| Summary: | An important virulence trait of <i>Salmonella enterica</i> serovar Typhimurium (<i>S.</i> Typhimurium) is the ability to avoid the host immune response, generating systemic and persistent infections. Host cells play a crucial role in bacterial clearance by expressing the enzyme heme oxygenase 1 (Hmox1), which catalyzes the degradation of heme groups into Fe<sup>2+</sup>, biliverdin, and carbon monoxide (CO). The role of Hmox1 activity during <i>S.</i> Typhimurium infection is not clear and previous studies have shown contradictory results. We evaluated the effect of pharmacologic modulation of Hmox1 in a mouse model of acute and persistent <i>S.</i> Typhimurium infection by administering the Hmox1 activity inductor cobalt protoporphyrin-IX (CoPP) or inhibitor tin protoporphyrin-IX (SnPP) before infection. To evaluate the molecular mechanism involved, we measured the colocalization of <i>S.</i> Typhimurium and autophagosome and lysosomal markers in macrophages. Administering CoPP reduced the bacterial burden in organs of mice 5 days post-infection, while SnPP-treated mice showed bacterial loads similar to vehicle-treated mice. Furthermore, CoPP reduced bacterial loads when administered after infection in macrophages in vitro and in a persistent infection model of <i>S.</i> Typhimurium in vivo, while tin protoporphyrin-IX (SnPP) treatment resulted in a bacterial burden similar to vehicle-treated controls. However, we did not observe significant differences in co-localization of green fluorescent protein (GFP)-labeled <i>S.</i> Typhimurium with the autophagic vesicles marker microtubule-associated protein 1A/1B-light chain 3 (LC3) and the lysosomal marker lysosomal-associated membrane protein 1 (LAMP-1) in macrophages treated with CoPP. Our results suggest that CoPP can enhance antimicrobial activity in response to <i>Salmonella</i> infection, reducing bacterial dissemination and persistence in mice, in a CO and autophagy- independent manner.
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