Collective nitric oxide production provides tissue-wide immunity during Leishmania infection
Romain Olekhnovitch, Bernhard Ryffel, Andreas J. Müller, Philippe Bousso
Romain Olekhnovitch, Bernhard Ryffel, Andreas J. Müller, Philippe Bousso
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Research Article Microbiology

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

Abstract

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.

Authors

Romain Olekhnovitch, Bernhard Ryffel, Andreas J. Müller, Philippe Bousso

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Figure 2

Rapid iNOS induction in mPhagocytes does not require cell infection.

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Rapid iNOS induction in mPhagocytes does not require cell infection. C57...
C57BL/6 mice were infected with L. major, and 2 weeks later, GFP-BMCs isolated from GFP-expressing Rag2–/– mice were transferred into infected recipients. (A) Ear tissues were analyzed from day 1 to day 5 after injection, and infection of GFP-expressing mPhagocytes was followed by flow cytometry. (B) Three days after injection, mice were anesthetized and intravital microscopy was performed on infected ears. Time-lapse images show cell invasion by L. major parasite. The area delimited by a white rectangle is shown at higher magnification; white arrows indicate the invading parasite. Scale bar: 30 μm (top); 20 μm (bottom). (C) Frequency of iNOS-expressing cells and of infected cells within recruited mPhagocytes detected by flow cytometry. (D) Frequency of infected cells among iNOS-expressing mPhagocytes from day 1 to day 5 after injection. Horizontal lines represent average values. Numbers shown in flow cytometry profiles represent the percentage of cells falling into the indicated region. *P < 0.05; **P < 0.01; ***P < 0.001. Data are representative of 3 independent experiments.