The MAVS Immune Recognition Pathway in Viral Infection and Sepsis.

Sharma, Arjun; Kontodimas, Konstantinos; Bosmann, Markus

SIGNIFICANCE It is estimated that close to 50 million cases of sepsis result in over 11 million annual fatalities worldwide. The pathognomonic feature of sepsis is a dysregulated inflammatory response arising from viral, bacterial, or fungal infections. Immune recognition of pathogen-associated molecular patterns (PAMPs) is a hallmark of the host immune defense to combat microbes and to prevent the progression to sepsis. MAVS is a ubiquitous adaptor protein located at the outer mitochondrial membrane, which is activated by the cytosolic pattern recognition receptors (PRRs), RIG-I and MDA5, following binding of viral RNA agonists. Recent Advances: Substantial progress has been made in deciphering the activation of the MAVS pathway with its interacting proteins, down-stream signaling events (IRFs, NFκB) and context dependent type I/III interferon response. CRITICAL ISSUES In the evolutionary race between pathogens and the host, viruses have developed immune evasion strategies for cleavage, degradation, or blockade of proteins in the MAVS pathway. For example, SARS-CoV-2 M protein and ORF9b protein antagonize MAVS signaling and a protective type I interferon response. FUTURE DIRECTIONS The role of MAVS as a sensor for non-viral pathogens, host cell injury and metabolic perturbations awaits better characterization in the future. New technical advances in multi-dimensional single-cell analysis and single-molecule methods will accelerate the rate of new discoveries. The ultimate goal is to manipulate MAVS activities in the form of immune-modulatory therapies to combat infections and sepsis.