ORGB 423 Lecture Notes - Lecture 4: Tobacco Mosaic Virus, Avian Influenza, Swine Influenza
12 Jun 2018
School
Department
Course
Professor
MIMM466: Viral Pathogenesis
2018-01-10 LEC 4 Influenza
Seasonal Flu: infects 1 billion annually, 3-5 million get severe disease, 300,000-500,000 deaths
Major pandemics
Pandemic
Date
Deaths
Subtype
Asiatic (Russian) flu
1889
1M
H2N2 (possibly)
Spanish flu
1918
50M
H1N1
Asian flu
1957
152M
H2N2
Hong Kong Flu
1968
1M
H3N2
Swine flu
2008
6k
Novel H1N1
Spanish Influenza (avian-like H1N1)
• 3 waves: spring 1918, November 1918, 1919
• Mortality rate: 2.5%, particularly high in young adults
o Death due to bacterial or viral pneumonia
• Elicit very strong immune response: cytokine storm
The discovery of Influenza virus
• 1876: beginning of microbiology era
• 1892: Pfeiffer “discovered” bacterium that causes influenza, named it Bacillus influenza
o They didn’t know about viruses at this time
o Later that year, Ivanovski reported that tobacco mosaic disease was caused by a filterable agent
§ I.e. can’t be a bacterium
• 1918: Nicolle and Lebaily claimed to transfer the disease to healthy volunteers using filtered sputum of
patients
• 1931: Shope obtained filterable agent that causes the flu in pigs
• 1933: human influenza isolated from a ferret (Smith, Andrewes, Laidlaw)
o Later that year, Dochez (et al) cultivated influenza in egg cultures
• Both Shope and Smith, Andrews, Laidlaw demonstrated that serum of 1918 flu patients could neutralize the
pig virus
The 1918 Influenza Strain
• 1951: search for 1918 influenza (Hultin, McKee, Geist, Layton)
o Lung biopsy materials were cultured in embryonated eggs
o Ferrets were inoculated, but no virus was found
• 1995: Technical advances (PCR, RT-PCR, sequencing, phylogenetics)
o Recovered genetic material from 1918 patients
o Small RNA fragments were recovered and sequenced (amplified via RT-PCR reverse genetics)
o Phylogeny determined, complete coding sequence found over the next decade
• Reconstruction of 1918 flu: RT-PCR used to clone viral DNA
o 8 segments were reconstructed in plasmids, and a fully infectious flu virus was recreated via reverse
genetics
o Infected mice, ferrets, and monkeys
§ Found that 1918 strain was much more pathogenic (higher & faster mortality) than regular flu
o Determined that the 1918 pandemic was similar to avian influenza
§ 1957, 1968, and 2009 pandemics all descend from the 1918 virus
• Chimeric viruses bearing:
o the 1918 H1 (or 1957 H2, 1968 H3, and 2009 H1) are pathogenic in mice
o The 1918 viral polymerase complexes are pathogenic in mice and ferrets
§ This reflects the polygenic nature of the innate virulence of the 1918 virus
Document Summary
Seasonal flu: infects 1 billion annually, 3-5 million get severe disease, 300,000-500,000 deaths. Novel h1n1: 3 waves: spring 1918, november 1918, 1919, mortality rate: 2. 5%, particularly high in young adults, death due to bacterial or viral pneumonia, elicit very strong immune response: cytokine storm. Found that 1918 strain was much more pathogenic (higher & faster mortality) than regular flu: determined that the 1918 pandemic was similar to avian influenza. Influenza general info: orthomyxoviridae, influenza a: human, pig, bird, horse. Ha and na are neutralization antigens: influenza b: human, seal. Influenza a and b cause annual human epidemics. A/turkey/ontario/6118/68(h8n4: hemagglutinin: 16 subtypes, neuraminidase: 9 subtypes. H1n1, h2n2, h3n2, h5n1 (avian flu) etc: h3n2 is currently circulating, the 1918 h1n1 virus did not leave the human population. Functions of the ns1 protein: limits apoptosis, limits induction of ifns and antivirals, blocks cellular mrna maturation, enhances viral mrna translation.
