Orthomyxoviruses Influenza

1
OrthomyxovirusesInfluenza

• Raymond Tellier MD MSc FRCPC CSPQMicrobiologist,
  Hospital for Sick Children

2
Influenza

• Influenza is a viral respiratory infection
  characterized by upper and lower respiratory
  symptoms, fever, generalized malaises and
  myalgias.
• Complications include viral pneumonia, bacterial
  superinfection, cytokine storm.
• Wide range of clinical outcome of infection, from
  asymptomatic to fatal.

3
Influenza

• La malatia per linfluenza della stella(the
  disease caused by the influence of the stars)
• In French grippe, from French verb agripper
  (clinging)

4
(No Transcript)
5
From Fields Virology 4th ed Chapter 47
EM Hosp. for Sick Children
6
TCID50 Tissue culture Infectious Dose 50
Douglas R.G. Influenza in Man. Pp 375-447 in The
Influenza Viruses and Influenza, Kilbourne E.D.
ed, Academic Press, New York 1975.
7
Orthomyxoviridae

• Influenza A
• Influenza B
• Influenza C
• Thogotovirus
• Isavirus

8
(No Transcript)
9
(No Transcript)
10
(No Transcript)
11
(No Transcript)
12
Antigenicity of surface glycoproteins

• Both HA (haemagglutinin) and NA (neuraminidase)
  are antigenic and trigger the apparition of
  antibodies
• However, neutralizing epitopes are found on the
  HA neutralizing antibodies against HA provide
  immunity this is the basis for the use of
  current killed vaccines.

13
Genetic Drift

• Minor changes resulting from point mutations in
  the gene segment coding for HA or NA approx.
  0.5 to 1 per year.
• In HA, changes occurred throughout the protein
  but cluster in five hypervariable domains.

14
(No Transcript)
15
Fig.5 Natural variation in the HA of H3 strains
from 1961987. Location of amino acid differences
shown on the HA monomer in strains from years of
significant influenza activity are shown by
solvent accessible surfaces to represent the
altered HA antigenic surface site A-red site
B-yellow site C-magenta site D-blue, and site
E-green (as defined by Wiley et al. Generally
when changes occur throughout antigenic sites
(A-E) a new epidemic strain emerges (Wilson I.A.,
Cox NJ Annu Rev Immunol 1990 8 737)
16
Antigenic Shift

• Unique to influenza A
• Changes of HA and/or NA subtypes through genetic
  reassortment between different strains of
  influenza A virus in cells dually infected.
• From the point of view of immune escape viruses,
  the changes in HA subtypes are the important ones.

17
Lipatov AS et al 2004 J Virol 78 8951-8959
18
(No Transcript)
19
Stevens et al, Nature Reviews in Microbiology
2006 4 857-864
20
Population in China

• 1968humans 790 millionspigs 5.2
  millionspoultry 12.3 millions

• 2004humans1.3 billionspigs 508
  millionspoultry 13 billions

Osterholm MT New Engl J Med 2005 18 1839-1842
21
(No Transcript)
22
(No Transcript)
23
Palese P. Nat Med 2004 12 S82-S87
24
Excess mortality20th century influenza pandemics

• A(H1N1) 1918 50-100 millions 1
• A(H2N2) 1957 at least 2 millions 2
• A(H3N2) 1968 1 million (est.) 2

1 Johnson NPAS, Mueller J Bull Hist Med 2002 76
105-115 2 Alvarado de la Barrera CA, Reyes-Teran
G. Arch Med Res 2005 36 628-636
25
Palese P. Nat Med 2004 12 S82-S87
26
Palese P. Nat Med 2004 12 S82-S87
27
Nations With Confirmed Cases H5N1 Avian Influenza
(July 7, 2006)(HHS website, updated 8 Nov 2006)
28
Cumulative Number of Confirmed Human Cases of
Avian Influenza A/ (H5N1) Reported to WHO ( 13
Nov 2006)
29
(No Transcript)
30
Palese P. Nat Med 2004 12 S82-S87
31
(No Transcript)
32
Stevens J, WilsonIAwww-ssrl.slac.stanford.edu/...
/1918flu.html
33
Steinhauer DA, Virology 1999 258 1-20
34
Steinhauer DA, Virology 1999 258 1-20
35
Horimoto T et al Nature Reviews in Microbiology
2005 3 591-600
36
(No Transcript)
37
(No Transcript)
38
(Ha et al Proc Natl Acad Sci USA 2005 9811181-86
39
Stevens J. et al J Mol Biol 2005 epub 11/2005
40
Shinya et al Nature 2006 440 435-436
41
Reactivity of human respiratory tissues with
lectins specific for different sialic acid
linkages. a,Nasal mucosa b, paranasal sinuses
c, bronchus d, bronchiole e, alveolus. Res,
respiratorybronchiole (adjacent to alveoli) Ter,
terminal bronchiole (distal to alveoli) Alv,
alveolus. Green, reaction with Sambucus nigra
lectin, indicating the presence of sialic acid
linked to galactose by an2,6-linkage (SA2,6Gal).
Red, reaction with Maackia amurensis lectin,
indicating the presence of SA2,3Gal. Shinya et al
Nature 2006440 435-436
42
(No Transcript)
43
(No Transcript)
44
Fig. 1. Attachment of H5N1 virus to respiratory
tissues of humans and four animal species. In
the trachea, H5N1 virusvisible as red-brown
stainingattached only to epithelial cells of
mice. In the alveoli, H5N1 virus attached
predominantly to type II pneumocytes
(arrowheads) in humans (Van Riel et al Science
2006 312 399)
45
Fields Virology 4th ed Chapter 46
46
(No Transcript)
47
(No Transcript)
48
(No Transcript)
49
(No Transcript)