Picking up a Fight: Fine Tuning Mitochondrial Innate Immune Defenses Against RNA Viruses

Abstract

As the world faces the challenge of the COVID-19 pandemic, it has become an urgent need of the hour to understand how our immune system sense and respond to RNA viruses that are often life-threatening. While most vaccine strategies for these viruses are developed around a programmed antibody response, relatively less attention is paid to our innate immune defenses that can determine the outcome of a viral infection via the production of antiviral cytokines like Type I Interferons. However, it is becoming increasingly evident that the "cytokine storm" induced by aberrant activation of the innate immune response against a viral pathogen may sometimes offer replicative advantage to the virus thus promoting disease pathogenesis. Thus, it is important to fine tune the responses of the innate immune network that can be achieved via a deeper insight into the candidate molecules involved. Several pattern recognition receptors (PRRs) like the Toll like receptors (TLRs), NOD-like receptors (NLRs), and the retinoic acid inducible gene-I (RIG-I) like receptors (RLRs) recognize cytosolic RNA viruses and mount an antiviral immune response. RLRs recognize invasive viral RNA produced during infection and mediate the induction of Type I Interferons via the mitochondrial antiviral signaling (MAVS) molecule. It is an intriguing fact that the mitochondrion, one of the cell's most vital organelle, has evolved to be a central hub in this antiviral defense. However, cytokine responses and interferon signaling via MAVS signalosome at the mitochondria must be tightly regulated to prevent overactivation of the immune responses. This review focuses on our current understanding of the innate immune sensing of the host mitochondria by the RLR-MAVS signalosome and its specificity against some of the emerging/re-emerging RNA viruses like Ebola, Zika, Influenza A virus (IAV), and severe acute respiratory syndrome-coronavirus (SARS-CoV) that may expand our understanding for novel pharmaceutical development.

Keywords: RNA virus; cytokine storm; innate immunity; mitochondria; mitochondrial antiviral signaling; retinoic acid inducible gene-I.

Figure 1

Overview of antiviral response at the mitochondrial antiviral signaling (MAVS) signalosome. Enveloped RNA virus can enter the cell via membrane fusion or endocytosis (Step 1). Following entry, the “ppp” group at the 5' end of the viral genome is recognized by the core domain of the retinoic acid inducible gene-I (RIG-I) like receptor (RLR) helicase RIG-I (Steps 2, 3, and 4). The activated RIG-I molecule binds to MAVS via caspase activation and recruitment domain (CARD)-CARD interaction at the N-terminal domain of MAVS leading to the formation of the “MAVS Signalosome” (Step 5). Two different signals can emanate from this signalosome, the first one leads to the activation of interferon regulatory factor 3/7 (IRF3/7), transcriptional activation of Type I Interferons and stimulation of interferon stimulated genes (ISGs; Steps 6 and 7) leading to a protective antiviral immunity. The second signal phosphorylates IκB via IKK and releases NFκB that translocates to the nucleus and results in the transcriptional activation of pro-inflammatory cytokines (Steps 8, 9, and 10). Events at this step needs to be finely tuned as hyperstimulation of the responses may lead to a “cytokine storm” that aids in viral persistence within the infected cells. To fine tune the hyperstimualtion of the MAVS-signalosome NLRX1 antagonizes IFN signaling by binding to MAVS that may act as a brake on the hyperactive immune response. COX 5B suppress ROS production via suppressing MAVS aggregation and the proteasomal subunit PSMA-7 inhibits MAVS by enhancing its proteasomal degradation. Further, PCBP1, 2 and Smurf2 similarly degrade MAVS via K48 linked polyubiquitination and inhibit Type I Interferon production (Step 11).