Star-Shaped Glatiramer Acetate Mitigates Pulmonary Dysfunction and Brain Neurodegeneration in a Murine Model of Cryptococcus-Associated IRIS

Anwar, S.; Zhou, J.; Kowalski, L.; Saylor, J.; Shukla, D.; Boetel, K.; Song, Z.; Sharma, K.; Cheng, J.; Inoue, M.

doi:10.1101/2025.01.07.631707

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bioRxiv · 10.1101/2025.01.07.631707

Star-Shaped Glatiramer Acetate Mitigates Pulmonary Dysfunction and Brain Neurodegeneration in a Murine Model of Cryptococcus-Associated IRIS

Anwar, S.·Zhou, J.·Kowalski, L.·Saylor, J.·Shukla, D.·Boetel, K.·Song, Z.·Sharma, K.·Cheng, J.·Inoue, M.

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Abstract

Cryptococcal-associated immune reconstitution inflammatory syndrome (C-IRIS) is a clinical worsening or new presentation of cryptococcal disease following the initiation of antiretroviral therapy. C-IRIS is primarily driven by an influx of pathological CD4+ T cells, which triggers a hyperinflammatory response. The murine model of C-IRIS is a way to study the disease in mice and understand how the immune system triggers life-threatening outcomes in patients. We previously developed a murine C-IRIS model and demonstrated that C-IRIS is triggered by pathological CD4+ T cells, particularly Th1 cells, in the brain, which triggers neurodegeneration and pulmonary dysfunction. Using this unique mouse model, we tested the therapeutic effect of a star-shaped glatiramer acetate (sGA), which is a more effective isomeric form than linear GA. Here, we observed that sGA suppresses Th1 differentiation in the lung tissues, reducing CD4+ T cell and Th1 cell count. It also reduced microglia populations in the brain. Together, these changes improved respiratory dysfunction caused by C-IRIS, lowered mortality rate, and reduced brain neurodegeneration. These findings suggest that sGA could be an effective therapeutic strategy for managing C-IRIS.

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Anwar, S., Zhou, J., Kowalski, L., Saylor, J., Shukla, D., Boetel, K., Song, Z., Sharma, K., Cheng, J., Inoue, M.. 2025-01-10. Star-Shaped Glatiramer Acetate Mitigates Pulmonary Dysfunction and Brain Neurodegeneration in a Murine Model of Cryptococcus-Associated IRIS. https://doi.org/10.1101/2025.01.07.631707

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