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

TL;DR

A new form of glatiramer acetate improves lung and brain symptoms in a mouse model of a severe immune-related disease linked to cryptococcus.

Contribution

Star-shaped glatiramer acetate (sGA) is shown to mitigate C-IRIS symptoms by reducing immune activation and neuroinflammation in a murine model.

Findings

sGA improved respiratory function and increased survival rate in C-IRIS mice.

sGA reduced Th1 and Th17 cells and attenuated brain microglia activation.

sGA rescued neuronal loss in specific brain regions by 25–40%.

Abstract

Background: Cryptococcus-associated immune reconstitution inflammatory syndrome (C-IRIS) is a life-threatening complication of immune recovery, often triggered by antiretroviral therapy and characterized by Th1-skewed CD4+ T cell hyperactivation, neuroinflammation, and pulmonary dysfunction. Methods: Using a validated murine model of unmasking C-IRIS, we assessed the therapeutic potential of star-shaped glatiramer acetate (sGA), a structurally enhanced derivative of the FDA-approved immunomodulator glatiramer acetate (GA). sGA was administered intraperitoneally on days 1 and 3 post-CD4+ T cell reconstitution. Results: sGA significantly ameliorated C-IRIS-associated respiratory dysfunction, including increasing breaths per minute by ~35% and improved minute volume, total respiratory cycle time, expiration time, and inspiration time. Survival rate grew to 75% on day 14 for sGA-treated C-IRIS mice. In both the lung and the brain, sGA reduced total CD4+ T cells and selectively diminished Th1 cells by 50–60% and Th17 cells by 40–50%. Activated microglia decreased by 45% within the brain, indicating attenuated innate immune activation. Golgi-Cox analysis revealed region-specific neuroprotection: neuronal loss in the prefrontal cortex, lateral hypothalamus, and periaqueductal gray was rescued by 25–40%, whereas hippocampal neurons were relatively preserved, and basolateral amygdala neurons showed no significant recovery. Conclusion: Collectively, our findings suggest that sGA exerts neuroprotection in C-IRIS by limiting peripheral CD4+ T cell effector activity and suppressing CNS-resident immune activation. This study supports the use of sGA as a promising preclinical therapeutic candidate for C-IRIS and other Th1-mediated neuroinflammatory conditions.

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