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  1. What is influenza? What is it caused by?
  2. Where does the virus attack?
  3. How is it transmitted?
  4. What types of virus are there?
  5. What is the impact of this disease?

  1. An endemic disease in humans, domestic animals, wild birds. Caused by an RNA virus of the orthromyxovirus group.
  2. Virus binds to cell surface receptors of mucous coated cells of respiratory tract.
  3. Transmitted mainly via inhalation of respiratory droplets containing the virus and by hand contact with contaminated materials followed by involuntary hand-to-eye contact.
  4. Three types, A, B, and C, exist, with various strains. Infect a wide variety of animals globally.
  5. Seasonal flu, 3 to 5 million severe cases per year, with 250,000 to 500,000 deaths worldwide. Pandemic flu, vastly greater impact on human health.


  1. Where do outbreaks usually start?

  1. Outbreaks follow a predictable seasonal pattern; occurs annually, typically starts in southern China where there is a lot of interaction betweem people and birds, and begins to spread globally. By later fall to early spring, seasonal flu reaches temperate climates. 


  1. Is there immunity?
  2. Who is most impacted?
  3. Is there a vaccine?
  4. How many U.S. deaths are there per year?

  1. Usually some immunity has built up in the human population from previous exposure.
  2. Healthy adults usually are not at risk for serious complications; the very young, the elderly, and those with certain underlying health conditions, however, are at increased risk for serious complications. 
  3. Vaccine is developed each year based on the flu strains found to be active in Asia in summer months of that year; the vaccine is then made available for the annual fall-winter flu season in temperate zone countries. Adequate supplies of antiviral medicines are usually available. 
  4. Approx. 36,000 per year, often caused by secondary bacterial and viral infections, such as pneumonia, and by stress-related heart attacks in the elderly.


  1. Do pandemics of the flu occur often?
  2. Why does the flu turn into a pandemic?
  3. Who is at risk during these times?
  4. Would there be any treatments?
  5. Are symptoms severe?

  1. No, there have been just six pandemics from the 19th to 21st centuries.
  2. Little or no pre-existing immunity, due to absence of prior exposure. New type or substantially new strain.
  3. Healthy adults may be at increased risk for serious complications.
  4. Vaccine probably would not be available in the early stages of a pandemic. Effective antiviral medicines may be in limited supply. Number of deaths could be quite high (Spanish flu approx. 500,000 deaths). 
  5. Symptoms may be more severe and complications more frequent. High potential to disrupt U.S. the world economy and society. 


  1. What is the causative agent?
    1. How big is its genome?
    2. What is a specific protein this virus needs
    3. Why do they need it?

  1. Influenza A - an RNA negative strand virus. (B and C types also exist).
    1. Segmented, eight linear single stranded RNA molecules, each ranges from 890 to 2341 nucleotides in length coding for eleven proteins total. Virus particle contains the genome and several viral proteins.
    2. One of these proteins is the virus RNA-dependent RNA polymerase. It copies the virus genome into plus-sense mRNA, which is then translated to proteins using host enzymes, and it copies the genome into more copies of minus-sense RNA which are then packaged into new virus particles.
    3. The host cell cannot provide this enzyme, it does not have it.


  1. What is attached outside the virus lipid bilayer?
  2. What does hemaglutinin do?
  3. What is neuraminidase do?
  4. How many HAs are there? How many NAs are there?

  1. Virus-specific proteins.
  2. 500 copies per virus, causes clumping of RBCs, which incidentally have same surface membrane component, sialic acid, as cells of the respiratory tract. HA binds to the sialic acid on respiratory epithelial cell membranes, this binding facilitates the fusion of the virus envelope with the host cell membrane.
  3. 100 copies per virus. Breaks down sialic acid component of respiratory cell membrane. Important for the virus particles to exit the host cell. 
  4. Sixteen different HAs (HA1-16), Nine different NAs (NA1-9)


How does HA contribute to binding?

  1. Virus binds via HA, to cell-surface receptors on cells of the repiratory tract.
  2. Binding is to sialic acid residues linked to galactose of glycoproteins on the surface of cells of the repiratory epithelium.
  3. Glycoproteins are proteins with oligosaccharide chains attached to them, and sialic acid is the terminal carbohydrate. 
  4. The sugar chains are there to help trap water to keep the tissue surface moist. 
  5. Avian influenza HA binds preferentially 2-3 sialic acid receptors, and human influenza HA binds preferentially 2-6 sialic acid receptors. Humans and Avian-type receptors at very low densities and birds have human-type receptors at very low densities.
  6. Swine influenza viruses have the ability to bind both types of sialic receptors.


How does NA help with the release of the virus from the cell?

  1. NA, cleaves the oligosaccharide at the sialic acid residue. Releases the newly formed virus from the host cell.
  2. Cell membranes of the epithelia of the upper respiratory tract of humans contain 2,6 N-linked sialic acid. 
  3. So, flu viruses that infect people are those that attach better to epithelia 
  4. Avian influenza viruses, however, bind preferentially to 2,3 N-linked sialic acids, which typically are found in birds. 
  5. The efficiency with which HA and NA work and the kind of sialic acid linkage on respiratory epithlia defines the host range and virulence of different influnza virus subtypes and strains.


  1. What is influenza A?
  2. What is influenza B?
  3. What is influenza C?

  1. Main cause of influenza in humans, also infects pigs and birds, many subtypes, all of which are present in birds. 8 RNA segments, encodes 11 genes. Evolves by antigenic drift and antigenic shift, much faster than B and C types.
  2. Infects humans and seals, 8 RNA segments, encodes 11 genes. Evolves by antigenic drift, but much slower than A type. Two genetic lineages, Yamagata and Victoria, but not categorized into subtypes.
  3. Infects humans and pigs. Rarely causes disease in humans, evolves very slowly, but can cause severe influenza and can cause local epidemics. 7 RNA segments, encodes 9 proteins.


  1. How does antigenic drift occur?
  2. How often does it occur?
  3. Where does it usually occur?
  4. Note: Look at slide 19

  1. From the accumulation of mutations in the genes for HA and NA in a single strain of influenza virus within a geographic area. Viral RNA polymerase lacks proofreading ability, so these changes persist, causes subtle changes in the structure of the HA and NA proteins that makes it difficult for the immune system to track and respond.
  2. Occurs often, and antigenically distinct varient can arise every 1 to 3 years.
  3. Typically occurs in South East Asia/China, where influenza is endemic, during the spring and summer months, causes a local increase in flu infections, and then spreads to temperate climates, giving rise to our seasonal flu epidemics.
    1. Antibody against one antigenic type or subtype may not protect against a new antigenic variant of the same type or subtype. So, new vaccine needs to be developed each year against the specific variants and strains of influenza causing flu that year.


  1. What is antigenic shift?
  2. What does co-infection allow for?
  3. Is there immunity after these shifts?
  4. What animal is a concern to humans?

  1. A more dramatic change than antigenic drift. Occurs when a new subtype of influenza A appears, potential to cause pandemic.
  2. Co-infection of two genetically distinct strains of influenza virus allows a re-assortment of the eight components of the genome, such that viruses arise that express different combinations of surface proteins, HA and NA.
  3. No, because HA and NA are the major targets of the immune system, there is little or no immunity to these "new" virus strains.
  4. Pigs, because they can be infected by strains of influenza that can infect humans and by strains that typically infect other animals. 


  1. Given an example of re-assortment.
  2. What are the key features of re-assortment virus that can cause pandemic?
  3. What were the results of the 2009 swine flu?

  1. Pigs can be infected with both, human and avian flu. Different versions of the virus can swap genes, and become highly dangerous for and transmissible between humans.
  2. Key Features:
    1. New subtype of influenza virus emerges.
    2. Causes serious illness in humans.
    3. Spreads easily among humans.
  3. Caused by the H1N1 virus gave rise to an influenza pandemic that killed over 150,000 people in a year. Started in Mexico, most people over 50 years old had some immunity. Younger people had no prior exposure, and more readily became infected. 1918 Spanish flu also effected younger people more than typical seasonal flu. 


  1. What is cytokine storms?
  2. What do cytokines signal?
  3. What is the risk of the body coming into contact with a new pathogen?

  1. A potentially fatal immune reactions consisting of a postive feedback loop between cytokines and immune cells, with highly elevated levels of various cytokines. A response of a healthy and vigorous immune system. 
  2. Signals immune cells to travel to the site of infection, and cytokines also activate those cells to produce more cytokines. Normally, this feedback loop is controlled.
  3. It gets out of control. If a cytokine storm occurs in the lungs, fluid and immune cells such as macrophages may accumulate and eventually block off the airways, potentially resulting in death. In this situation, a healthy immune system becomes a liability.


  1. The bird flu is capable of pandemic level, what two of the three conditions has it met, for the start of a pandemic?

  1. Conditions:
    1. A new subtype of influenza virus emerges. There is little to no immunity against H5N1 bird flu among humans.
    2. The virus infects humans, causing serious illness. H5N1 is highly lethal in those humans it has infected. 60% mortality.
    3. The virus spreads easily. So far, H5N1 bird flu does not spread easily from person to person.
      1. New avian flu, H7N9, has been identified as causing serious illness. 1/3 of infected have died. Has not made its way to the U.S.


  1. How does seasonal H1N1 and avian H5N1 differ?
  2. What does this difference influence?
  3. How could H5N1 spread more easily to humans?

  1. H1N1 binds 2,6 linked sialic acid residues, of the upper respiratory tract. H5N1 binds 2,3-linked sialic acid residues, which are present in the human lower respiratory tract.
  2. Influences the lethality of these viruses and their ability to spread.
  3. Swine can be infected by both, which reassortment in pigs of H5N1 with a subtype that more easily spreads from person to person. 


  1. How can we prevent the flu?
  2. What are the two kinds of vaccines?

  1. Frequent hand washing, especially during the flu season, can help. Covering your coughs and sneezes really can help limit the spread of the virus.
  2. Annual influenza vaccine - highly effective, recommended by health-care professionals for people 6 months of age and older who do not have health problems.
    1. TIV - trivalent inactivated vaccine - new in 2013 quadrivalent inactive vaccine (QIV).
    2. LAIV - live attentuated influenza vaccine.


  1. What are some treatments?
  2. Is there any resistance?

  1. Antiviral medications, can be effective for treatment after exposure to the virus.
    1. Oseltamivir (Tamiflu) and Zanamivir (Relenza). Neuraminidase inhibitors.
    2. amatadine (Symmetrel) and rimantadine (Flumadine). M2 inhibitors; M2 is a protein of the virus envelope, involved in protecting HA.
  2. Yes, to a couple medications. H1N1 is sensitive, with few exceptions, to oseltamivr.