STING mediates the
type I interferon production in response to intracellular DNA and a variety of intracellular pathogens, including
viruses,
intracellular bacteria and
intracellular parasites. Upon infection, STING from infected cells can sense the presence of
nucleic acids from intracellular pathogens, and then induce
interferon β and more than 10 forms of
interferon α production.
Type I interferon produced by infected cells can find and bind to
Interferon-alpha/beta receptor of nearby cells to protect cells from local infection.
Antiviral immunity STING elicits powerful
type I interferon immunity against viral infection. After
viral entry, viral
nucleic acids are present in the cytosol of infected cells. Several DNA sensors, such as
DAI,
RNA polymerase III,
IFI16,
DDX41 and
cGAS, can detect foreign
nucleic acids. After recognizing viral DNA, DNA sensors initiate the downstream signaling pathways by activating STING-mediated interferon response.
Adenovirus,
herpes simplex virus, HSV-1 and HSV-2, as well as the
negative-stranded RNA virus,
vesicular stomatitis virus (VSV), have been shown to be able to activate a STING-dependent
innate immune response. Point mutation of
serine-358 dampens STING-IFN activation in bats and is suggested to give bats their ability to serve as reservoir hosts.
Against intracellular bacteria Intracellular bacteria,
Listeria monocytogenes, have been shown to stimulate host immune response through STING. STING may play an important role in the production of
MCP-1 and
CCL7 chemokines. STING deficient monocytes are intrinsically defective in migration to the liver during
Listeria monocytogenes infection. In this way, STING protects host from
Listeria monocytogenes infection by regulating
monocyte migration. The activation of STING is likely to be mediated by
cyclic di-AMP secreted by intracellular bacteria.
Other STING may be an important molecule for protective immunity against infectious organisms. For example, animals that cannot express STING are more susceptible to infection from
VSV,
HSV-1 and
Listeria monocytogenes, suggesting its potential correlation to human infectious diseases.
Role in host immunity Although
type I IFN is absolutely critical for resistance to viruses, there is growing literature about the negative role of
type I interferon in host immunity mediated by STING. AT-rich stem-loop DNA motif in the
Plasmodium falciparum and
Plasmodium berghei genome and extracellular DNA from
Mycobacterium tuberculosis have been shown to activate
type I interferon through STING. Perforation of the phagosome membrane mediated by
ESX1 secretion system allows extracellular mycobacterial DNA to access host cytosolic DNA sensors, thus inducing the production of
type I interferon in macrophages. High
type I interferon signature leads to the
M. tuberculosis pathogenesis and prolonged infection. STING-TBK1-IRF mediated
type I interferon response is central to the pathogenesis of experimental cerebral malaria in laboratory animals infected with
Plasmodium berghei. Laboratory mice deficient in
type I interferon response are resistant to experimental cerebral malaria. == STING signaling mechanisms ==