Heme Oxygenase-1 Is an Anti-Inflammatory Host Factor that Promotes Murine Plasmodium Liver Infection

Epiphânio, Sabrina; Mikolajczak, Sebastian A.; Gonçalves, Lígia Antunes; Pamplona, Ana; Portugal, Sílvia; Albuquerque, Sônia Sousa Melo Cavalcanti de; Goldberg, Michael S.; Rebelo, Sofia; Anderson, Daniel G.; Akinc, Akin; Vornlocher, Hans‐Peter; Kappe, Stefan H. I.; Soares, Miguel P.; Mota, Maria M.

doi:10.1016/j.chom.2008.04.003

Cited by 125 publications

(124 citation statements)

References 46 publications

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“…Expression of HO-1 is significantly induced during the hepatic stages of Plasmodium infection [59]. More importantly, when Hmox1 is deleted by homologous recombination, generation of liver merozoites is reduced by~70-80% [59]. This would suggest that a viable interaction of Plasmodium with its host is strictly dependent on the induction of HO-1 expression during both liver and blood stages of infection.…”

Section: Expression Of Ho-1 Modulates the Onset Of Severe Malariamentioning

confidence: 86%

“…Nevertheless, assuming that in Plasmodiuminfected children the homozygous short (GT)n repeats afford high level of HO-1 expression but no protection against the onset of cerebral malaria, this might be explained by the following set of observations in mice. Expression of HO-1 is significantly induced during the hepatic stages of Plasmodium infection [59]. More importantly, when Hmox1 is deleted by homologous recombination, generation of liver merozoites is reduced by~70-80% [59].…”

Section: Expression Of Ho-1 Modulates the Onset Of Severe Malariamentioning

confidence: 99%

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A central role for free heme in the pathogenesis of severe malaria: the missing link?

et al. 2008

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Section: Expression Of Ho-1 Modulates the Onset Of Severe Malariamentioning

confidence: 86%

Section: Expression Of Ho-1 Modulates the Onset Of Severe Malariamentioning

confidence: 99%

A central role for free heme in the pathogenesis of severe malaria: the missing link?

et al. 2008

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“…The induction of HO-1 was demonstrated in tissue macrophages and monocytes in fatal malaria and sepsis [50]. The HO-1 expression is up-regulated in the liver following infection by P. berghei and P. yoelii sporozoites [51]. HO-1 polymorphism is associated with susceptibility to malaria [51][52][53].…”

Section: The Genomic Factors Associated With Vitamin D In Malariamentioning

confidence: 99%

“…The HO-1 expression is up-regulated in the liver following infection by P. berghei and P. yoelii sporozoites [51]. HO-1 polymorphism is associated with susceptibility to malaria [51][52][53]. A genetic predisposition to higher levels of HO-1 is associated with severe malaria in Gambian children [54].…”

Section: The Genomic Factors Associated With Vitamin D In Malariamentioning

confidence: 99%

The role of Vitamin D in malaria

Lương

Nguyễn

2015

J Infect Dev Ctries

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An abnormal calcium-parathyroid hormone (PTH)-vitamin D axis has been reported in patients with malaria infection. A role for vitamin D in malaria has been suggested by many studies. Genetic studies have identified numerous factors that link vitamin D to malaria, including human leukocyte antigen genes, toll-like receptors, heme oxygenase-1, angiopoietin-2, cytotoxic T lymphocyte antigen-4, nucleotide-binding oligomerization domain-like receptors, and Bcl-2. Vitamin D has also been implicated in malaria via its effects on the Bacillus CalmetteGuerin (BCG) vaccine, matrix metalloproteinases, mitogen-activated protein kinase pathways, prostaglandins, reactive oxidative species, and nitric oxide synthase. Vitamin D may be important in malaria; therefore, additional research on its role in malaria is needed.

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“…Mouse models of liver stage infection suggest that sporozoites induce a innate inflammatory response associated with liver macrophage activation (14) and formation of inflammatory foci in the liver (15,16). In mice, the severity of the inflammatory response depends on the genetic background, with, for example, BALB/c mice showing reduced sporozoite expansion in the liver and enhanced local inflammatory responses during malaria liver stage infection compared with C57BL/6 mice (17,18).…”

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confidence: 99%

TREM2 governs Kupffer cell activation and explains belr1 genetic resistance to malaria liver stage infection

Gonçalves

Rodrigues-Duarte

Rodo

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Plasmodium liver stage infection is a target of interest for the treatment of and vaccination against malaria. Here we used forward genetics to search for mechanisms underlying natural host resistance to infection and identified triggering receptor expressed on myeloid cells 2 (TREM2) and MHC class II molecules as determinants of Plasmodium berghei liver stage infection in mice. Locus belr1 confers resistance to malaria liver stage infection. The use of newly derived subcongenic mouse lines allowed to map belr1 to a 4-Mb interval on mouse chromosome 17 that contains the Trem2 gene. We show that Trem2 expression in the nonparenchymal liver cells closely correlates with resistance to liver stage infection, implicating TREM2 as a mediator of the belr1 genetic effect. Trem2-deficient mice are more susceptible to liver stage infection than their WT counterparts. We found that Kupffer cells are the principle cells expressing TREM2 in the liver, and that Trem2 −/− Kupffer cells display altered functional activation on exposure to P. berghei sporozoites. TREM2 expression in Kupffer cells contributes to the limitation of parasite expansion in isolated hepatocytes in vitro, potentially explaining the increased susceptibility of Trem2 −/− mice to liver stage infection. The MHC locus was also found to control liver parasite burden, possibly owing to the expression of MHC class II molecules in hepatocytes. Our findings implicate unexpected Kupfferhepatocyte cross-talk in the control Plasmodium liver stage infection and demonstrate that TREM2 is involved in host responses against the malaria parasite. M alaria liver stage infection is asymptomatic but is absolutely required in the progression of Plasmodium infection in the vertebrate host, preceding propagation of parasites in the blood and clinical manifestations of malaria (1, 2). Current efforts in therapy and vaccine development include strategies aimed at deterring infection at the liver stage, preventing subsequent clinical complications and malaria transmission (3, 4). During liver stage infection, one Plasmodium sporozoite develops into thousands of merozoites inside each infected hepatocyte (5). Identification of host genetic factors that control liver parasite expansion may help elucidate response mechanisms operating during liver stage infection.Gene deficiency models and gene expression studies focusing on hepatocyte infection have highlighted genes that control hepatocyte invasion and intrahepatocyte parasite expansion [e.g., CD81 (6), SR-B1 (7, 8)], but the mechanisms of host response to liver stage infection remain elusive. It has been proposed that sporozoites' ability to traverse liver macrophages (9) and/or hepatocytes (10) in the course of liver stage infection may favor the release of proinflammatory factors at liver sites of sporozoite expansion (11,12). Innate immune mechanisms might be involved in sensing Plasmodium sporozoites and in controlling liver stage infection (13).Mouse models of liver stage infection suggest that sporozoites induce a innate in...

show abstract

Heme Oxygenase-1 Is an Anti-Inflammatory Host Factor that Promotes Murine Plasmodium Liver Infection

Cited by 125 publications

References 46 publications

A central role for free heme in the pathogenesis of severe malaria: the missing link?

A central role for free heme in the pathogenesis of severe malaria: the missing link?

The role of Vitamin D in malaria

TREM2 governs Kupffer cell activation and explains belr1 genetic resistance to malaria liver stage infection

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