Photoconvertible Pathogen Labeling Reveals Nitric Oxide Control of Leishmania major Infection In Vivo via Dampening of Parasite Metabolism

Müller, Andreas J.; Aeschlimann, Salome; Olekhnovitch, Romain; Dacher, Mariko; Späth, Gérald F.; Bousso, Philippe

doi:10.1016/j.chom.2013.09.008

Cited by 55 publications

(68 citation statements)

References 35 publications

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“…This double-layered propagation of effector functions likely provides an effective strategy for the containment of intracellular pathogen in the infected tissue. Of note, we have recently observed that, in the first weeks of infection, NO could limit parasite metabolism without systematically inducing parasite death (52). The lethal and sublethal modes of parasite control mediated by NO likely correspond to distinct concentrations collectively produced by recruited phagocytes.…”

Section: Discussionmentioning

confidence: 99%

Collective nitric oxide production provides tissue-wide immunity during Leishmania infection

Olekhnovitch¹,

Ryffel²,

Müller³

et al. 2014

J. Clin. Invest.

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Nitric oxide (NO) production is critical for the host defense against intracellular pathogens; however, it is unclear whether NO-dependent control of intracellular organisms depends on cell-intrinsic or cell-extrinsic activity of NO. For example, NO production by infected phagocytes may enable these cells to individually control their pathogen burden. Alternatively, the ability of NO to diffuse across cell membranes might be critical for infection control. Here, using a murine ear infection model, we found that, during infection with the intracellular parasite Leishmania major, expression of inducible NO synthase does not confer a cell-intrinsic ability to lower parasite content. We demonstrated that the diffusion of NO promotes equally effective parasite killing in NO-producing and bystander cells. Importantly, the collective production of NO by numerous phagocytes was necessary to reach an effective antimicrobial activity. We propose that, in contrast to a cell-autonomous mode of pathogen control, this cooperative mechanism generates an antimicrobial milieu that provides the basis for pathogen containment at the tissue level. IntroductionTo tackle cell-invasive pathogens, multicellular organisms rely on a wide range of intracellular defense mechanisms. These are induced in infected cells by signals derived from pathogen-associated molecular pattern (PAMPs) recognition and/or by inflammatory cytokines (1). Among these effector mechanisms, the production of nitric oxide (NO) by the inducible NO synthase (iNOS, also known as NOS2) plays a key role against infections by intracellular bacteria (such as Mycobacterium tuberculosis, Listeria monocytogenes, Salmonella enterica) and parasites (Leishmania and intracellular Trypanosoma spp.) (2). However, how NO production is induced in vivo and results in the control of intracellular pathogens has not been fully clarified.Cutaneous Leishmania major infection in mice is a well-established model to study intracellular defense mechanisms such as NO production. L. major parasites reside and replicate in parasitophorous vacuoles (PVs) inside neutrophils and mononuclear phagocytes (mPhagocytes; including macrophages and dendritic cells) (3). Previous studies have demonstrated the central role of NO in the resolution of the infection: iNOS expression in phagocytes results in efficient killing of L. major parasites in vitro and is critical for controlling the infection in vivo (4-7).iNOS induction is a tightly regulated process that requires concomitant activation of the STAT and NF-κB pathways (8). Typically, pioneer in vitro experiments showed that a combination of IFN-γ with LPS or TNF-α efficiently triggered iNOS expression in macrophages (9, 10). Since then, several other stimuli, such as TLR agonists (CpG), costimulatory molecules (CD40L), inflammatory cytokines (Il-1β, IL-17, IL-18), or parasite/bacteria infection, have been shown to be potent iNOS inducers in

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Section: Discussionmentioning

confidence: 99%

Collective nitric oxide production provides tissue-wide immunity during Leishmania infection

Olekhnovitch¹,

Ryffel²,

Müller³

et al. 2014

J. Clin. Invest.

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“…First discovered in activated macrophages (52), the complex role played by NO in various biological systems is becoming increasingly appreciated (53). Aside from direct toxic effects exerted against infectious microorganisms (8,54,55), it appears that NO can also act in an inhibitory manner to limit the proliferation of pathogens such as Leishmania, thereby favoring clearance of the infection by the immune system (56). This inhibitory capacity has been previously noted in respect to T cells exposed to NO produced by activated macrophages (57) or monocytes (58).…”

Section: Discussionmentioning

confidence: 99%

Monocyte-Derived Dendritic Cells Promote Th Polarization, whereas Conventional Dendritic Cells Promote Th Proliferation

Chow

Lew

Sutherland

et al. 2016

The Journal of Immunology

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Monocyte-derived dendritic cells (moDCs) dramatically increase in numbers upon infection and inflammation; accordingly, we found that this also occurs during allogeneic responses. Despite their prominence, how emergent moDCs and resident conventional DCs (cDCs) divide their labor as APCs remain undefined. Hence, we compared both direct and indirect presentation by murine moDCs versus cDCs. We found that, despite having equivalent MHC class II expression and in vitro survival, moDCs were 20-fold less efficient than cDCs at inducing CD4+ T cell proliferation through both direct and indirect Ag presentation. Despite this, moDCs were more potent at inducing Th1 and Th17 differentiation (e.g., 8-fold higher IFN-γ and 2-fold higher IL-17A in T cell cocultures), whereas cDCs induced 10-fold higher IL-2 production. Intriguingly, moDCs potently reduced the ability of cDCs to stimulate T cell proliferation in vitro and in vivo, partially through NO production. We surmise that such division of labor between moDCs and cDCs has implications for their respective roles in the immune response.

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“…5). Correspondingly, several studies suggest that the action of NO against amastigotes may be based more on metabolic inhibition rather than killing (42,43), arising from a tissuewide "collective" effect (44). This would likely be less effective at low PIP densities seen in persistent infections.…”

Section: Do Slowly/nonreplicating Pips Enter a Quiescent Metabolic Stmentioning

confidence: 99%

“…Thus, other approaches will be required to explore the metabolic status of the slowly/nonreplicating L. major PIPs. NO synthesis may act to dampen parasite metabolism in AIPs (42,43), and this likely occurs with PIPs as well. The quiescent forms of many pathogens show differences in gene expression from actively replicating forms (48,49).…”

Section: Do Slowly/nonreplicating Pips Enter a Quiescent Metabolic Stmentioning

confidence: 99%

“…Thus, up-regulation of arginase does not contribute to PIP survival in iNOS + cells. PIPs could be intrinsically resistant to NO, as there is increasing evidence that NO may act against amastigotes by mechanisms other than toxicity (42)(43)(44). In the absence of an in vitro PIP model, as a surrogate we compared the relative NO tolerance of amastigotes to purified infectious metacyclic promastigotes following MΦ infection and induction of NO by IFN-γ/LPS activation (45).…”

Section: Arg1mentioning

confidence: 99%

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Continual renewal and replication of persistentLeishmania majorparasites in concomitantly immune hosts

Mandell

Beverley

2017

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

107

112

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In most natural infections or after recovery, small numbers of Leishmania parasites remain indefinitely in the host. Persistent parasites play a vital role in protective immunity against disease pathology upon reinfection through the process of concomitant immunity, as well as in transmission and reactivation, yet are poorly understood. A key question is whether persistent parasites undergo replication, and we devised several approaches to probe the small numbers in persistent infections. We find two populations of persistent Leishmania major: one rapidly replicating, similar to parasites in acute infections, and another showing little evidence of replication. Persistent Leishmania were not found in "safe" immunoprivileged cell types, instead residing in macrophages and DCs, ∼60% of which expressed inducible nitric oxide synthase (iNOS). Remarkably, parasites within iNOS + cells showed normal morphology and genome integrity and labeled comparably with BrdU to parasites within iNOS − cells, suggesting that these parasites may be unexpectedly resistant to NO. Nonetheless, because persistent parasite numbers remain roughly constant over time, their replication implies that ongoing destruction likewise occurs. Similar results were obtained with the attenuated lpg2 − mutant, a convenient model that rapidly enters a persistent state without inducing pathology due to loss of the Golgi GDP mannose transporter. These data shed light on Leishmania persistence and concomitant immunity, suggesting a model wherein a parasite reservoir repopulates itself indefinitely, whereas some progeny are terminated in antigen-presenting cells, thereby stimulating immunity. This model may be relevant to understanding immunity to other persistent pathogen infections.latency | quiescence | trypanosomatid protozoan parasite | vaccination | stem cell-like

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Photoconvertible Pathogen Labeling Reveals Nitric Oxide Control of Leishmania major Infection In Vivo via Dampening of Parasite Metabolism

Cited by 55 publications

References 35 publications

Collective nitric oxide production provides tissue-wide immunity during Leishmania infection

Collective nitric oxide production provides tissue-wide immunity during Leishmania infection

Monocyte-Derived Dendritic Cells Promote Th Polarization, whereas Conventional Dendritic Cells Promote Th Proliferation

Continual renewal and replication of persistentLeishmania majorparasites in concomitantly immune hosts

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