Activation of the DNA-sensing STING axis by RNA viruses plays a role in antiviral
response through mechanisms that remain poorly understood. Here, we show that the
STING pathway regulates Nipah virus (NiV) replication in vivo in mice. Moreover, we
demonstrate that following both NiV and measles virus (MeV) infection, IFN gamma-inducible
protein 16 (IFI16), an alternative DNA sensor in addition to cGAS, induces the activation
of STING, leading to the phosphorylation of NF-kappa B p65 and the production of IFN
beta and interleukin 6. Finally, we found that paramyxovirus-induced syncytia formation
is responsible for loss of mitochondrial membrane potential and leakage of mitochondrial
DNA in the cytoplasm, the latter of which is further detected by both cGAS and IFI16.
These results contribute to improve our understanding about NiV and MeV immunopathogenesis
and provide potential paths for alternative therapeutic strategies. Viruses belonging
to Paramyxoviridae family, such as Nipah and measles virus, represent a threat for
public health due to recurring zoonotic spillover events or increasing epidemic episodes,
respectively. In our previous work, we demonstrated the involvement of the DNA-sensing
cGAS/STING axis of innate immunity in the control of Nipah and measles virus infections.
However, the cellular and molecular mechanisms of STING activation by these RNA viruses
remained obscure. Here, we show first that STING regulates Nipah virus infection in
vivo and is activated both canonically and non-canonically by cGAS and IFI16 DNA sensors;
respectively, during Paramyxovirus infections. Moreover, we describe that syncytia
formation caused by both Nipah and measles viruses perpetrate mitochondrial perturbation,
thus responsible for the leakage of DNA. Globally, we linked the events demonstrating
that viral-induced syncytia formation triggers the leakage of mitochondrial DNA in
the cytoplasm and its further sensing by cGAS and IFI16.
