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JAK/STAT Signaling Predominates in Human and Murine Fungal Post-infectious Inflammatory Response Syndrome
Jessica C Hargarten1, Kenneth Ssebambulidde1,2, Seher H Anjum1
1Laboratory of Clinical Immunology and Microbiology (LCIM), Division of Intramural Research (DIR), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
Abstract:
Post-infection inflammatory syndromes have been increasingly recognized as a cause of host damage in a variety of infectious diseases including tuberculosis, bacterial meningitis, and COVID-19. Recently, a post-infectious inflammatory response syndrome (PIIRS) was described in non-HIV-infected cryptococcal fungal meningoencephalitis (CM) as a major cause of mortality. Inflammatory syndromes are particularly severe in neurological infections due to the skull's rigid structure which limits unchecked tissue expansion from inflammatory-induced edema. In the present studies, neurologic transcriptional pathway analysis utilizing a murine PIIRS model demonstrated a predominance of Janus kinase/signal transducer and activator of transcription (JAK/STAT) activation. JAK/STAT inhibitor treatment resulted in improvements in CNS damage markers, reductions in intrathecal CD44hiCD62lo CD4+ effector CD4+ T-cells and MHC II+ inflammatory myeloid cells, and weight gains in mice, the latter after treatment with antifungals. Based on these data, pathway-driven steroid-sparing human treatment for steroid-refractory PIIRS was initiated using short courses of the JAK/STAT inhibitor ruxolitinib. These were well tolerated and reduced activated HLA-DR+ CD4+ and CD8+ cells and inflammatory monocytes as well as improved brain imaging. Together, these findings support the role of JAK/STAT in PIIRS as well as further study of JAK/STAT inhibitors as potential adjunctive therapy for PIRS and other neural inflammatory syndromes.
Insights
Post-infection inflammatory response syndrome (PIIRS) involves JAK/STAT pathway activation. Inhibiting this pathway improved neurological damage markers and inflammatory cells in mice and humans.
Area of Science:
- Neuroscience
- Immunology
- Infectious Diseases
Background:
- Post-infection inflammatory syndromes (PIIRS) are a significant cause of host damage in various infections, including cryptococcal meningoencephalitis (CM).
- Neurological infections pose unique challenges due to the skull's limited space, exacerbating inflammatory edema and damage.
- PIIRS is a major mortality factor in non-HIV-infected cryptococcal meningoencephalitis.
Approach:
- Investigated PIIRS using a murine model of cryptococcal meningoencephalitis.
- Performed neurologic transcriptional pathway analysis to identify key molecular pathways involved in PIIRS.
- Administered JAK/STAT inhibitors in both murine models and human patients with steroid-refractory PIIRS.
Key Points:
- Murine model studies revealed predominant Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway activation in PIIRS.
- JAK/STAT inhibitor treatment in mice reduced central nervous system (CNS) damage markers and specific inflammatory immune cells.
- Human trials with ruxolitinib, a JAK/STAT inhibitor, demonstrated reduced inflammatory cells and improved brain imaging in PIIRS patients.
- Treatment in humans was well-tolerated and offered a steroid-sparing approach for refractory cases.
Conclusions:
- The JAK/STAT pathway plays a critical role in the pathogenesis of PIIRS.
- JAK/STAT inhibitors show promise as an adjunctive therapy for PIIRS and other neurological inflammatory syndromes.
- This research supports pathway-driven therapeutic strategies for managing severe post-infectious inflammatory conditions.
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