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

Autor: Melissa A. Brown, Richard Longnecker, Cooper K. Hayes, Douglas R. Wilcox, Yuchen Yang, Grace K. Coleman
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Central Nervous System
Male
Chemokine
Inflammasomes
Physiology
Interleukin-1beta
medicine.disease_cause
Biochemistry
Nervous System
White Blood Cells
Mice
0302 clinical medicine
Medical Conditions
Animal Cells
Infectious Diseases of the Nervous System
Immune Physiology
Chlorocebus aethiops
Medicine and Health Sciences
Biology (General)
Cells
Cultured
0303 health sciences
Innate Immune System
Immune System Proteins
Microglia
biology
Brain
Inflammasome
Animal Models
medicine.anatomical_structure
Infectious Diseases
Experimental Organism Systems
Neurology
Chemokines
CC
Encephalitis
Cytokines
Female
medicine.symptom
Cellular Types
Anatomy
Inflammation Mediators
medicine.drug
Research Article
QH301-705.5
Immune Cells
Immunology
Inflammation
Mouse Models
Glial Cells
Research and Analysis Methods
Microbiology
03 medical and health sciences
Model Organisms
Virology
Genetics
medicine
Animals
Molecular Biology
Microglial Cells
Vero Cells
Neuroinflammation
030304 developmental biology
Innate immune system
Blood Cells
business.industry
Viral encephalitis
Macrophages
Biology and Life Sciences
Proteins
Cell Biology
RC581-607
Molecular Development
medicine.disease
Viral Replication
CARD Signaling Adaptor Proteins
Mice
Inbred C57BL
Disease Models
Animal
Herpes simplex virus
Immune System
biology.protein
Animal Studies
Parasitology
Encephalitis
Herpes Simplex
Immunologic diseases. Allergy
business
030217 neurology & neurosurgery
Developmental Biology
Zdroj: PLoS Pathogens
PLoS Pathogens, Vol 17, Iss 2, p e1009285 (2021)
ISSN: 1553-7374
1553-7366
Popis: 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.
Author summary Although the immune system is critical for controlling herpes simplex virus (HSV) infection in the central nervous system (CNS), a prolonged or excessive immune response may be harmful. We studied the contribution of inflammasomes, innate immune proteins that initiate a pro-inflammatory response, to detrimental neuroinflammation in a murine model of herpes simplex encephalitis (HSE). We found that inflammasomes that rely on the adaptor protein ASC contribute to mortality and neuroinflammation independent of controlling viral replication. Additionally, we demonstrate that the inflammasome response to HSV is primarily mediated by microglia and leads to an influx of macrophages in the CNS. These results provide insights into the mechanisms that drive pathogenic inflammation in HSE and suggest a promising therapeutic target in treating HSE.
Databáze: OpenAIRE
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