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.

• Authors: Cooper K Hayes, Douglas R Wilcox, Yuchen Yang, Grace K Coleman, Melissa A Brown, Richard Longnecker
• Journal: PLoS pathogens (PLoS Pathog) Vol. 17 Issue 2 Pg. e1009285 (02 2021) ISSN: 1553-7374 [Electronic] United States
• PMID: 33524073 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• CARD Signaling Adaptor Proteins
• Chemokines, CC
• Inflammasomes
• Inflammation Mediators
• Interleukin-1beta
• Pycard protein, mouse
• Ccl6 protein, mouse

Topics

• Animals
• Brain (immunology)
• CARD Signaling Adaptor Proteins (immunology)
• Cells, Cultured
• Chemokines, CC (immunology)
• Chlorocebus aethiops
• Disease Models, Animal
• Encephalitis, Herpes Simplex (immunology, mortality)
• Female
• Inflammasomes (immunology)
• Inflammation Mediators (immunology)
• Interleukin-1beta (immunology)
• Macrophages (immunology)
• Male
• Mice
• Mice, Inbred C57BL
• Microglia (immunology)
• Vero Cells