The host transcriptional response to real-world cryptococcosis in the setting of advanced HIV disease defines dysregulated immune responses that underlie increased vulnerability to infection

Abstract

Background Cryptococcus causes life-threatening infections; however, immune programs driving pathogenesis of these infections in the human host remain incompletely described. We leveraged whole-blood transcriptomic analysis to define distinct, conserved elements of the host immune response in participants with cryptococcal infections. Methods RNA sequencing was performed on whole blood from adult febrile inpatients admitted to two hospitals in Moshi, Tanzania to compare gene expression between participants with cryptococcal, bacterial, or viral diseases, and adult community controls. Differential expression and gene set enrichment analyses were used to characterize expression differences between pathogen-class groups. Penalized logistic regression was used to identify gene expression signatures capable of identifying Cryptococcus disease. Results Out of 118 participants, 13 (11%) had cryptococcal disease and 41 (34.7%) were persons living with HIV (PLWH). Genes upregulated in response to cryptococcosis compared to non-acutely-infected community controls reflected complement activation, neutrophil activation, type I interferon signaling, and myeloid dendritic cell differentiation. When compared to combined bacterial or viral illnesses, cryptococcal disease demonstrated hyperactivation of both innate and humoral immune pathways. A series of classifiers were developed that distinguished between cryptococcal and combined bacterial or viral diseases with an AUC of 0.946. Conclusion Overall, the host response to cryptococcosis in individuals with advanced HIV as manifested in transcriptional profiles informs our understanding of the pathophysiology of and susceptibility to cryptococcal infection and may support development of novel diagnostic and therapeutic approaches.