Sexual HealthUSC Researchers Uncover Mechanism That Allows Influenza Virus To Evade The BodyÂðs Immune Response
California (USC) have identified a
critical molecular mechanism that allows
the influenza virus to evade the bodyÂðs immune response system.
The study will be published in the May 21 issue of the journal Cell Host &
Microbe.
ÂöWe have found a mechanism that the influenza virus uses to inhibit the
bodyÂðs immune response that emphasizes the vital role of a specific
protein
in defending against viruses," says Jae Jung, Ph.D., professor and chair
of
the Department of Molecular Microbiology and Immunology at the Keck School
of Medicine of USC, and the principal investigator of the study. ÂöAlong
with
our previous studies (Nature 2007 and PNAS 2008), this finding could
provide
researchers with the information needed to create a new drug to enhance
immunity and block influenza virus infection and replication."
Several specific intracellular receptors are responsible for detecting the
virus and activating the bodyÂðs defensive mechanisms. When a virus" RNA
enters the intracellular fluid, a receptor known as
retinoic-acid-inducible
gene I (RIG-I) detects it and triggers a response that limits virus
replication and calls the bodyÂðs defenses into action. RIG-I acts as the
sensor and security force against attacks, Jung explains. Then, a protein
known as TRIM25 helps RIG-I transmit an alarm signal, which ultimately
floods the cell and surrounding tissue with antiviral interferons.
The influenza virus is highly infectious and poses a serious and sometimes
deadly health risk because of its ability to mutate into new strains and
spread quickly during seasonal epidemics, as seen in the recent outbreak
of
the H1N1 swine flu virus, Jung says.
Researchers have long been working to understand how respiratory influenza
is able to slip past the bodyÂðs innate immune responses. They have found
that the influenza A virus has evolved by incorporating Non-structural
protein 1 (NS1) into its genome to escape the RIG-I alarm system.
This process is one reason why the virus kills an average of 36,000 people
every year. In fact, the 1918 "Spanish flu" pandemic influenza virus,
which
killed over 40 million people worldwide, muted the RIG-I response and
interferon activity much more efficiently than contemporary flu viruses,
Jung notes.
"Despite the conceptual linking of RIG-I with flu virus NS1, however, the
precise mechanism has been unclear for a long period of time," he says.
By studying the immune responses of animal models, researchers found that
the influenza A virus NS1 attacks TRIM25, inhibiting its ability to assist
RIG-I trigger the alarm system against the virus. Remarkably, a flu virus
carrying an NS1 mutant defective for this activity loses its virulence in
animal models, Jung says.
"We now know that the influenza virus escapes recognition via the
interaction of NS1 with TRIM25, which inhibits the bodyÂðs immune
response,"
he says. ÂöUnderstanding this host-virus interaction is an essential step
in
developing safe and effective drugs to target the influenza virus.²
This work was performed in collaboration with Adolfo Garcia-Sastre, Ph.D.,
at Mt. Sinai Medical School and the final doctorate experiments of
Michaela
Gack, Ph.D., who is the paperÂðs first author and currently a faculty
member
at Harvard Medical School.
"Influenza A Virus NS1 Targets the Ubiquitin Ligase TRIM25 to Evade Recognition by the Host VIral RNA Sensor RIG-I."
Michaela Ulrike Gack, Randy Allen Albrecht, Tomohiko Urano, Kyung-Soo Inn, I-Chueh Huang, Elena Carnero, Michael Farzan, Satoshi Inoue, Jae Ung Jung*, Adolfo Garica-Sastre*.
Cell Host & Microbe. DOI: 10.1016/j.chom.2009.04.006.
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