Heme Oxygenase-1 Promotes the Persistence ofLeishmania chagasiInfection

Abstract

Visceral leishmaniasis (VL) remains a major public health problem worldwide. This disease is highly associated with chronic inflammation and a lack of the cellular immune responses against Leishmania. It is important to identify major factors driving the successful establishment of the Leishmania infection to develop better tools for the disease control. Heme oxygenase-1 (HO-1) is a key enzyme triggered by cellular stress, and its role in VL has not been investigated. In this study, we evaluated the role of HO-1 in the infection by Leishmania infantum chagasi, the causative agent of VL cases in Brazil. We found that L. chagasi infection or lipophosphoglycan isolated from promastigotes triggered HO-1 production by murine macrophages. Interestingly, cobalt protoporphyrin IX, an HO-1 inductor, increased the parasite burden in both mouse and human-derived macrophages. Upon L. chagasi infection, macrophages from Hmox1 knockout mice presented significantly lower parasite loads when compared with those from wild-type mice. Furthermore, upregulation of HO-1 by cobalt protoporphyrin IX diminished the production of TNF-α and reactive oxygen species by infected murine macrophages and increased Cu/Zn superoxide dismutase expression in human monocytes. Finally, patients with VL presented higher systemic concentrations of HO-1 than healthy individuals, and this increase of HO-1 was reduced after antileishmanial treatment, suggesting that HO-1 is associated with disease susceptibility. Our data argue that HO-1 has a critical role in the L. chagasi infection and is strongly associated with the inflammatory imbalance during VL. Manipulation of HO-1 pathways during VL could serve as an adjunctive therapeutic approach.

Heme Oxygenase-1 and Carbon Monoxide PromoteBurkholderia pseudomalleiInfection

“…Additionally, we observed a significant increase in HO-1 expression in both murine macrophage RAW264.7 and hepatoma Hepa1-6 cells (unpublished data). This is consistent with previously published studies demonstrating an upregulation of HO-1 mRNA and/or protein expression in response to bacterial (29,(40)(41)(42)(43)(44)(45) or parasitic (26,27,46) infections and might be a general response of infected host cells.…”

“…Mortality in human melioidosis was also predicted by the presence of serum bilirubin among other factors (64), which may serve as a marker for increased HO-1 activity and inducibility in tissues (65). Consistent with our results, increased concentrations of HO-1 have also been found during Leishmania infection of mice, and elevated serum levels of TNF-a have been associated with human visceral leishmaniasis (46). The high amounts of cytokines might be a secondary effect of elevated bacterial counts in vivo and can induce higher levels of HO-1 as a counterregulatory response.…”

“…This is consistent with studies showing that HO-1 can induce dormancyassociated genes in Mycobacterium tuberculosis, leading to latency and survival of the pathogen inside macrophages (41,45). Additionally, adenovirus-mediated overexpression or CoPPIX-mediated induction of HO-1 promoted persistence of Leishmania chagasi in macrophages (46) and in murine Plasmodium liver infection (26), and it was required to protect infected host cells by controlling the inflammatory response. Recent work provided evidence that induction of HO-1 by S. typhimurium exerts detrimental effects in the control of infection, as HO-1 knockdown induced antibacterial immune effector pathways of macrophages and promoted bacterial elimination (58).…”

Immunohistochemical evidence of stress and inflammatory markers in mouse models of cutaneous leishmaniosis

“…Our study suggests no clear HO-1 is also a stress-responsive enzyme, and induction of HO-1 results in the catabolism of prooxidant heme to biliverdin and bilirubin, which are potent antioxidants [25]. Many anti-inflammatory properties are attributed to HO-1 and the beneficial effects of HO-1 have been reported in various models of inflammation, including pleural inflammation, renal injury and small bowel ischemia [11,25,38,48,63] showed that L. pifanoi and L. chagasi infections trigger an increase in HO-1 levels in cultures of macrophages and serum from patients with visceral leishmaniasis. In our study, HO-1 was detected in the footpad and rump models.…”

Acteoside Improves Survival in Cecal Ligation an Puncture-Induced Septic Mice via Blocking of High Mobility Group Box 1 Release

“…In addition, it is well known that the inducers of HO-1 expression inhibits the expression of the inflammatory genes (cyclooxygenase-2 and inducible nitric oxide synthase), and subsequently decreases PGE 2 and NO production (Oh et al, 2006;Suh et al, 2006). It also was recently reported that the HO-1 system provides a therapeutic effect in many experimental pathological conditions (Bonelli et al, 2012;Farombi and Surh, 2006;Luz et al, 2012). In oxidative injury and inflammation conditions, an increase in the synthesis of the HO-1 gene is linked to the transcription factors NFkB, Nrf2, and AP-1 (Paine et al, 2010;Srisook et al, 2005;Surh et al, 2009).…”