Recently there have been marked advances in determining the mechanisms by which innate immune cells respond to intracellular pathogens. The use of in vitro studies has resulted in the identification of mitochondrial antiviral signalling protein (MAVS; also known as IPS1, CARDIF and VISA) as an important adaptor protein that can link intracellular pathogen recognition with activation of the transcription factors nuclear factor-κB (NF-κB) and interferon-regulatory factor 3 (IRF3). New research shows a specific and essential role for MAVS in vivo in the innate immune response to viruses.

To elucidate the role of MAVS in vivo, Sun et al. generated Mavs−/− mice by homologous recombination. Mavs−/− and Mavs+/− mice infected with vesicular stomatitis virus (VSV) (an RNA virus) died within 4 days of infection, whereas most wild-type mice survived. This indicates an important role for MAVS in protection against VSV-induced mortality. In addition, mouse embryonic fibroblasts (MEFs) from Mavs−/− mice were more permissive to VSV replication compared with MEFs from wild-type mice.

Infection of MEFs, macrophages and conventional dendritic cells from Mavs−/− mice with Sendai virus (SEV) (an RNA virus) did not activate either NF-κB or IRF3, or induce type I interferons (IFNs). However, induction of type I IFNs was intact in Mavs−/− mice in response to Toll-like receptor (TLR) ligands, such as lipopolysaccharide and the synthetic double-stranded RNA analogue poly I:C (polyinosinic-polycytidylic acid). Because activation of NF-κB and IRF3 by viruses involves at least two signalling pathways — the TLR-signalling pathway and a pathway that uses cytoplasmic receptors, such as retinoic-acid-inducible gene I (RIG-I) and melanoma-differentiation-associated gene 5 (MDA5) — these data indicate that MAVS is required for antiviral immunity but not for TLR-induced immune responses.

Interestingly, induction of type I IFNs by transfection of MEFs with poly I:C, which introduces the RNA analogue into the cytosol, was dependent on MAVS. In addition, MAVS is required for type I IFN induction by poly I:C in vivo. A recent study has shown that IFNβ production induced by SEV and VSV requires RIG-I, whereas transfected poly I:C induces IFNβ production through MDA5. Therefore, it would seem that MAVS functions downstream of both of these receptors and might function as a convergence point for these signalling pathways.

Recent studies have also indicated that MAVS might be involved in the induction of type I IFNs in response to cytosolic B-form DNA and Listeria monocytogenes. However, induction of type I IFNs by macrophages transfected with B-form DNA or infected with L. monocytogenes was similar in Mavs−/− mice and wild-type mice. Similarly, a recent study published in FEBS Letters also showed, using siRNA (small interfering RNA)- mediated knockdown of Mavs, that loss of MAVS did not affect induction of type I IFNs by L. monocytogenes.

Therefore, MAVS is not an adaptor protein for all cytoplasmic pathogen sensors, but does have a specific and essential role in antiviral immunity independent of TLR signalling.