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1

Influenza virus structure

Large, enveloped, negative-stranded RNA viruses (ssRNA). Orthomyxovirus. Has 8 genome segments and each segment has RNA-dependent RNA polymerase proteins PB1, PB2 and PA. The envelope is a lipid bilayer from host cell with viral hemagglutinin and tetrameric neuraminidase. M1 protein under lipid bilayer and M2 protein forms ion channel

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enterovirus D68 structure

Small,non-enveloped, positive-stranded RNA viruses

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Influenza: Clinical Characteristics

headache, fever (38-41 over 1-5 days), sweating, chills, malaise, anorexia, sore throat, nasal congestion, myalgias, dry cough, pneumonia

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complications of influenza

influenza pneumonia, bacterial pneumonia, and rarely encephalopathy, myositis, myocarditis, pericarditis, transverse myelitis, reyes syndrome, guillan-barre syndrome

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risk factors for influenza

>65 years, chronic diseases (pulmonary, heart, diabetes), pregnancy, immunosuppression, long term aspirin therapy in kids

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Primary influenza infection pathogenesis

incubation period 24-48 hrs. Local virus replication in respiratory epithelium (no viremia) > Macrophage and lymphocyte infiltration into lung > Innate immune responses interferon and cytokines cause fever, myalgia etc > Direct virus damage and acquired immune responses kill infected epithelial cells and/or neutralize virus particles> Elicits antibodies and influenza-specific T cells, locally and systemically > Clearance of virus and dead cells from respiratory tract

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Length of influenza infection and immunity

Illness can last 5 days to 2 weeks. Immunity to re-infection is mediated by type-specific antibody in respiratory secretions, which is antibodies to epitopes on viral HA or NA glycoproteins. If levels of IgA in respiratory tract are high enough that person will be protected from that strain of virus in future. Partially immune people may get mild sx but still shed enough virus to infect others.

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Hemagglutinin functions

95% of spikes on influenza. 1. Binds to N-acetyl neuraminic acid on host cell surface. 2. HA cleavage by host cell proteolytic enzyme inot HA1 and HA2 required for viral infectivity. 3. HA2 undergoes conformational change at low pH in endosome following endocytosis. This is required for fusion of viral envelope with host cell membranes.

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HA structure in highly pathogenic strains of influenza A

have a longer series of basic amino acid sequences at the cleavage site in HA0.

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Neuraminidase functions

5% of influenza spikes. 1. cleaves N-acetyl neuraminic acid from host cell membrane (receptor destroying enzyme). 2. removes receptor from host cell membranes as they move through the Golgi so that newly budded virions do not stick to the infected cells, but can detach and infect other cells.

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Which drugs act on neuraminidase

zanamivir and oseltamivir inhibit NA enzyme activity, thus blocking the removal of receptors from infected cell surface and preventing release of new virions from infected cell. This prevents the spread of influenza A and B. Shortens sxs

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influenza matrix protein, M, functions

Three types, M1, M2, M3. during virus budding at the plasma membranes, M protein binds nucleocapsids containing each of the 8 genome segments to the viral envelope. M2 is ion pump that raises pH in endosomes of infected cells. Since acidic pH is required for release of viral genes into host cytoplasm via HA2, M2 prevents fusion of intracellular membranes and cytopathology

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Which drugs act on Matrix proteins

Amantadine and rimantadine target M2 (anti-influenza A only)

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influenza nucelocapsid protein functions

protects viral RNA from degradation. Differs antigenically btw influenza A, B and C

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Influenza non-structural proteins functions

NS1 is an antagonist of the host interferon response. Also virus assembly/ replication and transporting nucleocapsids in and out of nucleus.

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PA, PB1 and PB2 functions in influenza

Components of the virus-encoded RNA-dependent RNA polymerase complex. PB1 assembles the RNA polymerase complex. PB1-F2 is encoded by alternate reading frame and is pro-apoptotic, enhancing virulence. PB2 binds to cap on host pre-mRNAs, enhancing transmission. PA is an endonuclease needed for cap snatching

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Types of influenza

Based on different M and nucleocapsid antigens. Influenza A: humans, birds, horses, pigs, etc.=pandemics, epidemics. Influenza B host is only humans =epidemics. Influenza C host is only humans =epidemics

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influenza replication

Binds sialic acid receptor and endocytosed > HA2 conformational change (acidic pH)causes fusion of viral envelope and endosome > viral nucleocapsid released in cytoplasm > nucleocapsids transported to nucleus and disassembled > viral polymerase proteins steal caps from host mRNAs to prime new viral mRNA synthesis > nucleocapsid assembled in nucleus, transported to cytoplasm with NS1 > HA and NA synthesized in RER > budding of virions at apical plasma membrane of respiratory epithelial cells

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Naming of influenza virus

Type of virus, place, date isolated, number of specimen, host species, HA and NA antigen type . eg: A, Hong Kong, 1/68, 32, Human, H3N2

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Immune response to influenza

Infected individuals make serum IgM and IgG antibodies to HA, NA, M, NP, replicase and NS proteins. Circulating IgG antibody probably does NOT protect against re-infection in the respiratory tract, but it can reduce severity of lower respiratory tract disease. Infected individuals and people immunized with a live attenuated aerosolized influenza vaccine make local secretory IgA antibody in respiratory tract to HA and NA. This type-specific local IgA antibody to HA (and NA) protects against re-infection. Infected people also make cell-mediated immune responses to influenza virus peptides, which help to clear infected cells.

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Issue with vaccine development for flu

How to design and administer a vaccine that will elicit effective, long-lasting local mucosal IgA immunity

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Antigenic drift

Small random mutations in HA and NA gives a selective advantage to influenza A, B and C viruses

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Antigenic shift

reassortment of genome segments from human and non-human influenza viruses that simultaneously infect a single cell causes major change to many epitopes of HA and/or NA. Most often, antigenically new HA and NA genome segments in pandemic human viruses come from avian influenza strains, often after passage through pigs. ONLY occurs in influenza A

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Pandemics vs epidemics

Antigenic drift and shift can cause epidemics. Antigenic shift can cause pandemics if the new virus is also transmitted easily from person to person

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Which strain was involved in the 1918 flu pandemic and the 2009 flu pandemic

H1N1. The 2009 pandemic was due to a novel H1N1 strain with segments from pigs.

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2014-15 flu strain

H3N2

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10. Explain how and why different strains of virus are selected for inclusion in the influenza vaccine every year.

Every year in february, a committee decides which strains to include in the next flu vaccine based on isolates collected worldwide. Each vaccine contains 3 or 4 antigenically different strains and are only 50-70% effective

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7. Describe the current Trivalent, Inactivated influenza virus Vaccine (TIV) and Live Attenuated Inflenza Vaccine (LAIV) for influenza.

Trivalent inactivated vaccine: an A/California/7/2009 (H1N1)–like virus, an H3N2 virus antigenically like A/Victoria/361/2011, and a B/Massachusetts/2/2012–like (Yamagata lineage) virus. Live attenuated vaccine: quadrivalent. Contains the strains above plus a B/Brisbane/60/2008–like (Victoria lineage) virus

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6. Compare the patients most at risk of death from influenza in a normal influenza epidemic vs. in the 1918 and 2009 influenza pandemics.

1918: could kill young healthy adults in 1-2 days. 2009: more lethal in children, obese adults or underlying neurological conditions.

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new influenza vaccine development

Neutralizing monoclonal antibodies which target the stem of influenza HA would block conformational changes needed for virus entry

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Which virus caused the August 2014 outbreak of respiratory dz at Childrens hospitals

enterovirus D68- may possibly cause acute flaccid paralysis and/or cranial nerve palsy

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Sx of enterovirus D68

Wheezing/difficulty breathing (NOT seen in flu), fever/chills, cough, sneezing, myalgias, vomiting