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Preprint
Lipopolysaccharide Enhances Microglia Antiviral Control of Betacoronavirus Infection through TLR4-Dependent Induction of IFNβ with Concomitant Modulation of dsRNA Sensors MDA5 and TLR3
May 2024
Abstract
Microglia play a pivotal role in brain homeostasis and are essential to protective immunity within the central nervous system by coordinating the innate immune response to neuroinvasive pathogens. Bacterial endotoxin (lipopolysaccharide, LPS) is the most used pro-inflammatory stimulus for microglia, both in vitroand in vivo. However, the impact of LPS in microglia response to viral infection, including coronaviruses remains ill-defined. Murine coronaviruses productively infect microglia and are well established models of RNA virus-induced encephalitis and demyelination. In the present study, we investigated the effects of TLR4 stimulation with a TLR4-specific agonist [smooth (s)-form LPS (E. coli 0111:B4)] on murine coronavirus MHV-JHM and -A59 infection of microglia in vitro. Mechanistically, our data revealed that LPS stimulation of microglia restrict coronavirus replication through TLR4-dependent induction of interferon (IFN-b) with concomitant modulation of dsRNA sensors melanoma differentiation-associated gene 5 (MDA5) and toll-like receptor 3 (TLR3). Moreover, in the absence of coronavirus infection, LPS induces TLR4-dependent upregulation of MDA5 expression and activation of TLR3, as measured by phosphorylation of its residue Y759, a hallmark of TLR3 signaling initiation. Supporting LPS-induced TLR3 activation, we demonstrated that TLR3 selectively contributes to TLR4-dependent, LPS-induced neuroinflammation even in the absence of virus infection. Overall, the present study provides novel mechanistic insights regarding microglia responses to coronavirus infection and highlights a previously unrecognized crosstalk between bacterial TLR4 and dsRNA sensors in microglia with implications beyond viral infection.
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Details
- Title
- Lipopolysaccharide Enhances Microglia Antiviral Control of Betacoronavirus Infection through TLR4-Dependent Induction of IFNβ with Concomitant Modulation of dsRNA Sensors MDA5 and TLR3
- Creators
- Sonia Navas-Martin - Drexel University, Microbiology and ImmunologyElijah Hayes Davis - Drexel University, Microbiology and ImmunologyAdam M. GlassBrett LaBier - Drexel UniversityAlexis Tang - Drexel UniversityValeria Bornacelli Pabon - Drexel UniversityArmoni Mays - Drexel University
- Resource Type
- Preprint
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Other Identifier
- 991022047820304721