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A lack of hepatocyte STING favours HBV infection
HBV selectively infects hepatocytes
and can cause chronic hepatitis
that might lead to hepatocellular
carcinoma. Knowledge of how chronic
HBV infections are established was
previously limited. Research published
in Hepatology now provides insight into
this process, showing that hepatocytes
lack the ability to recognize foreign HBV
DNA, thereby hampering the innate
immune response.
The recognition of foreign DNA
(such as some viruses) is performed by
intracellular DNA-sensing proteins,
which then activate the stimulator of
interferon genes (STING) — ultimately
leading to the expression of interferons
that contribute to the immune response
towards viral infections. However,
how HBV has adapted to specifically
replicate in hepatocytes and which
immune mechanisms might be involved
in controlling the virus was not understood.
“[My] laboratory has experience in
innate immunology to DNA viruses,
mainly with a focus on herpesviruses,”
explains senior author Søren Paludan. As
STING had previously shown important
roles in controlling herpes and other
DNA viruses, and given that an earlier
immune response to HBV infection
might lead to a more effective clearance
of the virus by the host, the investigators
chose to examine the role of the STING
pathway in controlling HBV infections.
Using an in vivo mouse model of
HBV infection, in which the virus was
encoded in an adenoviral vector,
the most important finding was that
hepatocytes do not express STING and
do not induce antiviral interferons in
response to foreign DNA. However, when
STING was specifically introduced into
hepatocytes, DNA-sensing was enabled
and led to restricted HBV replication.
Furthermore, the researchers found
that primary human hepatocytes also
lacked detectable levels of STING and
had reduced responsiveness to foreign
DNA, validating the results from the
mouse model.
“It has been reported that hepatocytes
do not respond with strong interferon
responses to HBV infection. We now
provide the mechanism underlying
the phenomenon,” concludes Paludan,
which might also explain why HBV has
adapted to replicate in hepatocytes.
In terms of future work, he believes
two options are worthwhile: “One is
to understand why hepatocytes have
evolved to not respond immunologically
to foreign DNA. Another is to explore
how other cell types in the liver (resident
and infiltrating) sense HBV, and how the
virus seeks to evade these responses.”
Iain Dickson
ORIGINAL ARTICLE Thomsen, M. K. et al. Lack
of immunological DNA sensing in hepatocytes
facilitates hepatitis B virus infection. Hepatology
http://dx.doi.org/10.1002/hep.28685 (2016)
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发表于 2016-7-27 14:29