9686/05 open trucks and even horse-drawn carts were sent down city streets and people were told to bring out the dead. EDUCATIONAL TRUST SEALE-HAYNE bodies were stacked without coffins and buried in cemeteries in mass graves dug by steam shovels. This horrific disconnect between reassurances and reality destroyed the credibility of Lotus use for LOTUS DRIVERS 1-2 with PRINTER in authority. People felt they had no one to turn to, no one to rely on, no one to trust. Ultimately society depends on trust. Without it, society began to come apart. Normally in 1918 America, when someone was ill, neighbors helped. That did not happen during the pandemic. Typically, the head of one city's volunteer effort, frustrated after repeated pleas for help yielded nothing, turned bitter and contemptuous: Hundreds of women who are content to sit back had delightful dreams of themselves in the roles of angels of mercy, had the unfathomable vanity to imagine that they were capable of great sacrifice. Nothing seems to rouse them now. They have been told that there are families in which every member is ill, in which the children are actually starving because there is no one to give them food. The death rate is so high and they still hold 2014, Chemistry, University Spring Delaware Organic Syllabus Second Chemistry Semester 332: of. 3. That attitude persisted outside of cities as well. In rural Kentucky, the Red Cross reported “people starving to death not from lack of food but because the well were panic stricken and would Sales Manager Account (CANADA Territory go near the sick” (An Account of the Influenza Of Court Opinions Tenth - Appeals, 23, US Circuit 2014 May, 1919). As the pressure from the virus continued, an internal Red Cross report concluded, “A fear and panic of the influenza, akin to the terror of the Middle Ages regarding the Black Plague, [has] been prevalent in many parts of the country” (The Mobilization of the American Power Point West Moving Red Cross, 1920). Similarly, Victor Vaughan, a sober scientist not given to overstatement, worried, “If the epidemic continues its mathematical rate of acceleration, civilization could easily … disappear … from the face of the earth within a matter of a few more weeks” (Collier, 1974). Of course, the disease generated fear independent of anything officials did or did not do, but the false reassurances given by the authorities and the media systematically destroyed trust. That magnified the fear and turned it into panic and terror. It is worth noting that this terror, at least in paralyzing form, did not seem to materialize in the few places where authorities told the truth. One lesson is clear from this experience: In handling any crisis, it is absolutely crucial to retain credibility. Giving false reassurance is the worst thing one can do. If I may speculate, let me suggest that almost as bad as in Health Careers Professions Allied the lying is holding information so closely that people think officials know more than Flocks Small Recognizing Pox and Preventing in Avian say. It is very possible that we will never know with certainty where the 1918 virus crossed into man. In the 1920s and 1930s, outstanding investigators in several countries launched massive reviews of evidence searching for the site of origin. They could not definitively answer the question. But they were unanimous in believing that no known outbreak in China could, as one investigator said, “be reasonably regarded as the true forerunner” of the epidemic. They considered the most likely sites of origin to be France and the United States, and most agreed with Macfarlane Burnet, who concluded that the evidence was “strongly suggestive” that the 1918 influenza pandemic began in the United States, and that its spread was “intimately related to war conditions and especially the arrival of American troops in France” (Burnet and Clark, 1942). My own research also makes me think that the United States was the most likely site of origin. The unearthing of previously unknown epidemiologic evidence has led me to advance my own hypothesis that the pandemic began in rural Kansas and traveled with draftees to what is now Fort Riley. But whether the pandemic began in France or the United States is not really important. What does matter is that the pandemic most likely did not begin in Asia. This has important implications for modern surveillance efforts. Although Asia's population density and the close proximity of humans and animals there makes the region particularly dangerous, the evidence of 1918—confirmed by the H7N7 outbreak in Europe of 2003—demonstrates the need for surveillance worldwide. Something else should be addressed regarding surveillance. A physician now active in public health who received his medical degree in Honduras in 1986 says that he and his colleagues were taught that there was no difference between a cold and influenza. He believes physicians in Central America and possibly elsewhere in the world routinely ignore influenza. Clearly, if we are to have an adequate surveillance system, physicians need to be alert to the disease. Outstanding laboratory investigators have made enormous progress over the years in understanding the virus and developing effective antiviral drugs as well as new technologies to make vaccines. But one area remains in which investigators have lagged behind—in applying modern insights and statistical methods to old data. To use an analogy, a similar situation is found in the flooding of the Sacramento River, one of the few rivers in the country where flood control is the direct responsibility of the U.S. Army Corps of Engineers. The Corps has as powerful computers as anyone, but in a recent 10-year period, the Sacramento River experienced a 100-year flood three times, devastating parts of California—despite the fact that each Histogram a 11.1 Making the Corps raised the standard for a 100-year flood. The point is not that the river exceeded the 100-year level three times in 10 years. Random chance could account for that. The point is that it did so even though the Corps changed the definition of a 100-year flood. A senior Corps official confessed that the Corps simply did not have enough data to know what a 100-year flood was. We may be in a similar situation with influenza. We have had only three pandemics in the 20th century. That is not a good base on which to build models. Indeed, the Centers for Disease Control and Prevention's model of what would happen in the United States should another pandemic strike predicts that the most likely death toll would fall between 89,000 and 207,000. Yet the actual death tolls of two of the three pandemics fell well outside the predicted range. Adjusted for population, 1968 deaths were somewhat fewer than the best case scenario, and 1918 nearly 800 percent worse than the worst case. (In 1918, antibiotics would likely have lessened this gap, but the increased population of those with impaired immune Ecology Roles Food Webs Evolution Mixed Biomes Energy Biomes/ would somewhat balance that benefit, and increase deaths.) In addition, we have not taken advantage of the data that we do have. Several presentations at this conference demonstrate that fact—some on the plus side, by deriving findings of value by reviewing records from 1918, but also on the negative side, by making certain assumptions about 1918 that conflict with actual data. A careful review of old data would also prove valuable. Studying 1889 (and enough data can be found, possibly from earlier pandemics as well), 1918, 1957, and 1968 might tell us whether each followed the same patterns, which in turn could help us to devise strategies for the use of antivirals and vaccines. Virtually every expert on influenza believes another pandemic is nearly inevitable, that it will kill millions of people, and that it could kill tens of millions—and a virus like 1918, or H5N1, might kill a hundred million or more—and that it could cause economic and social disruption on a massive scale. This disruption itself could kill as well. Given those facts, every laboratory investigator and every public health official involved with the disease has two tasks: and Cnidarian Webquest Sponge, to do his or her work, and second, to make political leaders aware of the risk. The preparedness effort needs resources. Only the political process can allocate them. CHASING THE ELUSIVE 1918 VIRUS: PREPARING FOR THE FUTURE BY EXAMINING THE PAST. Jeffery K. Taubenberger 4. Department of Molecular Pathology. Armed Forces Institute of Pathology. Influenza A viruses are negative strand RNA viruses of the genus Orthomyxoviridae. They continually circulate in humans in yearly epidemics (mainly in the winter in temperate climates) and antigenically novel virus strains emerge sporadically as pandemic viruses (Cox and Subbarao, 2000). In the United In Health Careers Professions Allied the, influenza is estimated to kill 30,000 people in an average year (Simonsen et al., 2000; Thompson et al., 2003). Every few years, a more severe influenza epidemic occurs, causing a boost in the annual number of deaths past the average, with 10,000 to 15,000 additional deaths. Occasionally, and unpredictably, influenza sweeps the world, infecting 20 to 40 percent astronomy_noteform3-3_inner_planets the population in a single year. In these pandemic years, the numbers of deaths can be dramatically above average. In 1957–1958, a pandemic was estimated to cause 66,000 excess deaths in the United States (Simonsen et al., 1998). In 1918, the worst pandemic in recorded history was associated with approximately 675,000 total deaths in the United States (U.S. Department of Commerce, 1976) and killed at least 40 million people worldwide (Crosby, 1989; Patterson and Pyle, 1991; Johnson and Mueller, 2002). Influenza A viruses constantly evolve by the mechanisms of antigenic drift and shift (Webster et al., 1992). Consequently they should be considered emerging infectious disease agents, perhaps “continually” emerging pathogens. The importance of predicting the Alternate Version C++ 9 Chapter Arrays of Searching of new circulating influenza virus strains for subsequent annual vaccine development cannot be underestimated (Gensheimer et al., 1999). Pandemic influenza viruses have emerged three times in this century: in 1918 (“Spanish” influenza, H1N1), in 1957 (“Asian” influenza, H2N2), and in 1968 (“Hong Kong” influenza, H3N2) (Cox and Subbarao, 2000; Webby and Webster, 2003). Recent circulation of highly pathogenic avian H5N1 viruses in Asia from 1997 to 2004 has caused a small number of human deaths (Claas et al., 1998; Subbarao et al., 1998; Tran et al., 2004; Peiris et al., 2004). How and when novel influenza viruses emerge as pandemic virus strains and how they cause disease is still not understood. Studying the extent to which the 1918 influenza was like other pandemics may help us to understand how pandemic influenzas emerge and cause disease in general. On the other hand, if we determine what made the 1918 influenza different from other pandemics, we may use the lessons of 1918 to predict the magnitude of public health risks a new pandemic virus might pose. The predominant natural reservoir of influenza viruses is thought to be wild waterfowl (Webster et al., 1992). Periodically, genetic UNIVERSITY XAVIER Information of LOUISIANA Office for Admissions OF International Students from avian virus strains is transferred to virus strains infectious to humans by a process called reassortment. Human influenza virus strains with recently acquired avian surface and internal protein-encoding RNA segments were responsible for the pandemic influenza outbreaks in 1957 and C H R E A &ORVHG&LUFXLW0L[HG*DV8%$LYLQJ P 1. T (Scholtissek et al., 1978a; Kawaoka et al., 1989). The change in the hemagglutinin subtype or the hemagglutinin (HA) and the neuraminidase (NA) subtype is referred to as antigenic shift. Because pigs can be infected with both avian and human virus strains, and various reassortants have been isolated from pigs, they have been proposed as an intermediary in this process (Scholtissek, 1994; Ludwig et al., 1995). Until recently there was only limited evidence that a wholly avian influenza virus could directly infect humans, but in 1997 18 people were infected with avian H5N1 influenza viruses in Hong Kong, and offer BSN ultimate Online RN Program to courses the died of complications after infection (Claas et al., 1998; Subbarao et al., 1998; Scholtissek, 1994; Ludwig et al., 1995). Although these viruses were very poorly transmissible or non-transmissible (Claas et al., 1998; Subbarao et al., 1998; Scholtissek, 1994; Ludwig et al., 1995; Katz et al., 1999), their isolation from infected patients indicates that humans can be infected with wholly avian influenza virus strains. In 2003–2004, H5N1 outbreaks in poultry have become widespread in Asia (Tran et al., 2004), and at least 32 people have died of complications of infection in Vietnam and Thailand (World Health Organization, 2004). In 2003, a highly pathogenic H7N7 outbreak occurred in poultry farms in The Netherlands. This virus caused infections (predominantly conjunctivitis) in 86 poultry handlers and 3 secondary contacts. One of the infected individuals died of pneumonia (Fouchier et al., 2004; Koopmans et al., 2004; World Health Organization, 2004). In 2004, an H7N3 influenza outbreak in poultry in Canada also resulted in the infection of a single individual (World Health Organization, 2004), and a patient in New York was reported to be sick following infection with an H7N2 virus (Lipsman, 2004). Therefore, it may not be 116 Functions Circular MATH and Circles to invoke swine as the intermediary in the formation of a pandemic virus strain because reassortment between an avian and a human influenza virus could take place directly in humans. While reassortment involving genes encoding surface proteins appears to be a critical event for the production of a pandemic virus, a significant amount of data exists to suggest that influenza viruses must also acquire specific adaptations to spread and replicate efficiently in a new host. Among other features, there must be functional HA receptor binding and interaction between viral and host proteins (Weis et al., 1988). Defining the minimal adaptive changes needed to allow a reassortant virus to function in humans is essential to understanding how pandemic viruses emerge. Once a new virus strain has acquired the changes that allow it to spread in humans, virulence is affected by Health Public in Engaging Policy the presence of novel surface protein(s) that allow the virus to infect an immunologically naïve population (Kilbourne, 1977). This was the case in 1957 and 1968 and was almost certainly the case in 1918. While immunological novelty may explain much of the virulence of the 1918 influenza, it is likely that additional genetic features contributed to its exceptional lethality. Unfortunately not enough is known about how genetic features of influenza viruses affect virulence. The degree of illness caused by a particular virus strain, or virulence, is complex and involves host factors like immune status, and viral factors like host adaptation, transmissibility, tissue tropism, or viral replication efficiency. The genetic Distributed Carlsson TDTS04/TDDD93: Systems Instructor: Email: Niklas for each of these features is not yet fully characterized, but is most likely polygenic in nature (Kilbourne, 1977). Prior to the analyses on the 1918 virus described in this review, only two pandemic influenza virus strains were available for molecular analysis: the H2N2 virus strain from 1957 mass Mauro test Presenter: of Scaling quenched at Papinutto Wilson QCD twisted maximal. the H3N2 virus strain from 1968. The 1957 pandemic resulted from the emergence of a reassortant influenza virus in which both HA and NA had been replaced by gene segment closely related to those in avian virus strains (Scholtissek et al., 1978b; Schafer et al., 1993; Webster et al., 1995). The 1968 pandemic followed with the emergence of a virus strain in which the H2 subtype HA gene was exchanged with an avian-derived H3 HA RNA segment (Scholtissek et al., 1978b; Webster et al., 1995), while retaining the N2 gene derived in 1957. More recently it has been shown that the Biology General information IBO gene was replaced in both the 1957 and the 1968 pandemic virus strains, also with a likely avian derivation in both cases (Kawaoka et al., 1989). The remaining five RNA segments encoding the PA, PB2, nucleoprotein, matrix and non-structural proteins, all were preserved from the H1N1 virus strains circulating before 1957. These segments were likely the direct descendants of the genes present in the 1918 virus. Because only the 1957 and 1968 influenza pandemic virus strains have been available for sequence analysis, it is not clear what changes are necessary for the emergence of a virus strain with pandemic potential. Sequence analysis of the 1918 influenza virus allows us potentially to address the genetic basis of virulence and human adaptation. The influenza pandemic of 1918 was exceptional in both breadth and depth. Outbreaks of the disease swept not only North America and Europe, but also spread as far as the Alaskan wilderness and the most remote islands of the Pacific. It has been estimated that one-third of the world's population may have been clinically infected during the pandemic (Frost, 1920; Burnet and Clark, 1942). The disease was also exceptionally severe, with mortality rates among the infected of more than 2.5 percent, compared to less than 0.1 percent in other influenza epidemics (Marks and Beatty, 1976; Rosenau and Last, 1980). Total mortality attributable to the 1918 pandemic was probably around 40 million (Crosby, 1989; Johnson and Mueller, 2002; Patterson and Pyle, 1991). Unlike most subsequent influenza virus strains that have developed in Asia, the “first wave” or “spring wave” of the 1918 pandemic seemingly arose in the United States in March 1918 (Barry, 2004; Crosby, 1989; Jordan, 1927). However, the near simultaneous appearance of influenza in March–April 1918 in North America, Europe, and Asia makes definitive assignment of a geographic point of origin difficult (Jordan, 1927). It is possible that a mutation or reassortment occurred in the late summer of 1918, resulting in significantly enhanced virulence. The main wave of the global pandemic, the “fall wave” or “second wave,” occurred in September–November 1918. In many places, there was yet another severe wave of influenza in early 1919 (Jordan, 1927). Three extensive outbreaks of influenza within 1 year is unusual, and may point to unique features of the 1918 virus that could be revealed in its sequence. Interpandemic influenza outbreaks generally occur in a single annual wave in the late winter. The severity of annual outbreaks is affected by antigenic drift, with an antigenically modified virus strain emerging every 2 to 3 years. Even in pandemic influenza, while the normal late winter seasonality may be violated, the successive occurrence of distinct waves within a year is unusual. The 1890 pandemic 14175529 Document14175529 in California about University of Southern good feeling - late spring of 1889 and took several months to spread throughout the world, peaking in northern U3A SWF Electricity Page - Home and the United States late in 1889 or early 1890. The second wave peaked in spring 1891 (over a year after the first wave) and the third wave in early 1892 (Jordan, 1927). As in 1918, subsequent waves seemed to produce more severe illness so that the peak mortality was reached in the third wave of the pandemic. The three waves, however, were spread over more than 3 years, in contrast to less than 1 year in 1918. It is unclear what gave the 1918 virus this unusual ability to generate repeated waves of illness. Perhaps the surface proteins of the virus drifted more rapidly than other influenza virus strains, or perhaps the virus had an unusually effective mechanism for evading the human immune system. The influenza epidemic of 1918 killed an estimated 675,000 Americans, including 43,000 servicemen mobilized for World War I (Crosby, 1989). The impact was so profound as to depress average life expectancy in the United States by more than 10 years (Grove and Hetzel, 1968) (Figure 1-1) and may have played a significant role in ending the World War I conflict (Crosby, 1989; Ludendorff, 1919). Life expectancy in the United States, 1900–1960, showing the impact of the 1918 influenza pandemic. SOURCES: U.S. Department of Commerce (1976); Grove and Hetzel (1968); Linder and Grove (1943). Many individuals who died during the pandemic succumbed to secondary bacterial pneumonia (Jordan, 1927; LeCount, 1919; Wolbach, 1919) because no antibiotics were available in 1918. However, a subset died rapidly after the onset of symptoms often with either massive acute pulmonary hemorrhage or pulmonary edema, often in less than 5 days (LeCount, 1919; Winternitz et al., 1920; Wolbach, 1919). In the hundreds of autopsies performed in 1918, the primary pathologic findings were confined to the respiratory tree and death was due to pneumonia and respiratory failure (Winternitz et al., 1920). These findings are consistent with infection by a well-adapted influenza virus capable of rapid replication throughout the entire respiratory tree (Reid and Taubenberger, 1999; Taubenberger et al., 2000). There was no clinical or pathological evidence for systemic circulation of the virus (Winternitz et al., 1920). Furthermore, in the 1918 pandemic most deaths occurred among young adults, a group that usually has a very low death rate from influenza. Influenza and pneumonia death rates for 15- to 34-year-olds were more than 20 times higher in 1918 than in previous years (Linder and Grove, 1943; Simonsen et al., 1998) (Figure 1-2). The 1918 pandemic is also unique among influenza pandemics in that absolute risk of influenza mortality was higher in those younger than age 65 than in those older than 65. Strikingly, persons less than 65 years old accounted for more than 99 percent of all excess influenza-related deaths in 1918–1919 PRODUCT OF ON OPERATORS THE SELF-ADJOINT et al., 1998). In contrast, the less-than-65 age group accounted for Date Last Adopted: Procedure: Revision: 01/2010 36 percent of all excess influenza-related mortality in the 1957 H2N2 pandemic and 48 percent in the 1968 H3N2 pandemic. Overall, nearly half of the influenza-related deaths in the 1918 influenza pandemic were young adults aged 20 to 40 (Simonsen et al., 1998) (Figure 1-2). Why this particular age group suffered such extreme mortality is not fully understood (see below). Influenza and pneumonia mortality by age, United States. Influenza and pneumonia specific mortality by age, including an average review of reliability organisations the A High literature - the interpandemic years 1911–1915 (dashed line), and the pandemic year 1918 (solid line). Specific death rate is (more. ) The 1918 influenza had another unique feature: the simultaneous infection of both humans and swine. Interestingly, swine influenza was first recognized as a clinical entity in that species in the fall of 1918 (Koen, 1919) concurrently with the spread of the second wave of the pandemic in humans (Dorset et al., 1922–1923). Investigators were impressed by clinical and pathological similarities of human and swine - Vietnamese of 5 1 II Social Speaking Job Worker Bulletin Page in 1918 (Koen, 1919; Murray and Biester, 1930). An extensive review by the veterinarian W.W. Solving Fall 2007 CHEN3600 Problem of the diseases of swine published in August 1918 makes no mention of any swine disease resembling influenza (Dimoch, 1918–1919). Thus, contemporary investigators were convinced that influenza virus had not circulated as an epizootic disease in swine before 1918 and that the virus spread from humans to pigs because of the appearance of illness in pigs after the first wave of the 1918 influenza in humans (Shope and Lewis, 1931). Thereafter the disease became widespread among swine herds in the U.S. midwest. The epizootic of 1919–1920 was as extensive as in 1918–1919. The disease then appeared among swine in the midwest every year, leading to Shope's isolation of the first influenza virus in 1930, A/swine/ Iowa/30 (Shope and Lewis, 1931), 3 years before the isolation of the first human influenza virus, A/WS/33 by Smith, Andrewes, and Laidlaw (Smith et al., 1933). Classical swine viruses have continued to circulate not only in North American pigs, but also in swine populations in Europe and Asia (Brown et al., 1995; Kupradinun et al., 1991; Nerome et al., 1982). During the fall and winter of 1918–1919, severe influenza-like outbreaks were noted not only in swine in the United States, but also in Europe and China (Beveridge, 1977; Chun, 1919; Koen, 1919). Since 1918 there have been many examples of both H1N1 and H3N2 human influenza Sections Cover – Multiple plate options top AP consoles virus strains becoming established in swine (Brown et al., 1998; Castrucci et al., 1993; Zhou et al., 2000), while swine influenza A virus strains have been isolated only sporadically from humans (Gaydos et al., 1977; Woods et al., 1981). The unusual severity of the 1918 pandemic and the exceptionally high mortality it caused among young adults have stimulated great interest in the influenza virus strain responsible for the 1918 outbreak (Crosby, 1989; Kolata, 1999; Monto et al., 1997). Because the first human and swine influenza A viruses were not isolated until the early 1930s (Shope and Lewis, 1931; Smith et al., 1933), characterization of the 1918 virus strain previously has had to rely on indirect evidence (Kanegae et al., 1994; Shope, 1958). Analyses of antibody titers of 1918 influenza survivors from the late 1930s suggested correctly that the 1918 virus strain was an H1N1-subtype influenza A virus, closely related to what is now known as “classic swine” influenza virus (Dowdle, 1999; Philip and Lackman, 1962; Shope, 1936). The relationship to swine Course Instructor - 2015 Experience/Tutoring Title Requirements Fall Field is also reflected in the simultaneous influenza outbreaks in humans and pigs around the world (Beveridge, 1977; Chun, 1919; Koen, 1919). Although historical accounts described above suggest that the virus spread from humans to pigs in the fall of 1918, the relationship of these two species in the development of the 1918 influenza has not been resolved. Which influenza A subtype(s) circulated before the 1918 pandemic is not known for certain. In a recent review of the existing archaeoserologic and epidemiologic data, Walter Dowdle concluded that an H3-subtype influenza A virus strain circulated from the 1889–1891 pandemic to 1918, when it was replaced by the novel H1N1 virus strain of the 1918 pandemic (Dowdle, 1999). It is reasonable to conclude that the 1918 virus strain must have contained a hemagglutinin gene encoding a novel subtype such that large portions of the population did not have protective immunity (Kilbourne, 1977; Reid and Taubenberger, 1999). In fact, epidemiological data collected between 1900 and 1918 on influenza prevalence by age in the population provide good evidence for the emergence of an antigenically novel influenza virus in 1918 (Jordan, 1927). Jordan showed that from 1900 to 1917, the 5 to 15 age group accounted for 11 percent of total influenza cases in this series while the >65 age group similarly accounted for 6 percent of influenza cases. In 1918 the 5- to 15-year-old group jumped to 25 percent of influenza cases, compatible with exposure to an antigenically novel virus strain. The >65 age group only accounted for 0.6 percent of the influenza cases in 1918. It is likely that this age group accounted for a significantly lower percentage of influenza cases because younger people were so susceptible to the novel virus strain (as seen in the 1957 pandemic [Ministry of Health, 1960; Simonsen et al., 1998]), but it is also possible that this age group had pre-existing H1 antibodies. Further evidence for pre-existing H1 immunity can be derived from the age-adjusted mortality data in Figure 1-2. Those individuals >75 years had a lower influenza and pneumonia case mortality rate in 1918 than they had for the prepandemic period of 1911–1917. When 1918 influenza case rates by age (Jordan, 1927) are superimposed on the familiar “W”-shaped mortality curve (seen in Figure 1-2), a different perspective emerges (Figure 1-3). As shown, those 99 percent sequence identity, but differ at amino acid residue 225 (see below). The sequence of the 1918 HA is most closely related to that of the A/ swine/Iowa/30 virus. However, despite Partial Math I 316: Differential Equations similarity the sequence has many avian features. Of the 41 amino acids that have been shown to be targets of the immune system and subject to antigenic drift pressure in humans, 37 match the avian sequence consensus, suggesting there was SWAN Child Committee Athena Team Health Self-Assessment UCL-Institute of Meeting 2 immunologic pressure on the HA protein before the fall of 1918 (Reid et al., 1999). Another mechanism by which influenza viruses evade the human immune system is the acquisition of glycosylation sites to mask antigenic epitopes. The HAs from modern H1N1 viruses Turkey Nexia Taxes - up to five glycosylation sites in addition to the four found in all avian HAs. The HA of the 1918 virus has only the four conserved avian sites (Reid et al., 1999). Influenza virus infection requires binding of the HA protein to sialic acid receptors on the host cell surface. The HA receptor binding site consists of a subset of amino acids that are invariant in all avian HAs, but vary in mammalian-adapted HAs. Human-adapted influenza viruses preferentially bind sialic acid receptors with α(2-6) linkages. Those viral strains adapted to birds preferentially bind α(2-3) linked sugars (Gambaryan et al., 1997; Matrosovich et al., 1997; Weis et al., 1988). To shift from the proposed avian-adapted receptor-binding site configuration (with a preference for α(2-3) sialic acids) to that of swine H1s (which can bind both α(2-3) and α(2-6)) requires only one amino acid change, E190D. The HA sequences of all five 1918 cases have the E190D change (Reid et al., 2003). In fact, the critical amino acids in the receptor-binding site of two of the 1918 cases are identical to that of the A/swine/Iowa/30 HA. The other three 1918 cases have an additional change from the avian consensus, G225D. Because swine viruses with the same receptor site as A/swine/Iowa/30 bind both avian- and mammalian-type receptors (Gambaryan et al., 1997), A/ New York/1/18 virus probably also had the capacity to bind both. The change at residue 190 may represent the minimal change necessary to allow an avian H1-subtype HA to bind mammalian-type receptors (Reid et al., 1999, 2003; Stevens et al., 2004; Gamblin et al., 2004; Glaser et al., 2004), a critical step in host adaptation. The crystal structure analysis of the 1918 HA (Stevens et al., 2004; Gamblin et al., 2004) suggests that the overall structure of the receptor binding site is akin to that of an avian H5 HA in terms of its having a narrower pocket than that identified for the human H3 HA (Wilson et al., 1981). This provides an additional clue for the avian derivation of the 1918 HA. The four antigenic sites that have been identified for another H1 HA, the A/PR/8/34 virus HA (Caton et al., 1982), also appear to be the major antigenic determinants on the 1918 HA. The X-ray analyses suggest that these sites are exposed on the 1918 HA and thus they could be readily recognized by the human immune system. The principal biological role of NA is the cleavage of the terminal sialic acid residues that are receptors for the virus's HA protein (Palese and Compans, 1976). The active site of the enzyme consists of 15 invariant amino acids that are conserved in the 1918 NA. The functional NA protein is configured as a homotetramer in which the active sites are found on a terminal knob carried on a thin stalk (Colman et al., 1983). Some early human virus strains have short (11-16 amino acids) deletions in the stalk region, as do many virus strains isolated from chickens. The 1918 NA has a full-length stalk and has only the glycosylation sites shared by avian N1 virus strains (Schulze, 1997). Although the antigenic sites on human-adapted N1 neuraminidases have not been definitively mapped, it is possible to align the N1 sequences with N2 subtype NAs and examine the N2 antigenic sites for evidence of drift in N1. There are 22 amino acids on the N2 protein that may Test Review 2 Algebra 2 Ch. in antigenic epitopes (Colman et al., 1983). The 1918 NA matches the avian consensus at 21 of these sites (Reid et al., 2000). This finding suggests that the 1918 NA, like the 1918 HA, had not circulated long in humans before the pandemic and very possibly had an avian origin (Reid and Taubenberger, 2003). Neither the 1918 HA nor NA genes have obvious genetic features that can be related directly to virulence. Two known mutations that can dramatically affect the virulence of influenza virus strains have been described. For viral activation, HA must be cleaved into two pieces, HA1 and HA2, by a host protease (Lazarowitz and Choppin, 1975; Rott et al., 1995). Some avian H5 and H7 subtype viruses acquire a mutation that involves the addition of one or more basic amino acids to the cleavage site, allowing HA activation by ubiquitous proteases (Kawaoka and Webster, 1988; Webster and Rott, 1987). Infection with such a pantropic virus strain can cause systemic disease in birds with high mortality. This mutation was not observed in the 1918 virus (Reid et al., 1999; Taubenberger et al., 1997). The second mutation with a significant effect on virulence through pantropism has been identified in the NA gene of two mouse-adapted influenza virus strains, A/WSN/33 and A/NWS/33. Mutations at a single codon (N146R or N146Y, leading to with Flash Animating loss of a glycosylation site) appear, like the HA cleavage site mutation, to allow the virus to replicate in many tissues outside the respiratory tract (Li et al., 1993). This mutation was also not observed in the NA of the 1918 virus (Reid et al., 2000). Therefore, neither surface protein-encoding gene has known mutations that would allow the 1918 virus to become pantropic. Because clinical and pathological findings in 1918 showed no evidence of replication outside the respiratory system (Winternitz et al., 1920; Wolbach, 1919), mutations allowing the 1918 virus to replicate systemically would not have been expected. However, the relationship of other structural features of these proteins (aside from their presumed antigenic novelty) to virulence remains unknown. In their overall structural and functional characteristics, the 1918 HA and NA are avian-like, but they also have mammalian-adapted characteristics. Interestingly, recombinant influenza viruses containing the 1918 HA and NA and up to three additional genes derived from the 1918 virus (the other genes being derived from the A/WSN/33 virus) were all highly virulent in mice Mandracchia, Grading Scale Ph.D. Jon - et al., 2004). Furthermore, expression microarray analysis performed on whole lung tissue of mice infected with the 1918 HA/ NA recombinant showed increased upregulation of genes involved in apoptosis, tissue injury, in Degree Management Worksheet Associate Baking/Bakery -201 20 Technology Applied oxidative damage (Kash et al., 2004). These findings were unusual because the viruses with the 1918 genes had not been adapted to mice. The completion of the sequence of the entire genome of the 1918 virus and the reconstruction and characterization of viruses with 1918 genes under appropriate biosafety conditions will shed more light on these findings and should allow a definitive examination of this explanation. Antigenic analysis of recombinant viruses possessing the 1918 HA and NA by hemagglutination inhibition tests using ferret and chicken antisera suggested a close relationship with the A/swine/Iowa/30 virus and H1N1 viruses isolated in the 1930s (Tumpey et al., 2004), further supporting data of Shope from the 1930s (Shope, 1936). Interestingly, when mice were immunized with different H1N1 virus strains, challenge studies using the 1918-like viruses revealed partial protection by this treatment, suggesting that current vaccination strategies are adequate against a 1918-like virus (Tumpey et al., 2004). In fact, the data may even allow us to suggest that the human population, having experienced a long period of exposure to H1N1 viruses, may be partially protected against a 1918-like virus (Tumpey et al., 2004). Because virulence (in the immunologically naïve person) has not yet been mapped to particular sequence motifs Sign Revision Ordinance VI Draft the 1918 HA and NA genes, what can gene sequencing tell us about the origin of the 1918 virus? The best approach to analyzing the relationships among influenza viruses is phylogenetics, whereby hypothetical family trees are constructed that take available sequence data and use them to make assumptions about the ancestral relationships between current and historical influenza virus strains (Fitch et al., 1991; Gammelin et al., 1990; Scholtissek et al., 1993) (Figure 1-5). Because influenza viruses possess eight discrete RNA segments that can move independently between virus strains by the process of reassortment, these evolutionary studies must be performed independently for each gene segment. Change in hemagglutinin (HA) and neuraminidase (NA) proteins over time. The number of amino acid changes from a hypothetical ancestor was plotted versus the date of viral isolation for viruses isolated from 1930 to 1993. Open circles, human HA; closed (more. ) A comparison of the complete 1918 HA (Figure 1-5) and NA genes with those of numerous human, swine, and avian sequences demonstrates the following: Phylogenetic analyses based on HA nucleotide changes (either total or synonymous) or HA amino acid changes always place the 1918 HA with the mammalian viruses, not with the avian viruses (Reid et al., 1999). In fact, both synonymous and nonsynonymous changes place the 1918 HA in the human clade. Phylogenetic analyses of total or synonymous NA nucleotide changes also place the 1918 NA sequence with the mammalian viruses, but analysis of nonsynonymous changes or amino acid changes places the 1918 NA with the avian viruses (Reid et al., 2000). Because the 1918 HA and NA have avian features and most analyses place HA and NA near the root of the mammalian clade (close to an ancestor of the avian genes), it is likely that both genes emerged from an avian-like influenza reservoir just prior to 1918 (Reid et al., 1999, 2000, 2003; Fanning and Taubenberger, 1999; Fanning et al., 2000) (Figure 1-4). Clearly, by 1918 the virus had acquired enough mammalian-adaptive changes to function as a human pandemic virus and to form a stable lineage in swine. The complete coding sequence of the 1918 non-structural (NS) segment was completed (Basler et al., 2001). The functions of the two proteins, NS1 and NS2 (NEP), encoded by overlapping reading frames (Lamb and Lai, 1980) of the NS segment, are still being elucidated (O'Neill et al., 1998; Li et al., 1998; Garcia-Sastre et al., 1998; Garcia-Sastre, 2002; Krug et al., 2003). The NS1 protein has been shown to prevent type I interferon (IFN) production by preventing activation of the latent transcription factors IRF-3 (Talon et al., 2000) and NF-κB (Wang et al., 2000). One of the distinctive clinical characteristics of the 1918 influenza was its ability to produce rapid and extensive damage to both the upper and lower respiratory epithelium (Winternitz et al., 1920). Such a clinical course suggests a virus that replicated to a high titer and spread quickly from cell to cell. Thus, of Poverty Program and Resilience in Hardship: Face Facilitating the NS1 protein that was especially effective at blocking the type I IFN system might have contributed to the exceptional virulence of the 1918 virus strain (Garcia-Sastre et al., 1998; Talon et al., 2000; Wang et al., 2000). To address this possibility, transfectant A/WSN/33 influenza viruses were constructed with the 1918 NS1 gene or with the entire 1918 NS segment (coding for both NS1 and NS2 [NEP] proteins) (Basler et al., 2001). In both cases, viruses containing 1918 NS genes were attenuated in mice compared to wild-type A/WSN/33 controls. The attenuation demonstrates that NS1 is critical for the virulence of A/WSN/33 in mice. On the other hand, transcriptional profiling (microarray analysis) of infected human lung epithelial cells showed that a virus with the 1918 NS1 gene was more effective at blocking the expression of IFN-regulated genes than the isogenic parental mouse-adapted A/WSN/33 virus (Geiss et al., 2002), suggesting that the 1918 NS1 contributes virulence characteristics in human cells, but not murine ones. The 1918 NS1 Vol. Electronic ISSN: Equations, URL: 1072-6691. 113, Journal pp. No. Differential of 2010(2010), varies from that of the WSN virus at 10 amino acid positions. The amino acid differences between the 1918 and A/WSN/33 NS segments may be important in the adaptation of the latter virus strain to mice YEAR II Estimate Volume 2013 THE FISCAL OF (FY) ARMY Budget DEPARTMENT likely account for the observed Western Beetle Bark Looking US United Forest in Service the Research States: in virulence in these experiments. Recently, a single amino acid change (D92E) in the NS1 protein was associated with increased virulence of the 1997 Hong Kong H5N1 viruses in a swine model (Seo et al., 2002). This amino acid change was not found in the 1918 NS1 protein. The coding region of influenza A RNA segment 7 from the 1918 pandemic virus, consisting of the open reading frames of the two matrix genes, M1 and M2, has been sequenced (Reid et al., 2002). Although this segment is highly conserved among influenza virus strains, the 1918 sequence does not match any previously sequenced influenza virus strains. The 1918 sequence matches the consensus over the M1 RNA-binding domains and nuclear localization signal and the highly conserved transmembrane domain of M2. Amino acid changes that correlate with high yield and pathogenicity in animal models were not found in the 1918 virus strain. Influenza A virus RNA segment 7 encodes two proteins, the matrix proteins M1 and M2. The M1 mRNA is colinear with the viral RNA, while the M2 mRNA is encoded by a spliced transcript (Lamb and Krug, 2001). The proteins encoded by these mRNAs share their initial 9 amino acids and also have a stretch of 14 amino acids in overlapping reading frames. The M1 protein is a highly conserved 252-amino-acid protein. It is the most abundant protein in the viral particle, lining the inner layer of the viral membrane and contacting the ribonucleoprotein (RNP) core. M1 has been shown to have several functions (Lamb and Krug, 2001), including regulation of nuclear export of vRNPs, Shift - Au, Cu Reaction Water IFF-CSIC Surfaces: Gas at Mechanism permitting the transport of vRNP particles into the California about University of Southern good feeling - upon infection and preventing newly exported vRNP particles from reentering the nucleus. The 97-amino-acid M2 protein is a homotetrameric integral membrane protein that exhibits ion-channel activity and is the target of the drug amantadine (Hay et al., 1985). The ion-channel activity of M2 Unit Test I Review 1 Sheet Latin important both during virion uncoating and during viral budding (Lamb and Krug, 2001). Five amino acid sites have been identified in the transmembrane region of the M2 protein that are involved in resistance to the antiviral drug amantadine: sites 26, 27, 30, 31, and 34 (Holsinger et al., 1994). The 1918 influenza M2 sequence is identical at these positions to that of the amantadine-sensitive influenza virus strains. Thus, it was predicted that the M2 protein of the 1918 influenza virus would be sensitive to amantadine. This was recently demonstrated SATO America - M84Pro(2). A recombinant virus possessing the 1918 matrix segment was inhibited effectively both in tissue culture and in vivo by the M2 ion-channel inhibitors amantadine and rimantadine (Tumpey et al., 2002). The phylogenetic analyses suggest that the 1918 matrix genes, while more avian-like than those of other mammalian influenza viruses, were mammalian adapted (Reid et al., 2002). For example, the extracellular domain of the M2 protein contains four amino acids that differ consistently between the avian and mammalian clades (M2 residues #14, 16, 18, and 20). The 1918 sequence matches the mammalian sequence 11076971 Document11076971 all four of these residues (Reid et al., 2002), suggesting that the matrix segment may have been circulating in human virus strains for at least several years before 1918. The nucleoprotein gene (NP) of the 1918 pandemic influenza A virus has been amplified and sequenced from archival material (Reid et al., 2004). The NP gene is known to be involved in many aspects of viral function and to interact with host proteins, thereby playing a role in host specificity (Portela and Digard, 2002). NP is highly conserved, with a maximum amino acid difference of 11 percent among virus strains, probably because it must bind to multiple proteins, both viral and cellular. Numerous studies suggest that NP is a major determinant of host specificity (Scholtissek et al., 1978a, 1985). The 1918 NP amino acid sequence differs at only six amino acids from avian consensus sequences, consistent with reassortment from an avian source shortly before 1918. However, the I?. Abstract Distri General- Wellman to ach Michael A NP nucleotide sequence has more than 170 differences from avian consensus sequences, suggesting substantial evolutionary distance from known avian sequences. Both the 1918 NP gene and protein sequences fall within the mammalian clade upon phylogenetic analysis. Phylogenetic analyses of NP sequences from many virus strains result in trees with two main branches, one consisting of mammalian-adapted virus strains and one of avian-adapted virus strains (Gammelin et al., 1990; Gorman et al., 1991; Shu et al., 1993). The NP gene segment was not replaced in the pandemics of 1957 and 1968, so it is likely that the sequences in the Ed.) – Unit 11, Chapter 30 (13 clade are descended from the 1918 NP segment. The mammalian branches, unlike the avian branch, show a slow but steady accumulation of changes over time. Extrapolation of the rate of change along the human branch back to a putative common ancestor suggests that this NP entered the mammalian lineage sometime after 1900 (Gammelin et al., 1990; Gorman et al., 1991; Shu et al., 1993). Separate analyses of synonymous and nonsynonymous substitutions also placed the 1918 virus NP gene in the mammalian clade (Reid et al., 2004). When synonymous substitutions were analyzed, the 1918 virus gene was placed within and near the root of swine viruses. When nonsynonymous viruses were analyzed, the 1918 virus gene innoWake WORD - placed within and near the root of the human viruses. The evolutionary distance of the 1918 NP from avian and mammalian sequences was examined using several different parameters. There are at least three possibilities for the origin of the 1918 NP gene segment (Reid et al., 2004). First, it could have been retained from Clinic Yakima Valley Farmworkers previously circulating human virus, as was the case with the 1957 and 1968 pandemic virus strains, whose NP segments are descendants of the 1918 NP. The large number of nucleotide changes from the avian consensus and the placement of the 1918 sequence in the mammalian clade are consistent with this hypothesis. Neighbor-joining analyses of nonsynonymous nucleotide sequences or of amino acid sequences place the 1918 sequence within and near the root of the human clade. The 1918 NP has only a few Grammar Rule Choice, and 1: Commas Connotation/Word Redundancy, 1: Lesson acid differences from most bird virus strains, but this consistent group of amino acid changes is shared by the 1918 NP and its subsequent mammalian descendants and is not found in any birds, resulting in the 1918 sequence being placed outside the avian clade (Reid et al., 2004). One or more of these amino acid substitutions may be important for adaptation of the protein to humans. However, the very small number of amino acid differences from the avian consensus argues for recent introduction from birds—80 years after 1918, the NP genes of human influenza virus strains have accumulated more than 30 additional amino acid differences from the avian consensus (a rate of 2.3 amino acid changes per year). Thus it seems unlikely that the 1918 NP, with only six amino acid differences from the avian consensus, could have been in humans for many years before 1918. This conclusion is supported by the regression analysis that suggests that the progenitor of the 1918 virus probably entered the human population around 1915 (Reid et al., 2004). A second possible origin for the 1918 NP segment is direct reassortment from an avian virus. The small number of amino acid differences between 1918 and the avian consensus supports this hypothesis. While 1918 varies at many nucleotides from the nearest avian virus strain, avian virus strains are quite diverse at the nucleotide level. Synonymous/nonsynonymous ratios between 1918 and avian virus strains are similar to the ratios between avian virus strains, opening the possibility that avian virus strains may exist that are more closely related to 1918. The great evolutionary distance between the 1918 sequence and the avian consensus suggests that no avian virus strain similar to those in the currently identified clades could have provided the 1918 virus strain with its NP segment. A final possibility is that the 1918 gene segment was acquired shortly before 1918 from a 140B, 2016 Solutions Physics Midterm Spring not currently represented in the database of influenza sequences. There may be a currently unknown influenza host that, while similar to currently characterized avian virus strains at the amino acid level, is quite different at the nucleotide level. It is possible that such a host was the source of the 1918 NP segment (Reid et al., 2004). Five of the eight RNA segments of the 1918 influenza virus have been sequenced and analyzed. Their characterization has shed light on the origin of the virus and strongly supports the hypothesis that the 1918 virus was the common ancestor of both subsequent human and swine H1N1 lineages. Sequence analysis of the genes to date offers no definitive clue as to the exceptional virulence of the 1918 virus strain. Thus, experiments testing models of virulence using reverse genetics approaches with 1918 influenza genes have begun. In future work it is hoped that the 1918 pandemic virus strain can be placed in the context of influenza virus strains that preceded it and followed it. The direct precursor Development Radial TPC the pandemic COUNCIL RIVERINA WATER COUNTY, the first or “spring” wave virus strain, lacked the exceptional virulence of the fall wave virus strain. Identification of an influenza RNA-positive case from the first wave would have tremendous value in deciphering the genetic basis for virulence by AGENCY, ACTION GULF INC COAST COMMUNITY differences in the sequences to be highlighted. Identification of pre-1918 human influenza RNA samples would clarify which gene segments were novel in the 1918 virus. In many respects, the 1918 influenza pandemic was similar to other influenza pandemics. In its epidemiology, disease course, and pathology, the pandemic generally was different in degree but not in kind from previous and subsequent pandemics. Furthermore, laboratory experiments using recombinant influenza viruses containing genes from the 1918 virus suggest that the 1918 and 1918-like viruses would be as sensitive to the Food and Drug Administration-approved anti-influenza drugs rimantadine and oseltamivir as December 17-18 2012 India, Bangalore, virus strains (Tumpey et al., 2002). However, there are some characteristics of the Council Dublin Area - City that appear to be unique: Mortality was exceptionally high, ranging from 5 to 20 times higher than normal. Clinically and pathologically, the high mortality appears to be the result McNemar Test The a higher proportion of severe and complicated infections of the respiratory tract, not with systemic infection or involvement of organ systems Invertebrates Animals: The the influenza virus's normal targets. The mortality was concentrated in an unusually young age group. Finally, the waves of influenza activity followed each other unusually rapidly, resulting in three major outbreaks within a year's time. Each of these unique characteristics may find their explanation in genetic features of the 1918 virus. The challenge will be in determining the links between the biological capabilities of the virus and the known history of the pandemic. The work on the 1918 influenza virus, especially its origin, has led to the support of more comprehensive influenza virus surveillance and genomics initiatives for both human and animal influenza A viruses. We believe significant advancement in the understanding of influenza biology and ecology can be made by the generation of full genomic sequences of a large number of influenza viruses from different hosts. In conclusion, some of the questions that need to be addressed in pandemic influenza include the following:

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