Neuroinflammation in Cryptococcal Post-infectious Inflammatory Response Syndrome (PIIRS) is reduced by Ruxolitinib, a Janus Kinase (JAK) inhibitor.

Abstract

Abstract Recently, a PIIRS was described in non-HIV infected cryptococcal meningoencephalitis (CM) as a significant cause of neuropathology and mortality. Inflammatory syndromes are particularly severe in neurological infections due to the skull's rigid structure. In the present study, transcriptional profiling of RNA from brains of PIIRS model mice at peak inflammation identified a predominance of STAT1/STAT3-associated downstream genes. Since JAK is known to activate both pathways, we hypothesized that the JAK/STAT inhibitor ruxolitinib could reduce neuro-damaging inflammation from CM. Treatment with ruxolitinib reduced intrathecal STAT1/STAT3-associated gene expression as well as CD44hiCD62loCD4+ effector CD4+ T-cells and MHC II+ inflammatory myeloid cells with improved neuropathology and weight. Based on these data, the first human treatment of PIIRS with ruxolitinib was initiated in 5 patients with residual inflammation despite corticosteroids (CS). Ruxolitinib reduced cerebrospinal fluid (CSF) activated HLA-DR+ CD4+ and CD8+ cells, NK cells, and inflammatory monocytes as well as soluble markers sIL-2R, and IL-10 with a trend in IL-6 on a constant dose of CS. MRI brain imaging also demonstrated significant improvements and therapy was well tolerated. Together, these findings demonstrate a role for the JAK/STAT pathway in PIIRS and support ruxolitinib as a potential adjunctive therapy for further randomized clinical trials of PIIRS as a steroid-sparing therapeutic.