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Chemokine receptor CXCR3 is required for lethal brain pathology but not pathogen clearance during cryptococcal meningoencephalitis.

ABSTRACT: Cryptococcal meningoencephalitis (CM) is the major cause of infection-related neurological death, typically seen in immunocompromised patients. However, T cell-driven inflammatory response has been increasingly implicated in lethal central nervous system (CNS) immunopathology in human patients and murine models. Here, we report marked up-regulation of the chemokine receptor CXCR3 axis in human patients and mice with CM. CXCR3 deletion in mice improves survival, diminishes neurological deficits, and limits neuronal damage without suppressing fungal clearance. CD4⁺ T cell accumulation and T_H1 skewing are reduced in the CNS but not spleens of infected CXCR3^-/- mice. Adoptive transfer of WT, but not CXCR3^-/- CD4⁺ T cells, into CXCR3^-/- mice phenocopies the pathology of infected WT mice. Collectively, we found that CXCR3⁺CD4⁺ T cells drive lethal CNS pathology but are not required for fungal clearance during CM. The CXCR3 pathway shows potential as a therapeutic target or for biomarker discovery to limit CNS inflammatory damages.

SUBMITTER: Xu J

PROVIDER: S-EPMC7299622 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Chemokine receptor CXCR3 is required for lethal brain pathology but not pathogen clearance during cryptococcal meningoencephalitis.

Xu Jintao J Neal Lori M LM Ganguly Anutosh A Kolbe Jessica L JL Hargarten Jessica C JC Elsegeiny Waleed W Hollingsworth Christopher C He Xiumiao X Ivey Mike M Lopez Rafael R Zhao Jessica J Segal Benjamin B Williamson Peter R PR Olszewski Michal A MA

Science advances 20200617 25

Cryptococcal meningoencephalitis (CM) is the major cause of infection-related neurological death, typically seen in immunocompromised patients. However, T cell-driven inflammatory response has been increasingly implicated in lethal central nervous system (CNS) immunopathology in human patients and murine models. Here, we report marked up-regulation of the chemokine receptor CXCR3 axis in human patients and mice with CM. CXCR3 deletion in mice improves survival, diminishes neurological deficits, ...[more]

PMID: 32596454

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Project description:Although male predominance was documented in previous studies on cryptococcal meningoencephalitis (CM), there has been no statistical study about female CM patients despite recently noticeable increase in female prevalence. In the current study, we aimed to investigate the independent gender-specific contributing risk factors for onset of CM and factors related to survival time in female patients by chosen statistical tools.There have been 108 patients diagnosed with CM from July 1, 1998 to June 30, 2013 in Nanfang Hospital that were included in our study. This 15-year retrospective study compared demographic and clinical features of 31 female patients with 77 males. Multivariate analysis was performed for detection of the contributors to the onset of CM in female patients. The independent variables for multivariate analysis were selected according to statistical significance in univariate analysis. Furthermore, Cox regression model was used to evaluate the factors related to survival length.Use of corticosteroids or other immunosuppressants (32.3% versus 11.7%; p = 0.011) and history of systemic lupus erythematosus (SLE) and other autoimmune diseases (29% versus 3.9%; p < 0.001) were more common in females, but only the history of SLE or other autoimmune diseases was significant (OR 10.59, 95% CI 1.49-74.77, p = 0.02) by multivariate analysis. The ratio of cerebrospinal fluid (CSF) glucose-to-blood glucose was related to the survival time (p = 0.03, 95% CI 0-0.71).The results showed that the history of SLE or other autoimmune diseases rather than chronic use of corticosteroids and/or immunosuppressants was the independent gender-specific contributing risk factor in female CM patients. Therefore, more attention should be made to the prevention of infection from the genus Cryptococcus spp. in female patients with SLE or other autoimmune diseases. In addition, decreased ratio of CSF glucose-to-blood glucose before antifungal therapy predicted the worse prognosis.

Dataset Information

Chemokine receptor CXCR3 is required for lethal brain pathology but not pathogen clearance during cryptococcal meningoencephalitis.

Publications

Chemokine receptor CXCR3 is required for lethal brain pathology but not pathogen clearance during cryptococcal meningoencephalitis.

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