Induction of haem oxygenase‐1 increases infection of dog macrophages by <i>L. infantum</i>

Almeida, Breno Fernando Martins de; Silva, K L O; Venturin, Gabriela Lovizutto; Chiku, Vanessa Marin; Leal, Aline Aparecida Correa; Bosco, Álvaro Francisco; Ciarlini, Paulo César; Lima, Valéria Marçal Felix de

doi:10.1111/pim.12494

Cited by 5 publications

(4 citation statements)

References 34 publications

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“…L. donovani-improves control of pathogen replication in vivo in mice [223]. L. infantum chagasi-improves control of pathogen replication in vitro in dog macrophages [225]. T. cruzi-impairs control of pathogen replication in mice in vivo and in vitro in macrophages [231].…”

Section: Discussionmentioning

confidence: 99%

“…They further observed that treatment of cells with the HO-1 inducer CoPPIX results in impaired control of parasite replication associated with decreased superoxide, ROS and NO production. In the opposite direction, treatment with the HO-1 enzyme inhibitor SnPPIX resulted in a lower infection rate and decreased production of the anti-inflammatory cytokine IL-10 [225].…”

Section: Leishmaniasismentioning

confidence: 98%

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Modulation of Inflammation and Immune Responses by Heme Oxygenase-1: Implications for Infection with Intracellular Pathogens

et al. 2020

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Heme oxygenase-1 (HO-1) catalyzes the degradation of heme molecules releasing equimolar amounts of biliverdin, iron and carbon monoxide. Its expression is induced in response to stress signals such as reactive oxygen species and inflammatory mediators with antioxidant, anti-inflammatory and immunosuppressive consequences for the host. Interestingly, several intracellular pathogens responsible for major human diseases have been shown to be powerful inducers of HO-1 expression in both host cells and in vivo. Studies have shown that this HO-1 response can be either host detrimental by impairing pathogen control or host beneficial by limiting infection induced inflammation and tissue pathology. These properties make HO-1 an attractive target for host-directed therapy (HDT) of the diseases in question, many of which have been difficult to control using conventional antibiotic approaches. Here we review the mechanisms by which HO-1 expression is induced and how the enzyme regulates inflammatory and immune responses during infection with a number of different intracellular bacterial and protozoan pathogens highlighting mechanistic commonalities and differences with the goal of identifying targets for disease intervention.

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Section: Discussionmentioning

confidence: 99%

Section: Leishmaniasismentioning

confidence: 98%

Modulation of Inflammation and Immune Responses by Heme Oxygenase-1: Implications for Infection with Intracellular Pathogens

et al. 2020

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“…HO-1 is thought to be an intracellular enzyme ( 27 ), and its detection in plasma would indicate substantial tissue damage. In this scenario, the release of HO-1 occurs after cellular lysis during robust inflammation associated with infectious diseases such as VL ( 21 , 28 , 29 ), tuberculosis ( 30 ) and malaria ( 31 , 32 ). For sand fly bite-induced HO-1 expression in the skin, our data demonstrates that it is triggered in resident skin macrophages by saliva and as such could play a critical role in the early establishment of Leishmania infection.…”

Section: Discussionmentioning

confidence: 99%

Lutzomyia longipalpis Saliva Induces Heme Oxygenase-1 Expression at Bite Sites

et al. 2018

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Sand flies bite mammalian hosts to obtain a blood meal, driving changes in the host inflammatory response that support the establishment of Leishmania infection. This effect is partially attributed to components of sand fly saliva, which are able to recruit and activate leukocytes. Our group has shown that heme oxygenase-1 (HO-1) favors Leishmania survival in infected cells by reducing inflammatory responses. Here, we show that exposure to sand fly bites is associated with induction of HO-1 in vivo. Histopathological analyses of skin specimens from human volunteers experimentally exposed to sand fly bites revealed that HO-1 and Nrf2 are produced at bite sites in the skin. These results were recapitulated in mice ears injected with a salivary gland sonicate (SGS) or exposed to sand fly bites, indicating that vector saliva may be a key factor in triggering HO-1 expression. Resident skin macrophages were the main source HO-1 at 24–48 h after bites. Additionally, assays in vivo after bites and in vitro after stimulation with saliva both demonstrated that HO-1 production by macrophages was Nrf2-dependent. Collectively, our data demonstrates that vector saliva induces early HO-1 production at the bite sites, representing a major event associated with establishment of naturally-transmitted Leishmania infections.

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“…We have previously described that serum concentrations of both total heme ( 13 ) and of HO-1 ( 12 ) are substantially elevated in patients with VL than in uninfected healthy endemic controls. Besides that, it has been shown that HO-1 induction favors L. infantum replication inside dog macrophages ( 39 ). In the present study, performed in the same patient population, we show that serum concentrations of total heme exhibit positive correlation with HO-1 and LDH levels while being negatively correlated with peripheral blood neutrophil counts, suggesting that systemic levels of heme are linked to parameters associated with increased VL disease progression.…”

Section: Discussionmentioning

confidence: 99%

Heme Drives Oxidative Stress-Associated Cell Death in Human Neutrophils Infected with Leishmania infantum

et al. 2017

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Free heme is an inflammatory molecule capable of inducing migration and activation of neutrophils. Here, we examine the heme-driven oxidative stress-associated cell death mechanisms in human neutrophils infected with Leishmania infantum, an etiologic agent of visceral leishmaniasis (VL). We first performed exploratory analyses in a population of well characterized treatment-naïve VL patients as well as uninfected controls, who were part of previously reported studies. We noted a positive correlation between serum concentrations of heme with heme oxygenase-1 (HO-1) and lactate deydrogenase, as well as, a negative correlation between heme values and peripheral blood neutrophils counts. Moreover, in vitro infection with L. infantum in the presence of heme enhanced parasite burden in neutrophils, while increasing the production of reactive oxygen species and release of neutrophilic enzymes. Additional experiments demonstrated that treatment of infected neutrophils with ferrous iron (Fe+2), a key component of the heme molecule, resulted in increased parasite survival without affecting neutrophil activation status. Furthermore, stimulation of infected neutrophils with heme triggered substantial increases in HO-1 mRNA expression as well as in superoxide dismutase-1 enzymatic activity. Heme, but not Fe+2, induced oxidative stress-associated cell death. These findings indicate that heme promotes intracellular L. infantum survival via activation of neutrophil function and oxidative stress. This study opens new perspectives for the understanding of immunopathogenic mechanisms involving neutrophils in VL.

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Induction of haem oxygenase‐1 increases infection of dog macrophages by L. infantum

Cited by 5 publications

References 34 publications

Modulation of Inflammation and Immune Responses by Heme Oxygenase-1: Implications for Infection with Intracellular Pathogens

Modulation of Inflammation and Immune Responses by Heme Oxygenase-1: Implications for Infection with Intracellular Pathogens

Lutzomyia longipalpis Saliva Induces Heme Oxygenase-1 Expression at Bite Sites

Heme Drives Oxidative Stress-Associated Cell Death in Human Neutrophils Infected with Leishmania infantum

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