Cunnington, A.J., de Souza, J.B., Walther, M. & Riley, E.M. Malaria impairs resistance to Salmonella through heme- and heme oxygenase-dependent dysfunctional granulocyte mobilization. Nat. Med. 18, 120-127

Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.
Nature medicine (Impact Factor: 27.36). 12/2011; 18(1):120-7. DOI: 10.1038/nm.2601
Source: PubMed


In sub-Saharan Africa, invasive nontyphoid Salmonella (NTS) infection is a common and often fatal complication of Plasmodium falciparum infection. Induction of heme oxygenase-1 (HO-1) mediates tolerance to the cytotoxic effects of heme during malarial hemolysis but might impair resistance to NTS by limiting production of bactericidal reactive oxygen species. We show that co-infection of mice with Plasmodium yoelii 17XNL (Py17XNL) and Salmonella enterica serovar Typhimurium 12023 (Salmonella typhimurium) causes acute, fatal bacteremia with high bacterial load, features reproduced by phenylhydrazine-induced hemolysis or hemin administration. S. typhimurium localized predominantly in granulocytes. Py17XNL, phenylhydrazine and hemin caused premature mobilization of granulocytes from bone marrow with a quantitative defect in the oxidative burst. Inhibition of HO by tin protoporphyrin abrogated the impairment of resistance to S. typhimurium by hemolysis. Thus, a mechanism of tolerance to one infection, malaria, impairs resistance to another, NTS. Furthermore, HO inhibitors may be useful adjunctive therapy for NTS infection in the context of hemolysis.

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    • "This was in fact demonstrated by the enhanced susceptibility of IFN-í µí»¾-primed mice to bacterial sepsis, which showed increased TNF production upon LPS stimulation [46]. Higher sensitivity to secondary infections by bacteria, such as Salmonella, has also been observed in human malaria [47]. Moreover, this hyperactivation of the immune system may contribute for the posterior state of immune paralysis observed in septic patients [48]. "
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    DESCRIPTION: Although it has been established that effector memory CD4+ T cells play an important role in the protective immunity against chronic infections, little is known about the exact mechanisms responsible for their functioning and maintenance, as well as their effects on innate immune cells. Here we review recent data on the role of IFN-γ priming as a mechanism affecting both innate immune cells and effector memory CD4+ T cells. Suboptimal concentrations of IFN-γ are seemingly crucial for the optimization of innate immune cell functions (including phagocytosis and destruction of reminiscent pathogens), as well as for the survival and functioning of effector memory CD4+ T cells. Thus, IFN-γ priming can thus be considered an important bridge between innate and adaptive immunity.
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    • "Another strategy would be to modulate HO - 1 activity , since tin protoporphyrin can reverse HO - 1 – mediated neutrophil dysfunction ( Cunnington et al . , 2011 ) , but only after treatment of the hemolytic infection in order to avoid exacerbated heme toxicity . The greatest reduction in co - morbidity will undoubtedly come from public health measures to control or eliminate the hemolytic infections . Malaria control is already known to produce dramatic decreases in the population burden of NTS"
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    ABSTRACT: Increased susceptibility to co-infection with enteric Gram-negative bacteria, particularly non-typhoidal Salmonella, is reported in malaria and Oroya fever (Bartonella bacilliformis infection), and can lead to increased mortality. Accumulating epidemiological evidence indicates a causal association with risk of bacterial co-infection, rather than just co-incidence of common risk factors. Both malaria and Oroya fever are characterized by hemolysis, and observations in humans and animal models suggest that hemolysis causes the susceptibility to bacterial co-infection. Evidence from animal models implicates hemolysis in the impairment of a variety of host defense mechanisms, including macrophage dysfunction, neutrophil dysfunction, and impairment of adaptive immune responses. One mechanism supported by evidence from animal models and human data, is the induction of heme oxygenase-1 in bone marrow, which impairs the ability of developing neutrophils to mount a competent oxidative burst. As a result, dysfunctional neutrophils become a new niche for replication of intracellular bacteria. Here we critically appraise and summarize the key evidence for mechanisms which may contribute to these very specific combinations of co-infections, and propose interventions to ameliorate this risk.
    Frontiers in Microbiology 06/2015; 6:666. DOI:10.3389/fmicb.2015.00666 · 3.99 Impact Factor
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    • "because myeloid HO-1 is a potential target for therapeutic interventions in various inflammatory disorders such as sepsis [52] and malaria [53]. "
    Dataset: frbm2015

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