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.

A Review of the Current Status of Clinical Management of COVID-19 in the Elderly

“…Mitochondria are called the “power house” of cells because of their important role in cell respiration and ATP synthesis [ 27 ]. The mitochondrial DNA (mtDNA) genome is an independent genetic system that provides energy by regulating respiration [ 28 ].…”

Nicotinamide pathways as the root cause of sepsis – an evolutionary perspective on macrophage energetic shifts

“…All rights reserved [19,33]. Sensing of double-stranded RNA is known to trigger conserved mitochondrial response pathways [47][48][49]. We hypothesize that mitochondrial response to double-stranded RNA precipitates an acute cellular NAD insufficiency.…”

Type I and III IFN-mediated antiviral actions counteracted by SARS-CoV-2 proteins and host inherited factors

“…As depicted in Fig. 1 , a rapid IFN-I production is induced into the cell once the pattern recognition receptors (PRRs) sense pathogen-associated molecular patterns (PAMPs) such as viral nucleic acids (RNA from SARS-CoV-2), triggering a range of signaling cascades and subsequent gene activation [ 9 ]. As mentioned before, IFN-I is produced and released acting in both autocrine and paracrine ways, and generates an antiviral state supported by the rapid expression of ISGs [ 2 ].…”

“…The IFN-production process starts with an early event in the cytoplasm when cellular PRRs -including retinoic acid-inducible gene 1 (RIG-I), melanoma differentiation-associated gene 5 (MDA5), and the still enigmatic laboratory of genetics and physiology-2 (LGP2) along with the cooperation of MDA5, sense viral RNA. Upon PAMP (viral RNA)-PPRs (RIG-I/MDA-/LGP-2) interaction, sensors are activated and interact with the mitochondrial antiviral signaling protein (MAVS), a downstream adaptor, which promote its activation [ 9 , 12 ].…”