Control of Nipah Virus Infection in Mice by the Host Adaptors Mitochondrial Antiviral Signaling Protein (MAVS) and Myeloid Differentiation Primary Response 88 (MyD88)

Iampietro, Mathieu; Aurine, Noémie; Dhondt, Kévin P.; Dumont, Claire; Pelissier, Rodolphe; Spanier, Julia; Vallvé, Audrey; Raoul, Hervé; Kalinke, Ulrich; Horvat, Branka

doi:10.1093/infdis/jiz602

Cited by 20 publications

(33 citation statements)

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“…In parallel, the lower production of IFNβ ( Figure 1D and S1B) and IFNα ( Figure 1E and S1C) in the brains and spleens of MyD88/TRIF/MAVS KO and MyD88/TRIF/MAVS/STING KO mice compared to WT was associated with their inability to clear the virus. Overall, these results confirm our previous observations on the importance of the RLR signaling platform involving MAVS (Iampietro et al, 2020) and suggest a novel synergistic and non-redundant role of the STING pathway during NiV infection. harvested 2-13 days after infection.…”

supporting

confidence: 91%

“…Although, both MyD88 and MAVS are important to produce high levels of type-I IFNs (IFN-I), double KO mice still exhibit some resistance against NiV infection. This is in contrast to the interferon-α/β receptor (IFNAR) KO mice that lack any IFN-Irelated responses and are unable to control NiV infection (Dhondt et al, 2013;Iampietro et al, 2020). We thus hypothesized that the cGAS/STING axis of the innate immunity could also contribute to the control of NiV infection.…”

mentioning

confidence: 94%

“…Our previous work evaluating innate sensors involved in the protection of mice following NiV infection suggests control of the virus through the activation of MyD88 and MAVS pathways, while TRIF seems dispensable (Iampietro et al, 2020). Although, both MyD88 and MAVS are important to produce high levels of type-I IFNs (IFN-I), double KO mice still exhibit some resistance against NiV infection.…”

mentioning

confidence: 99%

“…Our previous study revealed a complementary role of MyD88 and MAVS in the partial containment of NiV, suggesting that the complete resistance of mice against NiV involves an additional activation pathway of the IFN-I response (Iampietro et al, 2020). The cGAS/STING axis has recently emerged as critical in the crosstalk between innate sensing of cytosolic DNA and RNA viruses (Ni et al, 2018).…”

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confidence: 99%

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Activation of cGAS/STING pathway upon paramyxovirus infection

Iampietro

Dumont

Mathieu

et al. 2020

Preprint

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SUMMARYDuring inflammatory diseases, cancer and infection, the cGAS/STING pathway is known to recognize foreign or self-DNA in the cytosol and activate an innate immune response. Here, we report that negative-strand RNA paramyxoviruses, Nipah virus (NiV) and Measles virus (MeV), can also trigger the cGAS/STING axis. While mice deficient for MyD88, TRIF and MAVS still moderately control NiV infection when compared to WT mice, additional STING deficiency resulted in 100% lethality, suggesting synergistic roles of these pathways in host protection. Moreover, deletion of cGAS or STING resulted in decreased type-I interferon production with enhanced paramyxoviral infection in both human and murine cells. Finally, the phosphorylation and ubiquitination of STING, observed during viral infections, confirmed the activation of cGAS/STING pathway by NiV and MeV. Our data suggest that cGAS/STING activation is critical in controlling paramyxovirus infection, and possibly represent attractive targets to develop countermeasures against severe disease induced by these pathogens.

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confidence: 91%

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confidence: 94%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Activation of cGAS/STING pathway upon paramyxovirus infection

Iampietro

Dumont

Mathieu

et al. 2020

Preprint

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“… Type I IFN synthesis pathway and production of pro-inflammatory cytokines. Virus-responsive induction of the IFN-β promoter is directed by cytoplasmic helicases RIG-I and MDA5 [ 74 ]. Intracellular RNA pathogen-associated molecular patterns (PAMPs; e.g., dsRNA) are recognized by cellular pattern recognition receptors (PRRs; e.g., RIG-I, MDA5, TLR3), triggering antiviral signalling cascades.…”

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confidence: 99%

The Intrinsically Disordered W Protein Is Multifunctional during Henipavirus Infection, Disrupting Host Signalling Pathways and Nuclear Import

Tsimbalyuk

Cross

Hoad

et al. 2020

Cells

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Nipah and Hendra viruses are highly pathogenic, zoonotic henipaviruses that encode proteins that inhibit the host’s innate immune response. The W protein is one of four products encoded from the P gene and binds a number of host proteins to regulate signalling pathways. The W protein is intrinsically disordered, a structural attribute that contributes to its diverse host protein interactions. Here, we review the role of W in innate immune suppression through inhibition of both pattern recognition receptor (PRR) pathways and interferon (IFN)-responsive signalling. PRR stimulation leading to activation of IRF-3 and IFN release is blocked by henipavirus W, and unphosphorylated STAT proteins are sequestered within the nucleus of host cells by W, thereby inhibiting the induction of IFN stimulated genes. We examine the critical role of nuclear transport in multiple functions of W and how specific binding of importin-alpha (Impα) isoforms, and the 14-3-3 group of regulatory proteins suggests further modulation of these processes. Overall, the disordered nature and multiple functions of W warrant further investigation to understand henipavirus pathogenesis and may reveal insights aiding the development of novel therapeutics.

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MyD88 and beyond: a perspective on MyD88-targeted therapeutic approach for modulation of host immunity

Saikh

2021

Immunol Res

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The continuous emergence of infectious pathogens along with antimicrobial resistance creates a need for an alternative approach to treat infectious diseases. Targeting host factor(s) which are critically involved in immune signaling pathways for modulation of host immunity offers to treat a broad range of infectious diseases. Upon pathogen-associated ligands binding to the Toll-like/ IL-1R family, and other cellular receptors, followed by recruitment of intracellular signaling adaptor proteins, primarily MyD88, trigger the innate immune responses. But activation of host innate immunity strongly depends on the correct function of MyD88 which is tightly regulated. Dysregulation of MyD88 may cause an imbalance that culminates to a wide range of inflammation-associated syndromes and diseases. Furthermore, recent reports also describe that MyD88 upregulation with many viral infections is linked to decreased antiviral type I IFN response, and MyD88-deficient mice showed an increase in survivability. These reports suggest that MyD88 is also negatively involved via MyD88-independent pathways of immune signaling for antiviral type I IFN response. Because of its expanding role in controlling host immune signaling pathways, MyD88 has been recognized as a potential drug target in a broader drug discovery paradigm. Targeting BB-loop of MyD88, small molecule inhibitors were designed by structure-based approach which by blocking TIR–TIR domain homo-dimerization have shown promising therapeutic efficacy in attenuating MyD88-mediated inflammatory impact, and increased antiviral type I IFN response in experimental mouse model of diseases. In this review, we highlight the reports on MyD88-linked immune response and MyD88-targeted therapeutic approach with underlying mechanisms for controlling inflammation and antiviral type I IFN response. Highlights • Host innate immunity is activated upon PAMPs binding to PRRs followed by immune signaling through TIR domain–containing adaptor proteins mainly MyD88. • Structure-based approach led to develop small-molecule inhibitors which block TIR domain homodimerization of MyD88 and showed therapeutic efficacy in limiting severe inflammation-associated impact in mice. • Therapeutic intervention of MyD88 also showed an increase in antiviral effect with strong type I IFN signaling linked to increased phosphorylation of IRFs via MyD88–independent pathway. • MyD88 inhibitors might be potentially useful as a small-molecule therapeutics for modulation of host immunity against inflammatory diseases and antiviral therapy. • However, prior clinical use of more in-depth efforts should be focused for suitability of the approach in deploying to complex diseases including COPD and COVID-19 in limiting inflammation-associated syndrome to infection.

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Control of Nipah Virus Infection in Mice by the Host Adaptors Mitochondrial Antiviral Signaling Protein (MAVS) and Myeloid Differentiation Primary Response 88 (MyD88)

Cited by 20 publications

References 21 publications

Activation of cGAS/STING pathway upon paramyxovirus infection

Activation of cGAS/STING pathway upon paramyxovirus infection

The Intrinsically Disordered W Protein Is Multifunctional during Henipavirus Infection, Disrupting Host Signalling Pathways and Nuclear Import

MyD88 and beyond: a perspective on MyD88-targeted therapeutic approach for modulation of host immunity

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