download report - Istituto Pasteur

P a r t i c i p a n t s :
Lucia Nencioni, Claudio Passariello, researchers; Rossella
Sgarbanti, post-doc fellow; Donatella Amatore, Ignacio
Celestino, Paola Checconi, PhD students; Felicia D’Auria,
Costantino Pichezzi, technicians.
C o l l a b o r a t i o n s :
Dipartimento di Biologia, Università di Roma Tor Vergata
(Prof. M. R. Ciriolo); Istituto di Biochimica “Giorgio Fornaini”,
Università di Urbino (Prof. M. Magnani); Institute of Molecular
Virology, University of Monaco, Germany (Prof. S. Ludwig);
Dipartimento di Patologia e Medicina di Laboratorio,
Università di Parma (Prof. W. Magliani).
Report of activity
Influenza A viruses continue to represent a severe
threat worldwide, causing large epidemics and pandemics
responsible for thousands of deaths and hospitalization
every year. Recently, there has been an
enormous increase in the circulation of influenza
viruses that are resistant to licensed anti-influenza
drugs directed towards viral proteins, namely neuroaminidase
(NA) and matrix (M1).
Targeting antiviral drug discovery to host cell factors
that are essential for viral replication instead of
against viral structures would decrease the likelihood
of acquiring drug resistance and increase the
effectiveness towards different virus types and
strains. Several intracellular signaling pathways,
(MAP kinases, NFkB, ER oxidoreductases), that are
involved in viral replication, are finely regulated by
small changes in intracellular redox state. An imbalance
in intracellular redox state has been extensively
described as occurring in several viral infections,
including influenza.
The virus induced pro-oxidant state may then contribute,
through different mechanisms, both to
influenza virus replication and to the pathogenesis of
virus-induced diseases.
Pathogenetic mechanisms of microbially associated diseases - AREA 2
Redox mediated mechanisms involved in the influenza virus
replication and in the pathogenesis of influenza
associated diseases
Principal investigator: Annateresa Palamara
Professor of Microbiology
Dipartimento di Scienze di Sanità Pubblica “G. Sanarelli”
Tel: (+39) 06 4468622, Fax: (+39) 06 4468625
annateresa.palamara@uniroma1.it
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The scientific activities of our group in 2008 were
aimed at defining the role of important redox regulated
intracellular pathways in the replication of
influenza virus and in the activation of inflammatory
responses. These activities have been organized in
the following main topics: 1) the definition of
p38MAPK role in influenza virus replication and
viral induced apoptosis 2) the study of redox mediated
pathways involved in hemagglutinin maturation
3) the identification of mechanisms involved in the
internalization of Staphylococcus aureus in influenza
virus-infected cells.
Role of p38MAPK in influenza virus
replication and viral induced apoptosis
Our previous reports have shown that various steps
in the influenza A virus life cycle are impaired in
cells that are characterized by high levels of glutathione
(GSH) and the expression of the antiapoptotic
protein Bcl-2. Over this year we have found
that Bcl-2 does not prevent host cells from undergoing
virally triggered apoptosis despite its negative
impact on viral replication. The protein’s
reduced antiapoptotic capacity was related to the
phosphorylation of its threonine 56 and serine 87
residues by virally activated p38MAPK. In contrast,
in Bcl-2-negative cells, which are fully permissive
to viral infection, p38MAPK activation contributed
to the phosphorylation of viral nucleoprotein
that is an essential step for its export from the
nucleus and virus assembly. Consistently, treating
infected cells with p38MAPK inhibitor was able to
strongly decrease vRNP traffic and viral release
from infected cells. Our data suggest that
p38MAPK’s impact on the influenza virus life cycle
and the apoptotic response of host cells to infection
depend on whether or not the cells express Bcl-2,
highlighting the possibility that the virus’ pathological
effects are partly determined by the type of
cell it targets. A paper reporting these results is in
press (Nencioni et al.).