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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.

SUBMITTER: Dutta S

PROVIDER: S-EPMC7487669 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Dutta Sourav S Das Nilanjana N Mukherjee Piyali P

Frontiers in microbiology 20200831

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 <i>via</i> the production of antiviral cytokines like Type I Interferons. However ...[more]

PMID: 32983015

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Project description:The keystone oral pathogen Porphyromonas gingivalis is associated with severe periodontitis. Intriguingly, this bacterium is known to secrete large amounts of an enzyme that converts peptidylarginine into citrulline residues. The present study was aimed at identifying possible functions of this citrullinating enzyme, named Porphyromonas peptidylarginine deiminase (PPAD), in the periodontal environment. The results show that PPAD is detectable in the gingiva of patients with periodontitis, and that it literally neutralizes human innate immune defenses at three distinct levels, namely bacterial phagocytosis, capture in neutrophil extracellular traps (NETs), and killing by the lysozyme-derived cationic antimicrobial peptide LP9. As shown by mass spectrometry, exposure of neutrophils to PPAD-proficient bacteria reduces the levels of neutrophil proteins involved in phagocytosis and the bactericidal histone H2. Further, PPAD is shown to citrullinate the histone H3, thereby facilitating the bacterial escape from NETs. Last, PPAD is shown to citrullinate LP9, thereby restricting its antimicrobial activity. The importance of PPAD for immune evasion is corroborated in the infection model Galleria mellonella, which only possesses an innate immune system. Together, the present observations show that PPAD-catalyzed protein citrullination defuses innate immune responses in the oral cavity, and that the citrullinating enzyme of P. gingivalis represents a new type of bacterial immune evasion factor.IMPORTANCE Bacterial pathogens do not only succeed in breaking the barriers that protect humans from infection, but they also manage to evade insults from the human immune system. The importance of the present study resides in the fact that protein citrullination is shown to represent a new bacterial mechanism for immune evasion. In particular, the oral pathogen P. gingivalis employs this mechanism to defuse innate immune responses by secreting a protein-citrullinating enzyme. Of note, this finding impacts not only the global health problem of periodontitis, but it also extends to the prevalent autoimmune disease rheumatoid arthritis, which has been strongly associated with periodontitis, PPAD activity, and loss of tolerance against citrullinated proteins, such as the histone H3.

Dataset Information

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

Publications

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

Similar Datasets

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