Modulation of heme oxygenase-1 during Cryptococcus neoformans infection

Heme oxygenase-1 (HO-1) degrades free heme, generating molecules with anti-inflammatory effects that may protect the host but can also promote immunosuppression and impair microbicidal mechanisms. Little is known about the role of HO-1 in fungal infections, such as cryptococcosis caused by Cryptococcus neoformans, which primarily affects immunocompromised individuals and can disseminate from the lungs to the brain, causing meningoencephalitis. Therefore, we investigated the role of HO-1 in host resistance to C. neoformans infection. In C57BL/6 mice infected intranasally, pulmonary HO-1 expression increased at 7, 14, and 21 days post-infection. Daily treatment with cobalt protoporphyrin IX (CoPP), an HO-1 inducer, reduced pulmonary fungal burden at 7 and 14 days post-infection and cerebral fungal burden at 14 days. In contrast, SnPP, an inhibitor of HO-1 enzymatic activity, had no relevant effect on fungal burden. Cytokine analysis in bronchoalveolar lavage (BAL) fluid by enzyme-linked immunosorbent assay (ELISA) showed no significant differences in TNF, IL-6, IL-12, IL-5, IL-13, IL-17, or IFNγ levels between infected animals treated with porphyrins or untreated controls. Differential leukocyte counts revealed increased cellular recruitment, particularly of eosinophils and neutrophils, but treatments did not alter this profile. In in vitro experiments, HO-1 protein levels increased after interaction between C. neoformans and murine peritoneal macrophages, whereas Hmox-1 transcription, assessed by RT-qPCR, did not increase, suggesting that protein stabilization may contribute to HO-1 accumulation. Overall, C. neoformans infection induces HO-1 protein accumulation in vivo and in vitro, while treatment with CoPP affects pulmonary and cerebral fungal burden. Further studies are needed to elucidate the mechanisms involved and the contribution of the immune response, particularly macrophages, to these effects.