Study of Heme Oxygenase-1 activity modulation In murine macrophage function and its in vivo effects during interaction with the fungus Sporothrix brasiliensis

Sporothrix brasiliensis is one of the main etiological agents of zoonotic sporotrichosis in Brazil. Heme oxygenase-1 (HO-1) is an isoenzyme responsible for the catabolism of free heme, producing metabolites with anti-inflammatory and antioxidant effects. Our hypothesis is that HO-1 increases host susceptibility by inhibiting mechanisms of resistance to infection. We evaluated the role of protoporphyrin IX (CoPP), an HO-1 inducer, and tin protoporphyrin IX (SnPP), an HO-1 inhibitor in mouse models of S. brasiliensis (MYA-4823) infection. Subcutaneous infection increased local skin HO-1 expression. Mice treated with CoPP exhibited marked weight loss and died by day 21, whereas control animals survived until day 35. At 15 days, CoPP treatment significantly increased spleen weight and fungal burden in this organ and in the skin, suggesting impaired host resistance. In contrast, animals treated with SnPP exhibited delayed healing of skin lesions, which were assessed every seven days. At day 35, these animals showed a significant increase in spleen and liver weight and fungal burden in these organs and the skin, changes that were not observed at day 15. Thus, SnPP treatment also interferes with host resistance, but at a later stage of infection. Inguinal lymph node cells restimulation revealed no differences in IFN-γ or IL-17 production between SnPP-treated and control animals. In vitro, conidia or yeast cells induced HO-1 expression by PMs. Regarding microbicidal activity, conidia and yeast cells were not eliminated by PMs. However, SnPP treatment increased the fungicidal activity of PMs against conidia, but not against yeast cells. Activation of PMs with IFN-γ/LPS promoted the elimination of both fungal forms, an effect reversed by CoPP, which also inhibited ROS and NO production. We are currently investigating the mechanisms by which SnPP enhances microbicidal activity against conidia and compromises host resistance to infection in vivo.