Of course you know, Mr.

Bell, that the flu you and everyone else

has caught is completely harmless.
Host range of influenza A viruses. Wild water birds represent the
natural reservoir of influenza A viruses, from which they can be
transmitted to a wide variety of other hosts, including horses, cats, dogs,
whales, seals, wild flying birds, chicken, pigs, and humans. Only
recently, influenza A virus has also been detected in bats, although the
origin is unclear. J. Virol. July 2013 vol. 87 no. 13 7200-7209
The role of A20 (TNF alpha-induced protein 3 or TNFAIP3) in club cells (bronchiolar
exocrine cells) of the bronchial epithelium in their response to influenza A virus (IAV).
Using airway epithelial cell-specific A20 knockout (A20AEC-KO) mice, we show that A20 in
club cells critically controls innate immune responses upon TNF or double stranded RNA
stimulation. Surprisingly, A20AEC-KO mice are better protected against IAV challenge than
their wild type littermates. This phenotype is not due to decreased viral replication.
Instead host innate and adaptive immune responses and lung damage are reduced in
A20AEC-KO mice. (A) Survival of A20AEC-KO (n = 30) or wild type littermates (A20WT, n =
28) infected with a lethal dose of IAV. (B) Weight loss of A20AEC-KO (n = 6) or wild type
littermates (A20WT, n = 8) monitored until 14 days post infection (days p.i.) upon
infection with a sublethal dose of IAV. (D) Total protein concentration in
bronchoalveolar washing fluid of A20AEC-KO and control A20AEC-WT littermates at different
time points after sublethal IAV infection. *p < 0.05; ***p<0.001.
PLOS|Pathogen . January 27, 2016. DOI: 10.1371/journal.ppat.1005410
Diagrammatic Representation of an Influenza A Virus
The two major surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA), along with
small numbers of the matrix 2 (M2) ion channel protein, are embedded in a lipid bilayer. The
matrix 1 (M1) protein underlies the envelope and interacts with the surface proteins and also
with the ribonucleoproteins (RNPs). RNPs consist of the eight negative-stranded RNA
segments and nucleoprotein (NP) and the polymerase complex heterotrimer (PB2, PB1, and
PA). The nuclear export protein (NEP, or nonstructural protein 2, NS2) is contained within the
virion, but the nonstructural protein 1 (NS1) is not. Cell Host & Microbe 7: 440-451, 2010
•PA-X is also synthesized from the PA segment. PA-X causes selective degradation of host
mRNAs by discriminating some aspect of Pol II-dependent RNA biogenesis in the nucleus.
•PLOS|Pathogen . January 27, 2016. DOI: 10.1371/journal.ppat.1005410
 CODIFICACION DEL GENOMA DE INFLUENZA
SEGMENT POLIPEPTIDO FUNCION
O
1 PB2 PARTE DEL COMPLEJO TRANSCRIPTASA*
2 PB1 PARTE DEL COMPLEJO TRANSCRIPTASA
3 PA PARTE DEL COMPLEJO TRANSCRIPTASA*
4 HA HEMAGLUTININA
5 NP NUCLEOCAPSIDE*
6 NA NEURAMINIDASA
7 M1 PROTEINA MATRIZ*
7 M2 FORMACION DE CANALES IONICOS (H+)
8 NS1 INHIBE SINTESIS DE IFN E IMPIDE EL
PROCESAMIENTO DE LOS PRE-mRNAs
CELULARES
8 NS2 ROL EN EXPORTAR DEL NUCLEO LAS
RIBONUCLEOPROTEINA

* Importantes para el empaquetamiento del vRNA. J. Virol. July 2012 86:7043-7051

 VIRUS INFLUENZA X 10,400 VIRUS INFLUENZA X 300,000

MICROBIOLOGY, DAVIS.
Influenza viruses inhabit a wide range of
host environments using a limited
repertoire of protein components. Unlike
viruses with stereotyped shapes,
influenza produces virions with
significant morphological variability
even within clonal populations. We
address these questions by developing a
strain of influenza A virus amenable to
rapid compositional characterization
through quantitative, site-specific labeling
of viral proteins. Using this strain, we find
that influenza A produces virions with
broad variations in size and
composition from even single infected
cells. This phenotypic variability
contributes to virus survival during
environmental challenges, including
exposure to antivirals.
Cell Volume 176, ISSUE 1, P281-
294.e19, January 10, 2019
FIG. 4 Influenza Virus Life Cycle and Host Factors
Upon infection, influenza virus is internalized by receptor-mediated endocytosis.
After membrane fusion between the virus envelope and the endosome, the viral
ribonucleoprotein (vRNP) complex is released into the cytoplasm and transported
into the nucleus by the active import machinery of the host cell nuclear pore
complex.
Replication and transcription of the viral genome take place in the nucleus, and
many host factors are believed to be involved in this process. Newly synthesized
viral RNA associates with NP and forms the viral ribonucleoprotein (vRNP)
complex together with viral polymerase proteins, which is then transported from the
nucleus to the cytoplasm. HA and NA are processed posttranslationally during their
transport from the ER to the Golgi apparatus. During assembly and budding, virion
components are transported to the assembly site, the lipid raft microdomains at the
apical plasma membrane of polarized epithelial cells. Progeny viruses then bud
from the cells.
The light-orange rectangles indicate individual steps of the influenza virus life
cycle. The light-blue rectangles indicate host cellular processes that may be
involved in the virus life cycle. Red circles indicate host factors identified in
the screens discussed here, and yellow circles indicate host factors identified
in other previous studies
CELL HOST AND MICROBE 7(6): 427-439, 2010
1) ESTORNUDO VIOLENTO 2) ESTORNUDO DE RESFRIADO
3) ESTORNUDO SOFOCADO 4) ESTORNUDO - MASCARA
5) TOS 6) ENUNCIAR LA “ F ”
 SUBTIPOS DE VIRUS
INFLUENZA A.
H: HEMAGLUTININA
N: NEURAMINIDASA.
La secuencia de amino
ácidos entre los
subtipos difiere en mas
del 30%

Recientemente en China
H7N9. 44 de 134 muertos
IMMUNOLOGY, ROITT
MICROBE 2 (10): 489-497, 2007
FIG. 1. Comparison of lectin staining in duck intestine (colon) and pig
trachea. The M. amurensis lectin specific for NeuAc2,3Gal (designated
2,3; detected with fluorescein isothiocyanate-labeled anti-digoxigenin
(DIG) antibody) bound to both duck intestinal epithelium and pig tracheal
epithelium, whereas S. nigra lectin specific for NeuAc2,6Gal (designated
2,6; detected with rhodamine-labeled anti-DIG antibody) bound only to
the latter. Blue staining in the connective tissue represents
autofluorescence. Magnification, ×300. J. Virology 72: 7367-7373, 1998

J. Virology 71: 7367-7373, 1998;
J.Virology 75: 5410-5415, 2001
FIG. 5. Models for the generation of
pandemic influenza virus strains in pigs.
(A) In the classical genetic reassortment
model, avian and human viruses bind,
respectively, to NeuAc2,3Gal and
NeuAc2,6Gal (2,3 and 2,6) linkages in pig
trachea, setting the stage for the emergence
of a reassortant that infects a large fraction
of the human population. The segments in
the center of each particle represent the
viral genome. The reassortant HA gene
(black) is derived from an avian virus. (B)
In this adaptation model, avian viruses
acquire the ability to replicate efficiently in
humans during adaptation to the
NeuAc2,6Gal linkage in pigs. This change
is mediated by a mutation in the HA gene.
(C) Alternatively, an avian influenza virus
is transmitted directly to humans where it
reassorts with a human virus, or (D) it
acquires the ability to recognize the
NeuAc2,6Gal linkage after direct
introduction from birds, leading to efficient
replication in humans.
Influenza A Virus Reassortment Is Limited by Compartmentalization of
Infection In Vivo. In ferrets, while coinoculation by an intranasal route yielded
abundant reassortment, spatially distinct inoculation resulted in anatomical
compartmentalization of infection, which in turn strongly limited reassortment.
J. Virol. March 2018 vol. 92 no. 5 e02063-17
Nature 437, 889-893 (6 October 2005)
Characterization of the 1918 influenza virus polymerase genes
Jeffery K. Taubenberger1, Ann H. Reid1,2, Raina M. Lourens1,2, Ruixue Wang1,
Guozhong Jin1 and Thomas G. Fanning1
The influenza A viral heterotrimeric polymerase complex (PA, PB1, PB2) is known to be
involved in many aspects of viral replication and to interact with host factors, thereby
having a role in host specificity. The polymerase protein sequences from the 1918
human influenza virus differ from avian consensus sequences at only a small number of
amino acids, consistent with the hypothesis that they were derived from an avian source
shortly before the pandemic.

Here we present sequence and phylogenetic analyses of the complete genome of the
1918 influenza virus, and propose that the 1918 virus was not a reassortant virus (like
those of the 1957 and 1968 pandemics), but more likely an entirely avian-like virus
that adapted to humans. A total of ten amino acid changes in the polymerase
proteins consistently differentiate the 1918 and subsequent human influenza virus
sequences from avian virus sequences. Notably, a number of the same changes have
been found in recently circulating, highly pathogenic H5N1 viruses that have caused
illness and death in humans and are feared to be the precursors of a new influenza
pandemic. The sequence changes identified here may be important in the adaptation of
influenza viruses to humans.
MICROBE 1(12):559-565, 2006
Microbe volume 8 (12): 499-505, 2013
Known as integrated livestock-fish farming, the technique involves transferring the wastes
from raising pigs, ducks or chickens directly to fish farms. At the right dosage, the nutrients
in the manure give an enormous boost to the growth of plankton in the ponds, which are the
main food of fish such as carp and tilapia. BirdLife International is now calling for an
investigation into the possibility that thousands of manure-fed ponds across Asia may be the
means by which the new potentially deadly strain of avian influenza, H5N1, is being
Spread of H5N1 influenza in Eurasia and absence (to date) in the Americas and
Australia. Three waves of H5N1 spread in Eurasia: First in mid 2003 – early 2004 in
Eastern Asia; second in mid 2004–late 2004 with resurgence in Eastern Asia and
China; third in December 2004/2006 spread through central Asia to Africa, Europe, and
India (for details see (www.who.int/influenza). MICROBE 1(12): 559-565, 2006
Lineage of the 2009 Swine Influenza Virus. Influenza A viruses have a segmented
negative-sense RNA genome that encodes up to 11 proteins including the surface
glycoproteins hemagglutinin (HA) and neuraminidase (NA) and the virulence factor NS1
(host interferon antagonist). The 2009 H1N1 swine virus is a triple reassortant.
Cell 137, 983-985, 2009.
Comparación entre el Influenza Aviar y Porcino
2009 Porcino H1N1 1997 Aviar H5N1

Transmisión entre humanos SI NO

Causa enfermedad en humanos SI (LEVE) SI (SEVERA)

Grado de inmunidad en la población PROBABLE NO

Marcadores moleculares de NO PB1-F2.

patogenicidad conocidos Lugar de corte polibásico
en la hemaglutinina

PB1-F2 es expresada de un segundo “open reading frame” (+1) del gen de PB1. La
traducción de esta nueva proteína empieza en el nucleotido 120 del segmento genomico
para PB1. La patogenicidad debida a mutaciones a nivel del PB1-F2 (posición 66) da
lugar a un mayor nivel de virus y citokinas en el pulmón y favorece las
superinfecciones por bacterias Gram -..
PLoS Pathology 3, 1414-1421, 2007; Cell 137, 983-985, 2009; J. Virol. September 2012
86:9035-9043.
In the 4 weeks following initial case reports in the US, 41 countries reported swine
flu infections, with Mexico and the US bearing the majority of disease burden. A
total of 11,034 cases and 85 deaths were reported worldwide during that time. By
comparison, 80,000 children die from malaria and more than twice that number die
of diarrheal diseases worldwide in any 4 week period. On a scale of global health
crises, the current H1N1 swine influenza outbreak would seem to rank low on the
list. Why, then, has this outbreak caused such alarm?

Fear around influenza viruses stems from the occurrence of three major
pandemics over the last century. Indeed, influenza viruses have the potential to
be among the deadliest of all known pathogens.
In an average 4 week period during the 1918 Spanish flu pandemic caused by
an H1N1 strain, 4,000,000 people died from influenza and secondary bacterial
infections worldwide. In a 4 week period, there were 150,000 deaths worldwide
during the 1957 Asian flu pandemic caused by an H2N2 strain, and 80,000
deaths worldwide during the 1968 Hong Kong flu pandemic caused by an H3N2
strain.
The history of influenza disease reveals a simple truth: all pandemic strains are
not created equal.
 MOLECULAR MARKERS FOR PATOGENICITY OF INFLUENZA VIRUS
First, presence of a coding sequence for PB1-F2 which is not present in all human
influenza viruses; but, it is consistently present in viruses known to be of increased
virulence in humans, including the viruses that caused the 1918, 1957, and 1968
pandemics.The protein directly permeabilizes mitochondria, releasing Cyt c.
A second marker of virulence that can be assessed by sequences alone is the
degree of identity between the viral hemagglutinin molecules of the new strain and
those of other human viruses. Low identity indicates antigenically distinct
hemagglutinin structures, suggesting that transmission from human to human
will not be blunted by a degree of herd immunity resulting from exposure to
similar viruses.
A third molecular marker known to be relevant in the pathogenicity of avian
influenza viruses is the polybasic cleavage site, a protease site in the viral
hemagglutinin that enables an expanded array of host proteases to activate the
hemagglutinin molecule, enabling virus fusion with a host cell.
Cell 137, 983-985, 2009
PB1-F2, helps H5N1 bird influenza viruses to overcome a human restriction
factor of the viral polymerase complex HAX-1 through binding to this molecule.
Interestingly, we found that human influenza A virus polymerase complexes are
already adapted to HAX-1 and do not require this function of PB1-F2.
Journal of Virology, June 2018 92:11 17 e00425-18; doi:10.1128/JVI.00425-18
Plasminogen activator
inhibitor (PAI-1) an ISG,
blocks surface
glycoprotein maturation of
influenza A virus by
targeting extracellular
airway proteases, inhibits
virus glycoprotein
cleavage, thereby
reducing infectivity of
progeny viruses and thus
reducing virus
spread in the airways and
revealing that
the innate immune
system, driven by type
I IFN, uses modulation of
the extracellular
environment to inhibit
viruses.
CELL Volume 160, Issue
4, p631–643, 12 February
2015
VIRAL FACTORS IMPORTANT IN HOST ADAPTATION
- The hemagglutinin (HA) is one of the key factors which determines the host range
of influenza A viruses. Adaptation from avian to human hosts has been shown to
target two main properties of HA. A switch in receptor specificity from avian (α-
2,3-linked) to human (α-2,6-linked) sialic acids as well as stabilization of the stalk
region to allow endosomal membrane fusion at the optimal pH is crucial for efficient
transmission between mammals and host adaptation.

- As an antagonist of the alpha/beta interferon (IFN-α/β)-mediated host immune

response, the NS1 protein plays a critical role during zoonotic transmission.
- Additionally, the viral nucleoprotein NP mediates escape from restriction by the
interferon-stimulated human MxA protein.

- Polymerase activity of various avian influenza A viruses was shown to be

strongly impaired in mammalian cells, restricting replication of avian viruses in
mammals. Low polymerase activity results not only in fewer copies of vRNA for
packaging into new viral particles but also in reduced mRNA synthesis and
expression of viral proteins. Perhaps most important for zoonotic viruses, low
polymerase activity results in fewer opportunities for the virus to create new
variant genomes containing potentially beneficial mutations. For this reason,
mutations in the polymerase subunits that increase transcriptional activity
are fundamental for avian influenza viruses to adapt to the human host.

J. Virol. July 2013 vol. 87 no. 13 7200-7209

Antibodies to the hemagglutinin (HA) and neuraminidase (NA) glycoproteins are the major
mediators of protection against influenza virus infection. Here, we report that current
influenza vaccines poorly display key NA epitopes and rarely induce NA-reactive B
cells. Conversely, influenza virus infection induces NA-reactive B. NA-reactive antibodies
display broad binding activity spanning the entire history of influenza A virus circulation in
humans, including the original pandemic strains of both H1N1 and H3N2 subtypes. The
antibodies robustly inhibit the enzymatic activity of NA, including oseltamivir-resistant
variants, and provide robust prophylactic protection, including against avian H5N1 viruses,
in vivo. These findings strongly suggest that influenza vaccines should be optimized to
improve targeting of NA for durable and broad protection against divergent influenza
strains. CELL Volume 173, Issue 2, p417–429.e10, 5 April 2018. DOI: https://
doi.org/10.1016/j.cell.2018.03.030
 VIDEO - CICLO DE MULTIPLICACION

https://www.youtube.com/watch?v=YSgkoldBNkI
ADICIONALES