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Transcriptomic analyses of mortality in HIV-associated Pneumocystis pneumonia

ABSTRACT: Pneumocystis jirovecii pneumonia (PCP) remains a leading cause of respiratory failure and mortality in individuals with advanced HIV. While severe disease is classically attributed to hyperinflammation, the specific biological determinants driving fatal outcomes in patients remain poorly understood. To address this, we employed an integrated systems biology approach, performing transcriptomics, proteomics, and metabolomics on bronchoalveolar lavage fluid from a prospective cohort of 42 patients with HIV-associated PCP. We demonstrate that mortality is not primarily driven by uncontrolled fungal burden or isolated hyperinflammation, but by profound immunometabolic failure. Non-survivors exhibited marked suppression of local humoral immunity, characterised by depletion of immunoglobulins and complement components, together with significant impairment of apolipoprotein E (ApoE)-mediated alveolar repair and dysregulation of arginine-nitric oxide metabolism. A predictive model combining ApoE and arginine achieved high prognostic accuracy. Crucially, using an ex vivo immunodeficient precision-cut lung slice model, we functionally reversed this opsonic deficit with intravenous immunoglobulin, which restored macrophage-mediated fungal clearance. These findings redefine fatal HIV-associated PCP as a syndrome of immunometabolic failure and provide a mechanistic rationale for evaluating immunoglobulin replacement as a host-directed adjunctive therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE320199 | GEO | 2026/03/02

REPOSITORIES: GEO

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Project description:Objective: Apolipoprotein E (Apo E) is a multifunctional protein, originally described in the context of lipoprotein metabolism and cardiovascular disease. More recently, anti-inflammatory functions of ApoE have been documented. ApoE was studied in the context of several inflammatory disorders, but its role in the pathogenesis of acute organ rejection is unknown. In this study, we test the hypothesis that ApoE attenuates acute renal allograft rejection. Materials and methods: The Dark Agouti (DA) to Lewis (Lew) and the Brown Norway (BN) to Lew rat strain combinations were used to investigate fatal acute rejection. In addition, Fischer 344 (F344) kidneys were transplanted to Lew rats to study reversible acute rejection. Isograft recipients and untreated Lew rats were used as controls. ApoE mRNA expression was quantified in intravascular leukocytes accumulating in the blood vessels of renal grafts and in graft tissue. Apo E protein levels were assessed in blood plasma. To test the protective potential of ApoE, recipients of BN kidneys were treated with ApoE-mimetic peptide. Results: Intravascular graft leukocytes and renal tissue obtained from animals undergoing reversible acute rejection expressed increased levels of ApoE mRNA, whereas during fatal rejection, ApoE expression remained unchanged in the BN to Lew rat strain combination or was significantly reduced when DA rats were used as donors of the kidney. On the protein level, no changes in ApoE were seen in plasma. However, we do not know if local leukocytic ApoE expression results in increased ApoE concentrations inside graft blood vessels. Peptide treatment of allograft recipients reversed fatal rejection and significantly improved animal survival. Conclusions: ApoE plays a protective role in acute organ rejection. Further studies are needed to understand the exact mechanism how ApoE reverses acute rejection. dual-color balanced dye-swap design with 4 biological replicates, hybridized on 4 arrays

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Transcriptomic analyses of mortality in HIV-associated Pneumocystis pneumonia

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