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Influenza Elysha Hussein Sarah Hall Ayesha Sattar

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1 Influenza Elysha Hussein Sarah Hall Ayesha Sattar
Tuesday, February 25, 2003

2 Structure of Virion HA - hemagglutinin NA - neuraminidase
M1 protein helical nucleocapsid (RNA plus NP protein) HA - hemagglutinin polymerase complex lipid bilayer membrane NA - neuraminidase 100 n m M1 protein unnderlies the lipid bilayer, is the most abundant protein. Genome organized in 7 or 8 segments. 3 integral membrane proteins that coordinate fusion are NA, HA, and M2 (not shown) NP protein important for subtyping NS protein, not shown, important for virulence. Influenza virions are SMALL. The average eukaryotic cell diameter is 10,000 nm (10 microns), which is 100 times bigger than the influenza virion diameter.

3 Influenza Subtypes Types A & B 8 Segments of RNA Type C 3 IMPs
HA NA M2 8 Segments of RNA Responsible for epidemics & pandemics Type C 1 IMP HEF Serves functions of both HA and NA 7 Segments of RNA Causes only mild infections Influenza strains are subtyped A, B, or C based on the relatedness of the matrix (M1) and nucleoprotein (NP) antigens All 3 subtypes can infect human, subtype A can also infect other mammals and birds Within each subtype, there are many variant strains A and B are similar, C is much different—both in terms of protein composition and virality.

4 Subtype Viral Structure/Carriers
Type A Type B Humans Swine Birds Horses Seals Humans Type C Because of A’s ability to infect numerous carriers, it is the most dangerous subtype, and will be focus of presentation. Dangerous outbreaks are often the result of genetic reassortment, which relies on cross infection of one host with more than one strain of the virus, followed by transmission from one species to humans. This can’t happen with B, so there are less outbreaks. Humans Swine

5 Integral Membrane Proteins (IMP)
Hemagglutinin Trimeric Protein 500 copies per virion Neuraminidase Tetrameric Protein 100 copies per virion HA and NA are the most important proteins for determining the exact strain (NP does the subtype, and then these two do the strain) They frequently mutate in the antigen recognition domain, and account for IV’s ability to evade the immune system Matrix 2 (M2) Tetrameric Protein 10 copies per virion

6 Fusion Schematic Fusion Schematic
1) HA binds a cell GP at a Sialic Acid Binding Site

7 Fusion Schematic Fusion Schematic
1) HA binds a cell GP at a Sialic Acid Binding Site Low pH 2) Clathrin-Coated pit endocytoses virion

8 Fusion Schematic Fusion Schematic
1) HA binds a cell GP at a Sialic Acid Binding Site 3) Conformational Change: Hydrophobic binding of HA to vesicle membrane Low pH 2) Clathrin-Coated pit endocytoses virion

9 Fusion Schematic Fusion Schematic
1) HA binds a cell GP at a Sialic Acid Binding Site 3) Conformational Change: Hydrophobic binding of HA to vesicle membrane Low pH 2) Clathrin-Coated pit endocytoses virion 4) RNPs are released into cytoplasm for replication and transcription (vRNA and mRNA)

10 Hemagglutinin (HA) IMP: homotrimer of non-covalently linked monomers
There are 15 variants of HA currently identified Precursor (HA0) is synthesized in the RER & Golgi, then transported to the cell membrane Activated when cleaved into 2 chains (HA1 & HA2) that join by disulfide bond HA1 is critical for initial fusion event Uses Sialic-acid-containing receptors on host cell glycoproteins. This receptor binding event is followed by endocytosis. Formation of protein via precursor has implications for infectivity of virus, on next slide 2 main fusion events, each active chain of HA is responsible for one event. Both were shown on fusion schematic HA2 is critical for fusion of virion w/ endosomal membrane Decrease in pH in endosome enables HA to undergo a confomational change that enables HA to fuse with the endosomal membrane

11 HA Cleavage Specific cleavage site is a basic sequence of AAs.
The site is conserved for specific species. Cleaving enzyme can determine pathogenicity of virus. If the enzyme is ubiquitous in cells, then those cells can make virulent influenza. Humans: Argenine is present at cleavage site Cleaving enzyme is a tryptase called Clara Only produced in Clara cells, which are only found in upper respiratory tract Influenza infection is confined to this region of the body Example of how a virus uses the host cell’s machinery for proliferation. Host cell enzyme cleaves the precursor.

12 Neuraminidase IMP: heterotrimer
There are 9 variants currently identified & sequenced Catalyzes cleavage of α–ketosidic linkage between sialic acid and adjacent D-galactose or D-galactosamine HA binds sialic receptors, NA releases virus or progeny virus from receptor Roles in viral entry/exit: Help virion navigate mucusal lining of respitory tract Release progeny virion from surface of host cell Newest Class of drugs: Neuraminidase Inhibitors On the other end of fusion, the viral budding process, NA plays critical role. Elysha will discuss NA inhibitors later, they prevent the cleavage of virion sform a host cell and can effectively limit infection if taken early on. Viral resistance is a big problme here.

13 Matrix 2 IMP: Homotetrameric Single pass transmembrane protein
Roles in last 2 steps of entry process Facilitates membrane fusion in endosome Low pH in endosome activates M2 to open ion channel. Hydrogens enter virus and activate HA to undergo conformational change that results in membrane fusion with endosome As a consequence, RNPs are released into cytoplasm Elysha will discuss the potential for using a highly conserved domain of this protein for vaccine development later.

14 Ribonucleoprotein Complexes (RNPs)
After virion fuses with the endosome membrane, RNPs are shuttled to nucleus Each (-) ssRNA segment associates with 3 polymerases and a nucleoprotein to form Ribonucleoprotein Complexes (RNPs) Replication: vRNAcRNAvRNA Transcription: vRNAmRNA(viral proteins) The RNA polymerase is unable to “proofread” during transcription This enables the virus to alter surface antigens and accounts for its ability to evade the immune system Genomes of all three subtypes have been sequenced. Compare with HIV: HIV has reverse transcriptase so it goes vRNA-> DNA and into nucleus. IV has a different way—no DNA involved. Both have high mutation rates.

15 A/Moscow/21/99/H3N2 Nomenclature
3 Subtypes, coupled with variance of the antigenicity of surface proteins (HA & NA) and the long history of influenza epidemics necessitate a nomenclature system to catalogue each strain. A/Moscow/21/99/H3N2 Subtype NP & MI Geographic Origin Strain Number Year of Isolation HA & NA Sub-strain Elysha and Ayesha will refer to outbreaks using this system, especially the type an dstrain.

16 Genetic Reassortment (HA & NA)
Antigenic Drift Minor changes in the antigenic character Mutation rate highest for type A, lowest for type C Most meaningful mutations occur in HA1 protein When 2 virions infect a cell, there are 256 possible combinations of RNA for offspring. Involves 1 strain, mutations in antigenic sequences---how virus evades immune system.

17 Antigenic Shift Phylogenic evolution that accounts for emergence of new strains of virus Immunologically distinct, novel H/N combinations Genetic reassortment between circulating human and animal strains is responsible for shifts Segmented genome facilitates reassortment Only been observed in type A, since it infects many species Process involves combining strains in an intermediate host (so it’s mostly A). This is where the big outbreaks stem from.

18 Antigenic Shift: 1997 Hong Kong
H5N1 virus, harbored in chickens, infected humans via direct contact, only 6 casualties What made H5N1 strain so virulent? Post-mortem examination revealed high levels of cytokines and TNF-α. Indicates an innate, but not specific, immune response Hong Kong researchers suggest that this strain of the virus exacerbates the cytokine response, possibly causing toxic-shock symptoms or death Example of shift. Ayesha will discuss more details fo this outbreak, and it’s implications for future outbreaks. Interesting research surrounding this outbreak—investigating why it was so virulent.

19 Antigenic Shift: 1997 Hong Kong
Webster et al: Use reverse genetics to identify the gene responsible for increased virulence and immune system evasion Remove nonstructural (NS) gene from H5N1 Insert this gene into benign strain Assess virulence of this new strain, compare to control Conclusion: NS1 is critical for limiting antiviral effects of cytokines. Downregulates expression of genes involved in the pathway which signals the release of cytokines Single point mutation is responsible for making NS1 a better downregulator Start with 1 gene, NS, and remove from virulent strain, put in benign strain—identify that the protein encoded by this gene, the NS1 protein, was responsible for the virulence. Pretty nuanced survival mechanism for the virus. Another way to evade immune system.

20 Where does influenza act in the body?
The influenza virus is a upper respiratory tract infection caused by one of the influenza virus pathogens (Type A, B, or C). Although it is called a respiratory disease, it affects the whole body, making you feel sick all over. Virions are usually roughly spherical and about 200nm in diameter. The envelope contains rigid "spikes" of haemagglutinin and neuraminidase which form a characteristic halo of projections around negatively stained virus particles. .

21 Transmission from person-to-person by:
Tiny droplets that come from a person’s mouth and nose when they cough and sneeze. Touching objects contaminated with particles from an infected person’s nose and throat.

22 Symptoms Symptoms begin 1-4 days after infection.
You can spread the flu before your symptoms start and 3-4 days after your symptoms appear. The following symptoms of the flu can vary depending on the type of virus, a person’s age and overall health: Sudden onset of chills and fever (101 – 103 degrees F) Sore throat, dry cough Fatigue, malaise Terrible muscle aches, headaches Diarrhea Dizziness Children can have additional gastro-intestinal symptoms, such as nausea, vomiting, and diarrhea, but these symptoms are uncommon in adults. The period when an infected person is contagious depends on the age of the person.  Adults may be contagious from one day prior to becoming sick and for three to seven days after they first develop symptoms. Some children may be contagious for longer than a week.

23 Is it a cold or the flu? Symptoms Cold Flu
Fever: Rare Characteristic,high (102 –104 °F),lasts 3 –4 days Headache: Rare Prominent General Aches: Pains Slight Usual Often severe Fatigue: Quite mild Can last up to 2 –3 weeks Extreme Exhaustion: Never Early and prominent Stuffy Nose: Common Sometimes Sneezing: Usual Sometimes Sore Throat: Common Sometimes Chest Discomfort: Mild to moderate Common:can become hacking cough severe

24 Complications – “Superinfection”
A bacterial “superinfection” can develop when the influenza virus infects the lungs. The result? The bacteria that live in the nose and throat can descend to the lungs and cause bacterial pneumonia. Who is most at risk? People over 50, infants, those with suppressed immune function or chronic diseases. Other complications include bronchitis, sinusitis and ear infections.

25 Complications in children:
Studies show a link between the development of Reye’s syndrome and the use of aspirin for relieving fevers caused by the influenza virus. The disease involves the CNS and the liver and children exhibit symptoms of drowsiness, persistent vomiting and change in personality.

26 Influenza outbreaks: Outbreaks are associated with cold weather and therefore occur mostly in the winter months. A reason for this: the contrast of the cold outdoor air and the heated indoor air can cause the drying of the respiratory tract tissues and render individuals more susceptible to contracting the flu. Outbreaks are likely to occur among individuals living together in settings such as nursing homes or among people who gather together indoors during the winter months.

27 Diagnosis: Individuals with symptoms of influenza should see their doctor for a thorough physical exam. Rapid influenza tests, viral cultures, and serum samples can be used to confirm infection by the influenza virus since the symptoms of the flu are similar to the symptoms caused by other infections. Serum samples also can be tested for influenza antibody to diagnose recent infections. Two samples should be collected per person: one sample within the first week of illness and a second sample 2-4 weeks later. If antibody levels increase from the first to the second sample, influenza infection likely occurred. Because of the length of time needed for a diagnosis of influenza by serologic testing, other diagnostic testing should be used if a more rapid diagnosis is needed. VACCINES

28 Rapid influenza tests:
These tests are 70% accurate for determining if the patient has been infected with the influenza virus and 90% accurate for determining the type of influenza pathogen. Examples of rapid influenza tests: Directigen Flu A, Directigen Flu A + B, Flu OIA, Quick Vue, and Zstat flu. Rapid influenza tests provide results in 24 hours and can be performed in the physician’s office.

29 Viral Cultures: Samples to be tested by viral cultures need to be collected from the first four days of infection. The viral culture can be performed from nasopharyngeal or throat swabs, nasal wash, or nasal aspirates. The results are made available within 3 to 10 days.

30 Serum samples: Blood samples can be tested for the presence of influenza antibody to diagnose recent infection. Two samples should be collected: one sample within the first week of illness and a second sample 2-4 weeks later. If antibody levels increase from the first to the second sample, influenza infection likely occurred

31 How do you prevent infection?
The only proven method for preventing influenza is a yearly vaccination approximately 2 weeks before the “flu season” begins. Since the influenza virus is subject to genetic mutations with the HA and NA proteins, new vaccines that consist of different influenza strains need to be developed each year. Every year, the vaccine is trivalent, meaning that it provides resistance to three strains of influenza viruses. The vaccine consists of 2 influenza A virus pathogens and 1 influenza B pathogen.

32 Surveillance The global surveillance network determines which strains of the influenza virus will make-up the vaccine. The networks is made up of 200 WHO laboratories in 79 countries and 4 WHO Influenza Collaboratory Centers coordinate the work of the labs. During the course of the year, influenza viruses from patients are sent to these centers. The centers, in conjunction with the FDA Vaccines and Related Biological Products Advisory Committee, make recommendations as to the IV strains they expect to circulating in the next year.

33 Surveillance Cont’d: After both parties agree, the vaccine is manufactured from inactivated viruses.

34 More on vaccination: Each year’s vaccine takes about six months to produce, package and distribute. The influenza vaccine is currently produced in embryonated chicken eggs. Future possibilities: a new growth medium could speed up vaccine production.

35 I already have the flu…Now what?
Increase liquid intake like water, juice, and soups. Get plenty of rest for the 7 to 10 days during which the symptoms may persist. Take anti-fever drugs to relieve the fever. Anti-viral drugs have recently been designed to treat the flu. If patients begin taking these drugs within 48 hours after their symptoms begin, the drugs may reduce the length of the illness by about 1 to 2 days.

36 Anti-viral drugs: General background
All anti-viral drugs inhibit viral replication but they act in different ways to achieve this. Drugs that are effective against influenza A viruses: amantadine and rimantadine. Drugs that are effective against influenza A viruses and influenza B viruses: zanamivir and oseltamivir. Amantadine Rimantadine Zanamivir Oseltamivir Type of Influenza virus infection indicated for use Influenza A Influenza B Administration oral oral inhalation Ages approved for treatment of flu 1 year 14 year 7 years 18 years Ages approved for prevention of flu not approved

37 Zanamivir and Oseltamivir
These drugs are neuraminidase inhibitors. They prevent the NA proteins on the surface of the IV from removing sialic acid from sialic acid-containing receptors. Viral budding and downstream replication of IV are inhibited when sialic acid remains on the virion membrane and host cell. The emerging IV’s stick to the cell plasma membrane or other viruses since the sialic acid is still on the surface of the cell and the virion.

38 Neuraminidase inhibition

39 Amantadine and Rimantadine
These drugs inhibit influenza virus A replication. They block they ion channel M2 protein which inhibits the delivery of IV RNP’s from the endosomes to the cytosol. However, the gene that codes for M2 can mutate and confer resistance from these drugs.

40 Future Directions for protection:
Neirynck et al. suggest a universal vaccine for all influenza A viruses. HA and NA proteins are variant between the influenza A viruses, but the extracellular domain of the M2 protein is highly conserved. Neirynck et al. propose a vaccine based on the M2 protein would protect infection by influenza A viruses.

41 Historically Speaking
Influenza can be traced as far back as 400 BC In Hippocrates’ Of the Epidemics, he describes a cough outbreak that occurred in 412 BC in modern-day Turkey at the turn of the autumn season

42 412 BC Outbreak Actual disease that affected the camp is still under debate – but is theoretically influenza High communicable rate and autumn season onset are notable characteristics of influenza Death and funerals were a daily spectacle Miasma rising from bodies was fatal to the sick and the sick were fatal to the healthy Hostile ranks were forced to withdraw from the camp

43 18th Century Outbreak Between , an influenza epidemic infected 2/3 of Rome’s population and ¾ of Britain’s population Disease spread to North America, West Indies, and South America Spread of pandemic culminated in New England, New York, and Nova Scotia in 1789 1781 marked the beginning of the year cycle of influenza epidemics and pandemics

44 19th Century Outbreaks Epidemics prevalent until 1851 Asia 1829
Spread to Indonesia by January 1831 Russia 1830 Spread throughout Russian and westward between 1830 and 1831 By November 1831, the influenza outbreak reached America Epidemics prevalent until 1851

45 19th Century Outbreaks After a forty year dormant cycle, Russian Flu pandemic occurred between 1889 and 1890 Mostly deadly pandemic to that date (1889) Began in Central Asia during summer of 1889 and spread to Russia, China, North America, parts of Africa, and major Pacific Rim countries 500,000 – 750,000 mortalities worldwide Influenza had been regarded as a joke, but the medical profession finally started to realize it’s severity

46 Influenza in the spotlight
1900 JAMA article recognized influenza as a serious health threat Variable forms of influenza suggested Catarrhal type affects the respiratory or gastro-intestinal regions Neurotic type affects the cerebral, neuralgic, and the cardiac regions Blending of these types produces typhoid

47 20th Century Outbreaks 1918 Spanish Flu 1957 Asian Flu
1968 Hong Kong flu 1976 Swine Flu scare 1977 Russian Flu scare 1997 Avian Flu scare

48 1918 Spanish Flu Most lethal and infectious pandemic ever
Flu first appeared in Kansas in March of 1918 Within one week of the first reported case, the flu had spread to every state in the US Those who fell ill in the morning were dead by nightfall Those who survived symptoms of the flu often died of complications (such as pneumonia) caused by bacteria By April, virus spread to Europe, China, Japan, Africa, and South America Characterized as the “First Wave” – high communicability, low lethality Despite low lethality, 800,000 worldwide had died by the summer

49 1918 Spanish Flu In late August, a second more virulent form emerged
Characterized as the “Main Wave” Virus killed over 100,000 people per week in some US cities Spread throughout Europe, the Alaskan wilderness, and remote islands of the Pacific By October 1919, flu strain vanished At least 20,000,000 dead worldwide within 18 months 850,000 Americans

50 1918 Spanish Flu Mortality was greater than the 4-year “Black Death” Bubonic Plague Mortality rate was 2.5%, other epidemics had been 0.1% Unusually, most deaths associated with young, healthy adults Researchers isolated a wide selection of bacteria – virus for influenza unknown Years later, H1NI strain found responsible for infection However, bacteria responsible for the severe secondary complications of pneumonia causing death

51 1957 Asian Flu Began in China and spread through Pacific
H2N2 Strain responsible Mortality rate of 0.25% Virus quickly identified Vaccine production began in May 1957 Virus entered US and spread through school children Deaths occurred between Sept 1957-March 1958 Highest rate of death in elderly 70,000 Americans dead

52 1968 Hong Kong Flu First detected in Hong Kong in early 1968
H3N2 Strain responsible Wildly spread to US by December Mildest pandemic in 20th Century Immunity may have developed from Asian Flu School children were home for the holidays Improved medical care and antibiotics for secondary infections were available

53 1976 Swine Flu Scare Novel virus identified in Fort Dix labelled “Killer Flu” Thought to be related to 1918 Spanish Flu Mass vaccination campaign in US Virus never moved outside Fort Dix area If it had spread, it would have been much less deadly than the Spanish Flu

54 1977 Russian Flu Scare Started in northern China
Influenza A/H1N1 responsible Epidemic disease in young children and young adults worldwide Persons born before 1957 had developed an immunity because of 1957Asian Flu Not considered a true pandemic because illness occurred primarily in children Virus was included in vaccine

55 1997 Avian Flu Scare Isolated in Hong Kong A/H5N1 flu responsible
Few hundred were infected 18 Hospitalized, 6 dead Flu did not spread from person to person Cause for concern because virus moved directly from chickens to people Pigs were NOT the intermediate host Chickens (1.5 million) were slaughtered No further spread afterwards

56 1999 Avian Flu scare Isolated in Hong Kong
Influenza A/H9N2 responsible 2 children infected Pandemic was not started but incident is a cause for ongoing concern Continued presence in birds Ability to infect humans without intermediate host Influenza virus able to change and become more transmissible among people

57 Weaponization & Bioterrorism
High mutation rate Antigenic shifts Antigenic drifts Both changes produce new influenza virus variants and strains Strains which humans have no immunity against are likely to be causative agents of pandemics Communicability

58 If Influenza Strikes Again…
Influenza’s destructive capacity resides in the pace and unpredictability of its virus evolution Can easily subvert the body’s immune response and outstrip society’s efforts at containment Scenario of greatest concern for medical, public health, and political leaders Lead to a catastrophic epidemic severely taxing society’s ability to care for the sick and dying

59 … How can we prepare? Build capacity for care for mass casualties
Physicians from all resources and space must be on hand Limited space sends the sick back home to further spread the virus Decentralized delivery of aid (i.e home care) Respect social mores relating to burial practices Proper treatment of the dead during an infectious disease emergency would require expeditious handling of corpses to prevent public health threats while avoiding dehumanizing mortuary practices Focus on developing a pneumonia vaccine, to prevent secondary, often fatal, infections which are facilitated by influenza infection.

60 … How can we prepare? Characterize outbreak accurately and promptly
Systematic reporting system would allow public health officials to keep the public informed For example gives a weekly influenza summary Latest reports are all available online

61 … How can we prepare? Earn public confidence in emergency measures
Neither support nor resistance to public health recommendations by the community should be taken for granted Successful plan for managing an epidemic would be conveying consistent and meaningful messages, serving audiences with diverse beliefs and languages, and acknowledging citizen concerns and grievances Guard against discrimination and allocate resources fairly Need to explain the disease to prevent prejudice that reinforces existing social schisms and inequalities Fairly allocate resources

62 References Burnett, Chiu, and Garcea. Structural Biology of Viruses. Oxford: Oxford University Press, 1997. Mahy, Brian WJ. A Dictionary of Virology. 2nd Ed. San Diego: Academic Press, 1997. Fields, Barnard N. et al. Fields Virology vol 1. 3rd Ed. Philadelphia: Lippincott-Raven, 1996. Structure and Genome Organization of Influenza Viruses. Expert Reviews in Molecular Medicine. Available: Cambridge University Press, 2001. Antler, Christine, Boyler, Erin. Who Knew? The Flu and You! From: Biotechnology Laboratory, University of British Columbia. Available Online: No date. Isin, Basak, et. al. Functional Motions of Influenza Virus Hemagglutinin: A Structure-Based Analytical Approach. Biophysical Journal. Feb 2002: vol. 82, Lagunoff, Michael. Viral Replication. Lecture notes from April 9, 2002 for Microbiology/Pathology University of Washington. Available Online: Pinto, Lawrence. The M2 Ion Channel Protein of Influenza Virus A. Detailed Research Summary from Northwestern University. Available Online: 8. Feliciano D, et. al. Five-year Experience with PTFE Grafts in Vascular Wounds. American Scientist 2003, 92: Pandemics and Pandemic Scares in the 20th Century from CDC: Pandemic Influenza [Online] Schoch-Spana M. Implications of Pandemic Influenza for Bioterrorism Response. Clinical Infectious Diseases 2000; 31: Puskoor, Rohit et al. Invfluenza Virus Book Chapter. Not yet published. Key Concepts: Some search engines work better for specific types of searches. While Yahoo will take your keyword and sort information into categories, a search engine like Hotbot will bring up the ten “hottest” (or most popular) sites for your keyword. While Hotbot might be useful for assessing the popularity of web sites in a cultural analysis paper, Yahoo might offer a more comprehensive listing of sites.


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