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Nitric oxide controls proliferation of Leishmania major by inhibiting the recruitment of permissive host cells.

ABSTRACT: Nitric oxide (NO) is an important antimicrobial effector but also prevents unnecessary tissue damage by shutting down the recruitment of monocyte-derived phagocytes. Intracellular pathogens such as Leishmania major can hijack these cells as a niche for replication. Thus, NO might exert containment by restricting the availability of the cellular niche required for efficient pathogen proliferation. However, such indirect modes of action remain to be established. By combining mathematical modeling with intravital 2-photon biosensors of pathogen viability and proliferation, we show that low L. major proliferation results not from direct NO impact on the pathogen but from reduced availability of proliferation-permissive host cells. Although inhibiting NO production increases recruitment of these cells, and thus pathogen proliferation, blocking cell recruitment uncouples the NO effect from pathogen proliferation. Therefore, NO fulfills two distinct functions for L. major containment: permitting direct killing and restricting the supply of proliferation-permissive host cells.

SUBMITTER: Formaglio P

PROVIDER: S-EPMC8691385 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Nitric oxide controls proliferation of Leishmania major by inhibiting the recruitment of permissive host cells.

Formaglio Pauline P Alabdullah Mohamad M Siokis Anastasios A Handschuh Juliane J Sauerland Ina I Fu Yan Y Krone Anna A Gintschel Patricia P Stettin Juliane J Heyde Sandrina S Mohr Juliane J Philipsen Lars L Schröder Anja A Robert Philippe A PA Zhao Gang G Khailaie Sahamoddin S Dudeck Anne A Bertrand Jessica J Späth Gerald F GF Kahlfuß Sascha S Bousso Philippe P Schraven Burkhart B Huehn Jochen J Binder Sebastian S Meyer-Hermann Michael M Müller Andreas J AJ

Immunity 20211022 12

Nitric oxide (NO) is an important antimicrobial effector but also prevents unnecessary tissue damage by shutting down the recruitment of monocyte-derived phagocytes. Intracellular pathogens such as Leishmania major can hijack these cells as a niche for replication. Thus, NO might exert containment by restricting the availability of the cellular niche required for efficient pathogen proliferation. However, such indirect modes of action remain to be established. By combining mathematical modeling ...[more]

PMID: 34687607

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Project description:BackgroundArginase is an enzyme that converts L-arginine to urea and L-ornithine, an essential substrate for the polyamine pathway supporting Leishmania (Leishmania) amazonensis replication and its survival in the mammalian host. L-arginine is also the substrate of macrophage nitric oxide synthase 2 (NOS2) to produce nitric oxide (NO) that kills the parasite. This competition can define the fate of Leishmania infection.Methodology/principal findingsThe transcriptomic profiling identified a family of oxidoreductases in L. (L.) amazonensis wild-type (La-WT) and L. (L.) amazonensis arginase knockout (La-arg-) promastigotes and axenic amastigotes. We highlighted the identification of an oxidoreductase that could act as nitric oxide synthase-like (NOS-like), due to the following evidences: conserved domain composition, the participation of NO production during the time course of promastigotes growth and during the axenic amastigotes differentiation, regulation dependence on arginase activity, as well as reduction of NO amount through the NOS activity inhibition. NO quantification was measured by DAF-FM labeling analysis in a flow cytometry.Conclusions/significanceWe described an arginase-dependent NOS-like activity in L. (L.) amazonensis and its role in the parasite growth. The increased detection of NO production in the mid-stationary and late-stationary growth phases of La-WT promastigotes could suggest that this production is an important factor to metacyclogenesis triggering. On the other hand, La-arg- showed an earlier increase in NO production compared to La-WT, suggesting that NO production can be arginase-dependent. Interestingly, La-WT and La-arg- axenic amastigotes produced higher levels of NO than those observed in promastigotes. As a conclusion, our work suggested that NOS-like is expressed in Leishmania in the stationary growth phase promastigotes and amastigotes, and could be correlated to metacyclogenesis and amastigotes growth in a dependent way to the internal pool of L-arginine and arginase activity.

Dataset Information

Nitric oxide controls proliferation of Leishmania major by inhibiting the recruitment of permissive host cells.

Publications

Nitric oxide controls proliferation of Leishmania major by inhibiting the recruitment of permissive host cells.

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