Transcriptomic Predictors of Paradoxical Cryptococcosis-Associated Immune Reconstitution Inflammatory Syndrome

Abstract

BackgroundParadoxical cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS) affects ~25% of human immunodeficiency virus (HIV)-infected patients with cryptococcal meningitis (CM) after they commence antiretroviral therapy (ART) resulting in significant morbidity and mortality. Genomic studies in cryptococcal meningitis and C-IRIS are rarely performed.MethodsWe assessed whole blood transcriptomic profiles in 54 HIV-infected subjects with CM who developed C-IRIS (27) and compared the results with control subjects (27) who did not experience neurological deterioration over 24 weeks after ART initiation. Samples were analyzed by whole genome microarrays.ResultsThe predictor screening algorithms identified the low expression of the components of interferon-driven antiviral defense pathways, such as interferon-inducible genes, and higher expression of transcripts that encode granulocyte-dependent proinflammatory response molecules as predictive biomarkers of subsequent C-IRIS. Subjects who developed early C-IRIS (occurred within 12 weeks of ART initiation) were characterized by upregulation of biomarker transcripts involved in innate immunity such as the inflammasome pathway, whereas those with late C-IRIS events (after 12 weeks of ART) were characterized by abnormal upregulation of transcripts expressed in T, B, and natural killer cells, such as IFNG, IL27, KLRB1, and others. The AIM2, BEX1, and C1QB were identified as novel biomarkers for both early and late C-IRIS events.ConclusionsAn inability to mount effective interferon-driven antiviral immune response, accompanied by a systemic granulocyte proinflammatory signature, prior to ART initiation, predisposes patients to the development of C-IRIS. Although early and late C-IRIS have seemingly similar clinical manifestations, they have different molecular phenotypes (as categorized by bioinformatics analysis) and are driven by contrasting inflammatory signaling cascades.

Microbial Shifts Following Five Years of Cover Cropping and Tillage Practices in Fertile Agroecosystems

“…The relative abundances (RAs, %) of each OTU were statistically analyzed to identify the responsive microbes and estimate the treatment effects. The initial set of responsive microbes were selected using a bootstrap forest partitioning method with the JMP ® predictor screening platform [ 52 , 53 , 54 ]. This led to a selection of 42 out of 1832 OTUs for bacteria, 5 out of 19 for archaea, and 36 out of 313 for fungi that contributed at least one percent to the variability in the model algorithms ( Table S2 ).…”

Blood neutrophil counts in HIV-infected patients with cryptococcal meningitis: Association with mortality

“…[49] Vlasova-St. Louis et al using genome wide transcriptomic analysis have found higher transcripts encoding markers for activated granulocytes, tissue infiltration and destruction among subjects that developed cryptococcal immune reconstitution syndrome. [50] Higher neutrophil percentages and neutrophil to lymphocyte ratios have also been found to be associated with mortality in patients with community acquired pneumonia and other chronic medical conditions. [51, 52] Curbelo et al hypothesize that the mortality is attributable to the sustained immune response rather than the infectious process.…”

Immune Reconstitution Disorders: Spotlight on Interferons

“…Several immune abnormalities were identified before ART commencement in patients who developed IRIS in comparison with those who did not [ 118 ]. The predominant abnormality was the down-regulation of interferon-response genes in individuals who went on to develop IRIS.…”

“…One was conducted in peripheral blood from advanced stage HIV-infected patients without opportunistic infections who were commenced on ART and did not exhibit IRIS. The other was conducted in the South African cohort of patients with opportunistic cryptococcal infections [ 118 ]. Both cohorts exhibited an upregulation of IFN I/II-STAT and NFkB pathways at baseline, followed by a subsequent decline as early as 4 weeks after ART initiation [ 128 ].…”

“…The clinical manifestations of IRIS usually begin within the first four weeks of ART initiation; however, late presentation beyond 8 weeks has also been reported [ 105 , 145 ]. We recently described peripheral blood changes during cryptococcal late IRIS events that occurred after 10 weeks of immune reconstitution on ART [ 118 ]. The screening analysis revealed biomarker genes that encode a variety of molecules in T, B, NK cells and neutrophils.…”