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Transcriptomic and lipidomic analysis of the cryptococcal lung granuloma reveals macrophage boundary programs and sphingolipid remodeling [Xenium]

ABSTRACT: Cryptococcosis is a life-threatening fungal disease caused by Cryptococcus neoformans. The immunocompetent response results in the formation of a lung granuloma, which contains the fungal cells. We have previously developed a mouse model of the cryptococcal granuloma that is histological similar to the human lung granuloma. In this study, we characterize the lung granuloma in mice using transcriptomics and lipidomics, elucidating the immune cell types present and the transcriptional landscape of macrophages at the granuloma border. Macrophage subtypes are identified, which form a characteristic boundary of the lung granuloma and were observed to have differentially expressed genes involved in the control of the infection. Lipidomic studies revealed that several sphingolipid-associated genes and their products involved in the regulation of phagocytosis were found to be upregulated and in vivo validation studies confirmed their key role in granuloma formation. Lastly, as the granuloma structure develops, the fungal replication inside the granuloma decreases concomitantly to the decrease of the macrophage activation. These studies identified important immune mechanisms of host protection at the granuloma site. Our results provide mechanistic insight into cryptococcal granuloma maturation and refine current models of host–pathogen interaction, which may open avenues for future immunomodulatory strategies

ORGANISM(S): Mus musculus

PROVIDER: GSE328931 | GEO | 2026/06/29

REPOSITORIES: GEO

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Project description:Fungal diseases impact the lives of millions of people across the globe ranging from superficial to systemic infections. Treatment options toward fungal diseases are limited given the emergence of new pathogens with intrinsic resistance and heightened evolution toward resistant strains. To effectively combat fungal disease, rapid and reliable diagnostic methods are required, including current methodologies using antigen detection, culturing, microscopy, and molecular tools. However, the flexibility of these platforms to diagnose infection using non-invasive methods and predict the outcome of disease are limited. In this study, we apply state-of-the-art mass spectrometry-based proteomics to perform dual perspective (i.e., host and pathogen) profiling of cryptococcal infection. Whole blood collected over a temporal scale following murine model challenged with the human fungal pathogen, Cryptococcus neoformans, revealed detection of >3,000 host proteins and 160 fungal proteins across all samples. From the host perspective, temporal regulation of known immune-associated proteins, including eosinophil peroxidase and lipocalin, along with suppression of lipoproteins, demonstrated infection- and time-dependent host remodeling. Conversely, from the pathogen perspective, known and putative virulence-associated proteins were detected, including proteins associated with fungal extracellular vesicles and host immune modulation. Moreover, we observed and validated a new mechanism of immune system activation by C. neoformans through modulation of haptoglobin. Further, we assessed the predictive power of dual perspective proteome profiling toward prognostics of cryptococcal infection and report a previously undisclosed integration among virulence factor production, immune system modulation, and individual model survival. Together, our findings pose novel biomarkers of cryptococcal infection from whole blood and highlight the potential of personal proteome profiles to determine the prognosis of cryptococcal infection, a new parameter in fungal disease management. his submission includes a partial dataset. Additional RAW files will be added shortly after manuscript publication to complete the full data submission.

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Transcriptomic and lipidomic analysis of the cryptococcal lung granuloma reveals macrophage boundary programs and sphingolipid remodeling [Xenium]

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