ASC-dependent inflammasomes contribute to immunopathology and mortality in herpes simplex encephalitis

Abstract

Herpes simplex virus encephalitis (HSE) is the most common cause of sporadic viral encephalitis, and despite targeted antiviral therapy, outcomes remain poor. Although the innate immune system is critical for restricting herpes simplex virus type I (HSV-1) in the brain, there is evidence that prolonged neuroinflammation contributes to HSE pathogenesis. In this study, we investigated the contribution of inflammasomes to disease pathogenesis in a murine model of HSE. Inflammasomes are signaling platforms that activate the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. We found that mice deficient in the inflammasome adaptor protein, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), had significantly improved survival and lower levels of IL-1β and IL-18 in the brain. Importantly, this difference in survival was independent of viral replication in the central nervous system (CNS). We found that microglia, the resident macrophages of the CNS, are the primary mediators of the ASC-dependent inflammasome response during infection. Using in vitro glial infections and a murine HSE model, we demonstrate that inflammasome activation contributes to the expression of chemokine (C-C motif) ligand 6 (CCL6), a leukocyte chemoattractant. The lower concentration of CCL6 in the brains of ASC-/- mice correlated with lower numbers of infiltrating macrophages during infection. Together, these data suggest that inflammasomes contribute to pathogenic inflammation in HSE and provide a mechanistic link between glial inflammasome activation and leukocyte infiltration. The contribution of inflammasomes to survival was independent of viral replication in our study, suggesting a promising new target in combating harmful inflammation in HSE.

Single-cell transcriptomics of the ventral posterolateral nucleus-enriched thalamic regions from HSV-1-infected mice reveal a novel microglia/microglia-like transcriptional response

“…These pro-inflammatory TMEM119 + /IBA-I + “in transition” microglia/microglia-like cells can activate NLRP3-inflammasome-mediated IL-1β production in the infected thalamus. A recent study revealed that inflammasome response to HSV is primarily mediated by microglia and contributes to mortality independent of controlling viral replication [ 87 ]. Similar to our novel HSE-associated microglial transcriptomic findings, a novel subset of high-grade glioma-associated microglia exhibiting inflammasome-mediated pro-inflammatory and proliferative signatures has been recently described [ 88 ].…”

Herpesviruses and Inflammasomes: One Sensor Does Not Fit All

“…Specific inflammasomes are thus named by their sensor and different sensors are required for inflammasome activation by different viruses. For example, herpes simplex virus 1 ( Human alphaherpesvirus 1 , HSV-1/HHV-1) activates the NLRP3 inflammasome ( 15 – 17 ), while cytomegalovirus Human betaherpesvirus 5 (CMV/HHV-5) activates the AIM2 inflammasome ( 18 ). After recognition of a cognate PAMP or DAMP, these sensor proteins recruit ASC molecules that undergo oligomerization, followed by the recruitment of pro-caspase-1 to the complex.…”

“…Furthermore, NLRP3 inflammasome activation in response to HSV-1 is mediated via STING ( 76 ). VZV activates the inflammasome via NLRP3, whereas CMV activates the inflammasome through AIM2 ( 17 , 54 ). Additionally, the CMV immediate early 86-KD protein (IE-86) inhibits IL-1β release from infected cells ( 17 ).…”

“…VZV activates the inflammasome via NLRP3, whereas CMV activates the inflammasome through AIM2 ( 17 , 54 ). Additionally, the CMV immediate early 86-KD protein (IE-86) inhibits IL-1β release from infected cells ( 17 ). It is hypothesized that HHV-6 activates the inflammasome through AIM2, similarly to CMV.…”

“…Furthermore, more virulent strains of HSV-1 cause more severe corneal pathology that is associated with increased IL-1β and IL-18 levels ( 53 ), and IL-18 contributes to HSV-2 pathology in a genital model of infection ( 54 ). Finally, HSV-1 infection of ASC KO and NLRP3 KO mice led to decreased inflammation and mortality compared to WT controls in a model of encephalitis ( 17 ). These findings are consistent with those of a study in humans which found that a ratio of high IL-1β in the cerebral spinal fluid to low IL-1 receptor antagonist (IL-1RA) in plasma was associated with a poor outcome in HSV-1 encephalitis ( 55 ).…”