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Chapter 43 : Influenza Virus

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Influenza Virus, Page 1 of 2

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Abstract:

Influenza viruses are unique among the respiratory viruses with regard to their frequent antigenic changes, seasonality, and impact on the general population. They can cause explosive outbreaks of febrile respiratory illness across all age groups and often substantial mortality, particularly in aged and chronically ill persons. Epidemics resembling influenza have been recorded since antiquity. The plague of Athens in 430 to 427 BC, described by Thucydides, has been postulated to have been due to epidemic influenza complicated by toxigenic staphylococcal disease (1). The greatest effects of influenza are seen when novel strains, to which most persons are susceptible, cause worldwide outbreaks, or pandemics. The most profound of these in modern times was the 1918 pandemic that may have claimed as many as 100 million lives worldwide (2). Sequencing of RNA fragments from tissue samples taken from 1918 pandemic victims enabled reconstruction of the extinct 1918 virus and study of its virulence in animal models (3, 4).

Citation: Hayden F, Palese P. 2017. Influenza Virus, p 1009-1058. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch43
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Image of FIGURE 1
FIGURE 1

Circulation of human influenza A and B viruses. Solid lines indicate that strains have been isolated and characterized. Three different influenza A virus HA subtypes (H1, H2, and H3) and two NA subtypes (N1 and N2) were identified in humans over the last 100 years. The RNA genome of the extinct pandemic 1918 virus has been sequenced from RNA fragments in formalin-fixed and frozen tissue samples from 1918 victims following RT-PCR ( ). The virus was then reconstructed in the laboratory by reverse genetics (solid square) ( ).

Citation: Hayden F, Palese P. 2017. Influenza Virus, p 1009-1058. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch43
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Image of FIGURE 2
FIGURE 2

Phylogenetic tree of influenza virus hemagglutinins (HA) () and influenza neuraminidase (NA) (). Twelve HA subtypes, including two bat HAs, make up group 1 (blue) and 6 HA subtypes make up group 2 HAs (orange). There is only one influenza B virus HA type (no subtypes). Four NA subtypes make up group 1 (green) Influenza A virus NAs, and 5 are in group 2 (red). Influenza A virus NA. The bat NAs (N10 and N11) and the influenza B virus NA (no subtypes) are evolutionarily divergent. Scale represents a 7% change in amino acid differences. Courtesy of Krammer ( ), reprinted with permission.

Citation: Hayden F, Palese P. 2017. Influenza Virus, p 1009-1058. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch43
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Image of FIGURE 3
FIGURE 3

A) Schematic diagram of an influenza A virus. HA, NA, and M2 are transmembrane proteins anchored in the lipid membrane of the virus. Inside the lipid membrane is a layer of the M1 protein. The RNP core consists of the different RNA segments, which are covered by NP molecules. In addition, they carry an RNA-dependent RNA polymerase complex (P proteins). The 3′ and 5′ ends of the RNA segments are stabilized by the polymerase complex into panhandle structures. NEP is also part of the viral core structure. (B) Schematic depiction of influenza virus HA. Antigenic changes cluster into five highly variable regions surrounding the receptor-binding pocket (purple oval). Courtesy of James Stevens and Ian Wilson ( ), reprinted with permission.

Citation: Hayden F, Palese P. 2017. Influenza Virus, p 1009-1058. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch43
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Image of FIGURE 4
FIGURE 4

Reverse genetics of influenza viruses. (A) Genetic map of influenza A/PR/8/34 (H1N1) virus. Purified RNAs were separated on a polyacrylamide gel; assignment of genes coding for one or two viral proteins is indicated. (B) Plasmid-only rescue of infectious influenza virus. Twelve plasmids are introduced into mammalian cells: four plasmids lead to expression of the viral proteins required for viral RNA replication (PA, PB1, PB2, and NP), and eight plasmids express precise copies of the eight viral RNA segments (PA, PB1, PB2, HA, NP, NA, M, and NS). The resulting viral RNAs are replicated and transcribed by the reconstituted influenza virus RNA-dependent RNA polymerase. Recombinant infectious influenza virus is generated 48 to 72 hours after transfection of cells ( ). Recently, several improvements of the plasmid-only rescue for influenza A viruses have been introduced ( ). Also, reverse-genetics systems for influenza B and C viruses have been successfully developed ( , 30 ).

Citation: Hayden F, Palese P. 2017. Influenza Virus, p 1009-1058. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch43
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Image of FIGURE 5
FIGURE 5

Reassortment of influenza A viruses leading to a new pandemic strain. Co-infection of the same cell with a human A(H2N2) (thin blue lines) virus and an animal (avian) strain with an H3 HA (thick orange lines) results in reassortment. The A(H3N2) virus responsible for the pandemic in 1968 is postulated to derive its PB1 and H3 genes (thick lines) from the animal strain and its remaining six RNAs, including the N2 gene, from the A(H2N2) parent (thin lines) ( ).

Citation: Hayden F, Palese P. 2017. Influenza Virus, p 1009-1058. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch43
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Image of FIGURE 6
FIGURE 6

General replication scheme of influenza virus. For a description of different replication steps, see the text.

Citation: Hayden F, Palese P. 2017. Influenza Virus, p 1009-1058. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch43
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Image of FIGURE 7
FIGURE 7

RNA transcription/replication by influenza virus polymerase. Structure of the influenza A virus (bat) polymerase from Ortin and Martin-Benito ( ) according to Pflug et al. ( ). The PB1 (green), PB2 (red), and PA (magenta), and the cap binding (part of PB2) and endonuclease (part of PA) domains are indicated. The synthesis of viral mRNA is initiated by cap-snatching, which involves the binding of the cap of a host RNA followed by an endonuclease (PA) cleavage. The host mRNA-derived capped RNA primer is then used to allow the RNA synthesis by the PB1 domain of the viral polymerase complex ( ).

Citation: Hayden F, Palese P. 2017. Influenza Virus, p 1009-1058. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch43
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Image of FIGURE 8
FIGURE 8

Peak month of influenza activity, USA, 1982–2014. During 2008–2009, influenza activity peaked twice because of the 2009 H1N1 pandemic. Activity in the United States peaked once in February due to seasonal influenza activity and then again in June, with the first wave of A(H1N1)pdm09 virus, followed by a second, larger peak of A(H1N1)pdm09 virus activity occurring in October, the peak of the 2009–2010 season. (Figure reproduced with permission from Influenza Division, US CDC.)

Citation: Hayden F, Palese P. 2017. Influenza Virus, p 1009-1058. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch43
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Image of FIGURE 9
FIGURE 9

Pneumonia and influenza (P&I) deaths presented as a percentage of total deaths in the United States, 2011 to 2016. Total deaths and those attributed to pneumonia and influenza deaths are reported weekly from 122 cities in the United States to the CDC. Excess mortality above the epidemic threshold has been seen particularly in association with influenza A (H3N2) subtype activity. A(H3N2) viruses predominated nationally during the 2012–13 and 2014–15 seasons, and there was a mismatch with the vaccine strain during the latter season. However, during the 2013–14 season, A(H1N1)pdm09 viruses predominated and increased overall mortality, and higher rates of hospitalization among adults aged 50 to 64 years occurred. Figure reproduced with permission from the Influenza Division, US CDC.

Citation: Hayden F, Palese P. 2017. Influenza Virus, p 1009-1058. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch43
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Image of FIGURE 10
FIGURE 10

Photomicrographs of lung tissue from patients dying with primary viral (A-D) or secondary bacterial (E) pneumonia following influenza A(H1N1)pdm09 infection. Unless otherwise indicated, histologic sections were stained with hematoxylin and eosin. (A) Diffuse alveolar damage and alveolar hemorrhage with erythrocytes and exudate filling alveoli; (B) extensive hyaline membrane formation; (C) widespread influenza A nucleoprotein antigen staining by immunohistochemistry; (D) early regenerative phase with type II pneumocyte hyperplasia and alveolar exudates; (E) polymorphonuclear leukocytes (PMNs) filling alveolar spaces in suprainfection. Photomicrographs kindly provided by Dr. Sherif Zaki, US Centers for Disease Control and Prevention, Atlanta, Georgia; republished with permission from reference .

Citation: Hayden F, Palese P. 2017. Influenza Virus, p 1009-1058. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch43
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Image of FIGURE 11
FIGURE 11

Sequential chest radiographs from a 30-year-old nonimmunocompromised female with acute influenza A virus pneumonia. (A) Her symptoms began 1 day before first radiograph, which shows right middle and bilateral lower lobe infiltrates. Her respiratory status deteriorated rapidly, and she required mechanical ventilation but survived. (B) The second radiograph, taken approximately 24 hours after admission, shows diffuse infiltrates.

Citation: Hayden F, Palese P. 2017. Influenza Virus, p 1009-1058. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch43
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Image of FIGURE 12
FIGURE 12

Computed tomography of chest without contrast in a HSCT patient who developed severe A(H1N1)pdm09 pneumonia approximately 5 months posttransplantation, while taking prednisone 20 mg/day for chronic GVHD. The study was made approximately 5 days after illness onset and shows diffuse bilateral interstitial opacities, bronchial wall thickening, and a denser left posterior chest consolidation with air bronchograms. Figure courtesy of Dr. Michael Ison, Northwestern University, reprinted with permission.

Citation: Hayden F, Palese P. 2017. Influenza Virus, p 1009-1058. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch43
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Image of FIGURE 13
FIGURE 13

Chimeric hemagglutinin-based universal influenza virus vaccine approach. Most humans have preexisting immunity against the H1 hemagglutinin (HA) (green). The majority of the antibodies is directed against the immunodominant head of the HA (green) because of repeated exposure to H1N1 viruses. Few antibodies (green) are made against the immunosubdominant stalk of the HA. Upon vaccination with a chimeric HA vaccine containing, for example, a cH5/1 HA, the HA stalk antibodies (green) will be boosted, but only a primary (low) response against the novel H5 head (yellow) will be measured. A second boost with another chimeric vaccine cH6/1, which expresses the same H1-stalk (green), will further enhance the stalk antibodies. The response to the H6 head domain is again a (low) primary response (black). For a complete universal influenza virus vaccine, two chimeric influenza A virus components are needed (one, expressing a group 1 HA stalk and the other, expressing a group 2 HA stalk) and a third one, which expresses an influenza B virus stalk (all in the context of exotic HA head domains). Such a vaccine with chimeric HAs should also result in enhanced protective anti-NA responses mediated by the (immunosubdominant) neuraminidases present in the preparation. Courtesy of Krammer reprinted with permission.

Citation: Hayden F, Palese P. 2017. Influenza Virus, p 1009-1058. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch43
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