Abstract
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Abstract; Background: Cryptococcal meningitis (CM) is a major cause of death in HIV-infected patients in sub-Saharan Africa. Many CM patients experience cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS), which is often fatal. We sought to identify transcriptomic biomarker pathways in peripheral blood that are associated with, or, predict the development of death or fatal C-IRIS among patients with CM who were enrolled in the Cryptococcal Optimal ART Timing (COAT) Trial. Methods: We assessed peripheral blood gene expression using next-generation RNA sequencing in 4 groups of patients with CM: 1) no C-IRIS or Death; 2) C-IRIS survivors; 3) fatal C-IRIS; 4) Death without C-IRIS. Gene expression was assessed at the time of ART initiation, at 1, 4, and 8 weeks on ART, and at the time of C-IRIS events. Results: We identified 12 inflammatory and stress response pathways, including interferon type 1 signaling, that were upregulated at the time of ART initiation in patients with future fatal C-IRIS, as compared with survivors. The upregulation of transcripts involved in innate immunity (inflammasome, Toll-like receptor signaling), was observed at the time of fatal or nonfatal C-IRIS events. At the time of fatal C-IRIS events, numerous transcripts within fMLP, Rho family GTPases, HMGB1, and other acute phase response signaling pathways were upregulated, which reflect the severity of inflammation and systemic oxidative stress. Those who died without recognized C-IRIS also had increased expression of pathways associated with oxidative stress and tissue damage. The Partial Least Squares model estimated above mentioned pathways as predictors of fatal outcome.Conclusions: Our results showed that overactivated innate immunity, involving Toll-like receptor/inflammasome, and inflammation-induced oxidative stress, are associated with fatal outcomes. The results of this study provide insight into the molecular drivers of death and fatal C-IRIS to inform future diagnostic test development or guide targeted treatments.