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 TH1 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.

CCR2 Signaling Promotes Brain Infiltration of Inflammatory Monocytes and Contributes to Neuropathology during Cryptococcal Meningoencephalitis

“…CCR2-dependent entry of IM into the CNS contributes to immunopathology in several neurological diseases ( 27 – 29 ). We thus evaluated the function of the CCL2-CCR2 axis in the pathological process of CM using our murine model, which reproduces human neuronal pathology associated with severe CM ( 12 , 13 ). We found a significantly elevated level of CCL2 during CM, which began to increase at 14 days postinfection (dpi) and peaked at 21 dpi ( Fig.…”

“…While required for anticryptococcal defenses, CD4 + T cells have emerged as critical drivers of immunopathology in both human and murine CM ( 10 – 13 ). Rapid reconstitution of T cells in HIV + CM patients by antiretroviral therapy (ART) can lead to immune reconstitution inflammatory syndrome (c-IRIS), characterized by a dysregulated T cell response ( 14 ).…”

“…Likewise, noncompromised CM patients often develop severe neurological pathology that is steroid responsive ( 6 ). CD4 + T cells also orchestrate lethal immune pathology in animal models ( 12 , 13 , 15 ). However, CD4 + cells do not perform their immune functions on their own but require antigen-presenting cellular partners to become activated and to execute their effector functions in neuroinflammatory diseases ( 16 ).…”

“…At the same time, upon activation by the T cells, these cells can produce cytotoxic molecules, such as reactive oxygen species known to cause collateral tissue damage ( 17 , 18 ). CD45 high Ly6C + CD11b + inflammatory monocytes (IM) are recruited in the CNS during CM ( 13 , 19 , 20 ), but their function and mechanisms responsible for their recruitment remain unclear.…”

Effects of Gliadin on Autoimmune Responses of Central Nervous System of C57BL/6 Mice

“…CXCL-10 provokes T cells accumulation in MS pathogenesis. 17,18 Another chemokine that recruits immune cells in the CNS during EAE is C-C motif chemokine ligand-2 (CCL2), which has been proposed as a new target for medical intervention in neuroinflammatory disorders. 19 Gluten sensitivity contributes to various degrees of neurological manifestations associated with an immunological attack on the CNS and neurodegenerative changes 20 .…”