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Lectures 7 and 8 notes

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University of Guelph
PATH 3610
Rob Foster

LECTURE 7 AND 8 - RESPIRATORY Characteristics of Influenza virus - Negative sense, single-stranded, segmented RNA virus - Enveloped with glycoprotein spikes o HA – haemagglutinin o NA – neuraminidase o Matrix - Particles are relatively labile Influenza symptoms - Headaches, chills, dry cough, body aches and fever - Upper respiratory symptoms; nasal congestion, stuffy nose, sore throat - Immune response is only partially protective Transmission: - Spread from person to person, coughing and sneezing - Enters the body through mucous Role of NA and HA proteins of influenza Haemagglutinin (HA) • Binds sialic acid containing receptors • Variable • Role in immunity • 18 sub-types - It mediates binding of virus to host cell - HA cleavage is essential for viral infectivity because it mediates fusion between the viral envelope and the endosome, an essential step for vRNP release to the cytoplasm. - HA cleavability is determined by cleavage site aa sequence o Low pathogenic avian viruses and non-avian influenza viruses possess a single Arg residue at the cleavage site that is cleaved by proteases in the respiratory and/or intestinal organs, and hence restricts viral replication locally. o Highly pathogenic H5 and H7 viruses possess several basic amino acids at the HA cleavage site o Increased pathogenicity of avian influenza viruses has been linked to the acquisition of multibasic HA cleavage sites. Neuraminidase (NA) • Cleaves the glycosidic bond joining the sialic acid to D-galactose causing elution • Prevents virus-aggregation • Promotes release of virus • Role in protection Antigenic shift vs drift Antigenic shift • Reassortments: new combinations of HA and NA can occur by reassortment of the RNA segments coding for HA and NA proteins when cells are co-infected with 2 different sub- type viruses. • Pigs and ducks act as “mixing vessels” Antigenic drift • Spontaneous mutations, due to selection pressure of antibodies Influenza virus receptor preferences HA subtypes and host distribution  H5 o Primary reservoir: wild water birds, birds (++), chickens (++) o Secondary reservoir: -  H2 o Primary reservoir: wild water birds, birds, chickens o Secondary reservoir: human  H1 o Primary reservoir: wild water birds, birds, chickens o Secondary reservoir: human, pig  H3 o Primary reservoir: wild water birds, birds, chickens o Secondary reservoir: human, pig and horse Host specificity Influenza virus host specificity can be explained in part by the difference in receptor-binding specificity for human and avian influenza viruses.  Human influenza virus type A HA, and swine influenza virus HA bind: o N-acetylneuraminic acid-α-2.6 galactose in humans  Avian and equine influenza virus HA bind: o N-acetylneuraminic acid-α-2.3 galactose in birds  Pig trachea contains: both 2.6 and 2.3, therefore, pigs can serve as a mixing vessel  Infection of humans with HPAI H5N1 was surprising because the isolated from individuals in Hong Kong preferentially recognized SA2,3Gal o Later studies showed avian-type receptors on human epithelial cells that line the respiratory bronchiole and the alveolar walls (express receptors in the low respiratory tract) o Finding avian-type receptors in human lungs explains the severe pneumonia seen in humans with highly pathogenic avian H5N1 viruses Evolution of human influenza viruses Spanish  Asian  Hong Kong  Russian  Avian Spanish Influenza (H1N1) - Children under the age of 15 experienced the highest attack rates - The genomic sequence revealed an avian-like H1N1 virus that contained human-like signature amino acids in several proteins  Spanish influenza virus lacks a multibasic HA cleavage site which is the hallmark of highly pathogenic avian influenza viruses - Reverse genetics: the HA, NA and PB1 genes contributed significantly to the efficient replication and enhanced virulence of the pandemic strain. - The virus leads to overstimulation of the immune system - The 1918 pandemic killed unusual numbers of young adults, which may have been due to their healthy immune systems mounting an overly strong and damaging response to the infection - Pandemic strain: wide dissemination, high and rapid replication. Asian influenza (H2N2) - The pandemic was caused by a human/avian reassortant that introduced avian virus H2 HA and N2 NA genes into human populations - The Asian influenza virus also possessed a PB1 gene of avian virus origin Hong Kong influenza (H3N2) - Virus of the H2N2 subtype were replaced by another human/avian reassortant that possessed an H3 HA gene of avian virus origin - The PB1 gene of the pandemic virus was derived from an avian virus Russian influe
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