Transcript Welcome to the Hannover Medical School

presented by Jan Haas
Institute for Immunology
Influenzaviruses: Orthomyxoviridae
16 Haemagglutinin
9 Neuraminidase
- types
3 Polymerase
Subunits
Nucleoprotein
Nuclear Export
Protein (NEP)
Matrix Protein (M1)
Ion Channel Protein
(M2)
Interferon
Antagonist (NS1)
PB1-F2 Protein
The viral life cycle
o(-) RNA virus
oenveloped
oInfluenza A responsible for
pandemic outbreaks
ospread via aerosols and
droplets
Historical overview
Genetic Relationships among Human and
‘Russian’
influenza
(H1N1, 1977) Relevant Swine Influenza Viruses, 1918–
‘Spanish’ influenza
(H1N1,
1918-1919)
otheunusual:
re-emerging
H1N1
virus did not replace
2009. the
o mortality pattern
young
adults
H3N2
viruses circulating
at systemic
the time
Yellow arrows reflect exportation of one or more
orestricted to the
respiratory
tract, lack of
‘Asian’
influenza
(H2N2,
1957-1958)
oboth subtypes are co-circulating in humans
thisthe avian influenza A virus gene
genes to
from
infection
owasday
caused
by
a
human/avian
reassortant
that
‘H5N1’
influenza
(1997-2003)
pool. The dashed red arrow indicates a period
omost patients died of
bacterial
pneumonia,
some
introduced
avian
virus
H2
HA
and
N2
NA
genes
oHong Kong:
highly
pathogenic
avian
virus
between
viruses
of these
subtypes
without
circulation. Solid red arrows indicate the
as well of viral oreassortment
pneumonia
into human
populations
osix
marked
firsttoviruses
reported
of humans
withvirus
resulted
in fatalities,
the
emergence
ofthe
H1N2
in fatal infections
evolutionary
paths of human
influenza
‘Hongkong’
influenza
(H3N2,
1968-1970)
oaberrant innate
immune
responses
contributing
avian
influenza
populations
in viruses
2001subtype werelineages;
oviruses
of the H2N2
replacedsolid
by blue arrows, of swine influenza
its virulence human
ofurthermore,
the
Asian
influenza
virus
also
oafter
a
period
of
local
and
sporadic
outbreaks,
a new
outbreak arrow, of a
oH1N2
viruses
have sincereassortant
disappeared.
viruspossessed
lineages; and
the blue-to-red
another
human/avian
that
possessed started
a PB1 gene
of avian virus origin swine-origin human influenza virus. All influenza
2003
an H3 HAingene
of avian virus origin
osustained human-to-human infection
hascontain
not occurred
A viruses
eight genes that encode the
oH5N1the
viruses
are characterized
by avirus
highproteins
mortality
ratefrom
but top to bottom
following
(shown
oagain,
PB1 gene
of the pandemic
was
inefficient
among
derived
fromspread
an avian
virushumans within each virus): polymerase PB2, polymerase
PB1, efficiently
polymeraseamong
PA, hemagglutinin
 in contrast, S-OIVs seem to spread
humans but (HA),
nuclear
protein (NP), neuraminidase (NA),
‘S-OIV
H1N1’
influenza
have
caused
a limited
number (2009)
of fatal
infections
proteins (M), and
oS-OIVs probably resulted frommatrix
the reassortment
of nonstructural
recent Northproteins
(NS).
The genes
theavian/human/swine
1918 human and swine
American H3N2 and H1N2 swine
viruses
(thatofis,
and the
1979 H1N1
influenza
A viruses
‘triple’ reassortant viruses) with H1N1
Eurasian
avian-like
swine
viruses
recentlyAmerican
descended
fromvirus
avian
oS-OIVs possess: PB2 and PAwere
genesallof North
avian
influenza
genes,HAand
some
been
origin, a PB1 gene of human H3N2
virusAorigin,
(H1),
NP, have
and NS
“donated”
to NA
the pandemic
H1N1of
strain.
genes of classical swine virus origin,
and
(N1) andhuman
M genes
Eurasian avian-like swine virus origin (hence their original description
as ‘quadruple’ reassortants)
Genesis of swine-origin H1N1 influenza
viruses
‘mixing vessel’
Electron microscopic picture: H1N1
Role of HA in viral pathogenicity
Receptor distribution on host cells:
ohuman influenza preferentially bind to sialic acid that is linked to galactose by an a2,6linkage (SAa2,6Gal)
othis preference is matched by SAa2,6Gal on epithelial cells in the human trachea
oin contrast, avian influenza viruses preferentially recognize SAa2,3Gal that is matched
by SAa2,3Gal on epithelial cells in the intestinal tract of waterfowl (the main replication
site of avian influenza viruses)
osurprisingly H5N1 binds preferentially to SAa2,3Gal
ostudies showed avian-type receptors (SAa2,3Gal) on human epithelial cells that line the
respiratory bronchiole and the alveolar walls, but human-type receptors (SAa2,6Gal) on
human epithelial cells in nasal mucosa, paranasal sinuses, pharynx, trachea and bronchi
HA receptor specificity: amino acid residues in the HA receptor binding pocket determine
binding to human/avian type receptors
HA cleavage: HA cleavability determined by the amino acid sequence at the cleavage site
oLow pathogenic viruses possess a Arg residue at the cleavage site
ohighly pathogenic H5 and H7 viruses possess several basic amino acids at the HA
cleavage site
 pathogenicity correlates with acquisition of multibasic HA cleavage sites
Role of PB2, NS1 and PB1-F2 in pathogeniciy
and host specificity
PB2: belongs to the viral replication complex
PB1-F2: is expressed from the +1 reading frame, induces apoptosis by interaction with
two mitochondrial proteins
NS1: the NS1 protein is an interferon antagonist that blocks the activation of
transcription factors and IFN-b-stimulated gene products, and binds to double-stranded
RNA (dsRNA) to prevent the dsRNA-dependent activation of 2’-5’ oligo(A) synthetase,
and the subsequent activation of RNase L; can block RIG-I, MDA5 and TLR-3,7 & 8
Prevention and control
Antiviral drugs:
M1: Adamantanes
NA: Oseltamivir (Tamiflu) and
Zanamivir, Peramivir
CS-8958 (NA)  Phase II
T-705 (Nucleoside analogue)
 Phase III
mAb against HA
Vaccines: produced in allantoid fluid of
embryonated chicken/cell culture
Pandemrix (GSK) (dead vaccine)
Focetria (Novartis) (dead vaccine)
Celvapan (Baxter) (cell culture)
Celtura (Behring) (cell culture)
Live attenuated viruses yield higher
humoral and cellular immune
responses
Thank you for your attention!
“History” of the virus