The Journal of infectious diseases · 2026
MHC-I Upregulation and Increased Glucose Dependence Define Innate Antifungal Immune Responses to Cryptococcus neoformans.
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Nair Ayesha S, Wozniak Karen L
Аннотация
BACKGROUND: Cryptococcus neoformans, the etiologic agent of cryptococcosis, can survive and replicate within host immune cells, contributing to development of cryptococcal meningitis. Within the lung, C neoformans interacts with innate immune subsets, including macrophages and dendritic cells (DCs). Our previous work demonstrated that Ly6c- monocyte-like macrophages restrict fungal proliferation, whereas CD11b+ DCs promote fungal growth. Transcriptomic profiling revealed differential expression of MHC-I gene H2-K1, calreticulin, and metabolic genes. Therefore, we hypothesized that H2-K1 and metabolic pathways modulate intracellular fungal fate within pulmonary macrophages and DCs.
METHODS: H2-K1 expression was knocked down by siRNA in J774 macrophages and bone marrow-derived DCs induced by granulocyte-macrophage colony-stimulating factor. Antifungal activity was determined by colony-forming unit enumeration. Phagocytic uptake, cathepsin B activity, Nos2 expression, and reactive oxygen species production were quantified by flow cytometry. Metabolic dependencies were evaluated through SCENITH assay (single-cell energetic metabolism by profiling translational inhibition).
RESULTS: H2-K1 knockdown in J774 cells significantly reduced antifungal activity as compared with controls. H2-K1 knockdown also decreased calreticulin gene expression, suggesting that H2-k1 has downstream effects in the pathway. H2-K1 silencing did not significantly alter phagocytic uptake, cathepsin B activity, or Nos2 expression. However, reactive oxygen species production was significantly reduced in H2-K1 knockdown J774 cells, indicating impaired responses. SCENITH analysis revealed that antifungal macrophages shift their metabolism toward glucose oxidation for ATP generation, which is important for antifungal activity.
CONCLUSIONS: These findings indicate that metabolic reprogramming is critical for effective antifungal responses. Our data provide a foundation for future studies aimed at targeting host immune and metabolic pathways to enhance antifungal immunity.
METHODS: H2-K1 expression was knocked down by siRNA in J774 macrophages and bone marrow-derived DCs induced by granulocyte-macrophage colony-stimulating factor. Antifungal activity was determined by colony-forming unit enumeration. Phagocytic uptake, cathepsin B activity, Nos2 expression, and reactive oxygen species production were quantified by flow cytometry. Metabolic dependencies were evaluated through SCENITH assay (single-cell energetic metabolism by profiling translational inhibition).
RESULTS: H2-K1 knockdown in J774 cells significantly reduced antifungal activity as compared with controls. H2-K1 knockdown also decreased calreticulin gene expression, suggesting that H2-k1 has downstream effects in the pathway. H2-K1 silencing did not significantly alter phagocytic uptake, cathepsin B activity, or Nos2 expression. However, reactive oxygen species production was significantly reduced in H2-K1 knockdown J774 cells, indicating impaired responses. SCENITH analysis revealed that antifungal macrophages shift their metabolism toward glucose oxidation for ATP generation, which is important for antifungal activity.
CONCLUSIONS: These findings indicate that metabolic reprogramming is critical for effective antifungal responses. Our data provide a foundation for future studies aimed at targeting host immune and metabolic pathways to enhance antifungal immunity.