Influenzavirus. Influenzavirus 10/27/15. Lord Randolphs report from Queen Marys trip to Scotland in 1562

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A disease under the influence of the stars or the moon.

which passed through her whole court neither sparing lords, ladies, nor madmoiselles, not French or

Influenza B virus infects primarily humans.

1 A disease under the influence of the stars or the moon. Lord Randolphs report from Queen Marys trip to Scotland in 1562 She fell acquaintance with a new disease which passed through her whole court neither sparing lords, ladies, nor madmoiselles, not French or English. Influenzavirus Influenza A virus infects birds, humans, pigs etc. Influenza B virus infects primarily humans. (Influenza C virus) - disease Influenzavirus Symptoms of influenza Influenza virus originate from birds (ducks, shorebirds.). Birds are a reservoar for all influenza A viruses. Normally no disease symptoms in birds. GastrointesLnal infeclons in birds. 1

Influenza - pathogenesis Influenzavirus infects respiratory mucosa in humans

Mucosal cells destroyed by lysis, apoptosis och local inflammalon.

Influenza virus Influenza virus M2 ion channel pumping in H + into the virion.

2 Influenza - pathogenesis Influenzavirus infects respiratory mucosa in humans primarily but not exclusively the upper respirtory tract. Mucosal cells destroyed by lysis, apoptosis och local inflammalon. Influenza virion & genome Virus is also present in monocytes/macrophages but does not replicate well in these cells. Induced cytokines give rise to the classical influenza symptoms. Influenza virus Influenza virus M2 ion channel pumping in H + into the virion. Hemagglu*nine binds virus receptor (sialic acid). Neuraminidase cuts off sialic acid from cell surface. Mims. Medical microbiology Influenza virus Influenza virus genome =NS2 2

M2 pumps in H + into the virion thereby dissolving it and releasing the viral

3 Influenza replicahon cycle HemaggluHnine binds sialic acid Low ph in the endosome induces fusion between cell and virus envelope. M2 pumps in H + into the virion thereby dissolving it and releasing the viral genome. Mims. Medical microbiology Fields Virology, 3 ed Influenzavirus M2 is an ion channel that pumps H + into the virion 3

TranscripHon of the influenza virus genome - produchon of mrna: Cap snatching.

CAP Approx 10nt. A U POL U 5-7 AAAAAAAAAAAA 15-22 nt.

POL POL NP A U U 5-7 15-22 nt. A U U 5-7 NP 3 5 3 5 - vrnas have phosphates at their ends. - POL is primed by NP.

4 TranscripHon of the influenza virus genome - produchon of mrna: Cap snatching. TranscripHon of the influenza virus genome - produchon of mrna: polyadenylahon. CAP POL Approx 10nt. A U U nt. CAP Approx 10nt. A U POL U 5-7 AAAAAAAAAAAA nt ReplicaHon of the influenza virus genome produchon of vrna ReplicaHon of the influenza virus genome produchon of vrna POL POL NP A U U nt. A U U 5-7 NP vrnas have phosphates at their ends. - POL is primed by NP. - NP is an anl- terminator - vrnas have phosphates at their ends. - POL is primed by NP. - NP is an anl- terminator Influenza virus replicahon cycle H protein binds sialic acid. N protein cuts off sialic acid. Tamiflu M2 protein pumps H + into the virion. 4

Export of the genome from the nucleus Export from the nucleus NP + P + M1 are imported to the nucleus. Forms complex with the newly synthesized 8 vrnas (- ssrna).

PLoS Pathog 8(12). Neuraminidase Influenzavirus neuraminidase Influenzavirus hemagglulnine (H) binds sialic acid.

5 Export of the genome from the nucleus Export from the nucleus NP + P + M1 are imported to the nucleus. Forms complex with the newly synthesized 8 vrnas (- ssrna). Cellular export factor: NS2= NS2/NEP mediates nuclear export of the viral genomic vrnas. Paterson D, Fodor E (2012) Emerging Roles for the Influenza A Virus Nuclear Export Protein (NEP). PLoS Pathog 8(12). Neuraminidase Influenzavirus neuraminidase Influenzavirus hemagglulnine (H) binds sialic acid. Influenza virus neuraminidase (NA) cuts off terminal sialic acid groups as virus is produced. Removal of sialic acid by neuraminidase is required to prevent de novo synthesized virus from slcking to the cell surface. Neuraminidase is essenlal for influenzavirus virulence. NEJM, 2005 AnHgenic variahon in influenza Influenza virus variability AnLgen varialon by two different mechanisms: An*genic dri= - point mutalons Influenza A and B An*genic shi= - exchange of gene segments Influenza A 5

AnHgenic dris Point mutalons in the influenza virus glycoproteins hemagglulnine och neuraminidase. Less than a percentage change from year to year. Gives rise to annual epidemics.

6 AnHgenic dris Point mutalons in the influenza virus glycoproteins hemagglulnine och neuraminidase. Less than a percentage change from year to year. Gives rise to annual epidemics. The HA gene of influenza A (H3N2) (1968 to 2002). AnHgenic shis AnLgenic shig exchange of gene segments. Two different influenza viruses infeclng the same cell. Reason for annual influenza virus vaccinalon. AnHgenic shis PB2 PB1 AnHgenic shis PA HA NP NA M Human influenza A virus Avian influenza virus NS PB2 PB1 PB2 PB1 PA PA HA HA Infection of the same cell. NP NA M NS NP NA M NS New human influenza A virus PB2 PB1 PA HA New avian hemagglutinine New RNA segment encoding avian hemagglutinin. NP NA M NS Novel H7N9 Citation style for this article: Kageyama T, Fujisaki S, Takashita E, Xu H, Yamada S, Uchida Y, Neumann G, Saito T, Kawaoka Y, Tashiro M. Genetic analysis of novel avian A(H7N9) influenza viruses isolated from patients in China, February to April Euro Surveill. 2013;18(15):pii= Available online: aspx?articleid=20453 AnHgenic shis Human influenzavirus AnHgenic shis Can give rise to novel influenza viruses by reasortment of gene segements between human and avian influenzaviruses. Avian influensavirus A host that can accomodate both human and avian influenza viruses may be needed. Pigs are suggested as they contain receptors for both avian and human i influensa A viruses. ScienLfic American

Influenza A virus pandemics 1889 H3N8 1900 H3N?

Hongkong flu 1977 H1N1, H3N2 2009 H1N1 v H1N1 variant ( Swine

flu Three pandemic waves of flu in Great Britain in 1918-19.

7 Influenza A virus pandemics 1889 H3N H3N? 1918 H1N1 Russian flu Spanish flu 1957 H2N2 Asian flu 1968 H3N2 Hongkong flu 1977 H1N1, H3N H1N1 v H1N1 variant ( Swine flu ) The pandemic 1918 influenza virus (Spanish flu) Spanish flu Three pandemic waves of flu in Great Britain in MMWR 48,29:621,1999 Mortality in relahon to age during the influenza in H1N1 Influenzavirus Why was the 1918 H1N1 influenzavirus so pathogenic and from where did it come? Can it be found somewhere today? 7

Biopsies of lung Hssue from Spanish flu vichms Spanish flu RNA extrachon

Swine flu 2009 NEJM 353; 2209, 2005 Influenza A virus pandemics 1889 H3N8 1900

flu 1977 H1N1, H3N2 2009 H1N1 v H1N1 variant ( Swine flu ) Influenza A (H1N1)

City. April 17, 2009: two first cases with confirmed influensa A (H1N1) v

8 Biopsies of lung Hssue from Spanish flu vichms Spanish flu RNA extrachon Läkartidningen 103;1937, 2006 Nature 2005? Swine flu 2009 NEJM 353; 2209, 2005 Influenza A virus pandemics 1889 H3N H3N? 1918 H1N1 Russian flu Spanish flu 1957 H2N2 Asian flu 1968 H3N2 Hongkong flu 1977 H1N1, H3N H1N1 v H1N1 variant ( Swine flu ) Influenza A (H1N1) v 2009 March 11, 2009: first palent with influenza- like symptoms is Mexico City. April 17, 2009: two first cases with confirmed influensa A (H1N1) v (California, USA). August, 2010: transmission of the Swine flu to 214 countries with millions of infeclons and > deaths. 8

Influenza A (H1N1) v 2009 Influenza A (H1N1) v 2009 in Sweden Was ogen a relalvely benign disease laslng for 3-4 days. A few palents developed severe symptoms on day 4 5 and needed intensive care.

9 Influenza A (H1N1) v 2009 Influenza A (H1N1) v 2009 in Sweden Was ogen a relalvely benign disease laslng for 3-4 days. A few palents developed severe symptoms on day 4 5 and needed intensive care. Epidemic in Sweden in the autumn of Mostly children and younger people contracted flu. RelaLvely few elderly were infected. ProtecLve anlbodies against previous influensa A H1N1 virus infeclons? ProtecHve anhbodies to H1N1 flu in the Finnish populahon The rise of swine flu in 2009 AnLbodies to the 2009 Swine flu (H1N1) v virus Born AnLbodies % % % % % % % % Eurosurveill 2010;15 (5) Avian flu Avian influenza virus 9

Highly pathogenic avian influenza virus. Transmission of highly pathogenic avian flu What determines the pathogenic properhes of avian flu?

10 Avian flu Avian influenza virus Ducks and shorebirds are the natural hosts of avian influenza A virus. 12% of ducks and sea gulls at the Onenby bird observatory are influenza virus infected. Low pathogenic avian influenza virus. Highly pathogenic avian influenza virus. Transmission of highly pathogenic avian flu What determines the pathogenic properhes of avian flu? NEJM; 355: 2174, 2006 HemaggluHnine, neuraminidase Influenzavirus hemaggluhnine is glycosylated and requires proteolyhc cleavage. Mims. Medical microbiology Flint et al. Principles of Virology, 2:nd ed 10

HemaggluHnine HA. HA 0 cleaved to HA 1 + HA 2. LPAI HPAI Flint et al.

Different sialic acid receptors on different cells.

Avian fluvirus binds another sialic acid receptor than human influenza A virus.

11 HemaggluHnine HA. HA 0 cleaved to HA 1 + HA 2. LPAI HPAI Flint et al. Principles of Virology, 2:nd ed Nature Microbiology Reviews Avian influenzavirus Different sialic acid receptors on different cells. In rare cases, humans may be directly infected by highly pathogenic avian flu. This may cause serious disease..but confirmed transmission of avian flu between humans has not occurred. Avian fluvirus binds another sialic acid receptor than human influenza A virus. Explains why avian flu causes serious disease in humans, but is not easliy transmined. Microbe 2; 489, 2007 Highly pathogenic influenza virus may cause lower respiratory tract infechons in humans Highly pathogenic avian influenza As of (August 2012), there are 608 confirmed human cases of avian flu. Of those, 359 have died (59 %) 11

is thereager transmined to humans. a pig virus is transmined to humans. an avian influenza virus is transmined to humans, and adapts.

12 How do novel influenzaviruses arise? Transmission of influenzavirus to humans A new human influenzavirus can arise by: various influenza viruses meet and mix in pigs and is thereager transmined to humans. a pig virus is transmined to humans. an avian influenza virus is transmined to humans, and adapts. NEJM, 2004 Influenza vaccine Influenza vaccine produchon VaccinaLon Takes around 6 months to produce a vaccine. Annual vaccinalon. AnLviral tretament M2 innhibitors. Neuraminidase innhibitors. Scientific American 293; 23,

Influenza viruses. Virion. Genome. Genes and proteins. Viruses and hosts. Diseases. Distinctive characteristics

Influenza viruses. Virion. Genome. Genes and proteins. Viruses and hosts. Diseases. Distinctive characteristics Influenza viruses Virion Genome Genes and proteins Viruses and hosts Diseases Distinctive characteristics Virion Enveloped particles, quasi-spherical or filamentous Diameter 80-120 nm Envelope is derived