Rapid Sequestration of Leishmania mexicana by Neutrophils Contributes to the Development of Chronic Lesion

Benjamin P Hurrell, Steffen Schuster, Eva Grün, Manuel Coutaz, Roderick A Williams, Werner Held, Bernard Malissen, Marie Malissen, Shida Yousefi, Hans-Uwe Simon, Andreas J Müller, Fabienne Tacchini-Cottier

Research output: Contribution to journalArticle

Abstract

The protozoan Leishmania mexicana parasite causes chronic non-healing cutaneous lesions in humans and mice with poor parasite control. The mechanisms preventing the development of a protective immune response against this parasite are unclear. Here we provide data demonstrating that parasite sequestration by neutrophils is responsible for disease progression in mice. Within hours of infection L. mexicana induced the local recruitment of neutrophils, which ingested parasites and formed extracellular traps without markedly impairing parasite survival. We further showed that the L. mexicana-induced recruitment of neutrophils impaired the early recruitment of dendritic cells at the site of infection as observed by intravital 2-photon microscopy and flow cytometry analysis. Indeed, infection of neutropenic Genista mice and of mice depleted of neutrophils at the onset of infection demonstrated a prominent role for neutrophils in this process. Furthermore, an increase in monocyte-derived dendritic cells was also observed in draining lymph nodes of neutropenic mice, correlating with subsequent increased frequency of IFNγ-secreting T helper cells, and better parasite control leading ultimately to complete healing of the lesion. Altogether, these findings show that L. mexicana exploits neutrophils to block the induction of a protective immune response and impairs the control of lesion development. Our data thus demonstrate an unanticipated negative role for these innate immune cells in host defense, suggesting that in certain forms of cutaneous leishmaniasis, regulating neutrophil recruitment could be a strategy to promote lesion healing.

Original languageEnglish
Article numbere1004929
JournalPLOS Pathogens
Volume11
Issue number5
DOIs
Publication statusPublished - May 2015

Fingerprint

Leishmania mexicana
Parasites
Neutrophils
Neutrophil Infiltration
Communicable Disease Control
Infection
Dendritic Cells
Genista
Cutaneous Leishmaniasis
Helper-Inducer T-Lymphocytes
Photons
Disease Progression
Monocytes
Microscopy
Flow Cytometry
Lymph Nodes
Skin

Keywords

  • Animals
  • Cells, Cultured
  • Chronic Disease
  • Cytokines
  • Dendritic Cells
  • Flow Cytometry
  • Leishmania mexicana
  • Leishmaniasis, Cutaneous
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Monocytes
  • Neutrophil Infiltration
  • Neutrophils
  • RNA, Messenger
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction

Cite this

Hurrell, Benjamin P ; Schuster, Steffen ; Grün, Eva ; Coutaz, Manuel ; Williams, Roderick A ; Held, Werner ; Malissen, Bernard ; Malissen, Marie ; Yousefi, Shida ; Simon, Hans-Uwe ; Müller, Andreas J ; Tacchini-Cottier, Fabienne. / Rapid Sequestration of Leishmania mexicana by Neutrophils Contributes to the Development of Chronic Lesion. In: PLOS Pathogens. 2015 ; Vol. 11, No. 5.
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abstract = "The protozoan Leishmania mexicana parasite causes chronic non-healing cutaneous lesions in humans and mice with poor parasite control. The mechanisms preventing the development of a protective immune response against this parasite are unclear. Here we provide data demonstrating that parasite sequestration by neutrophils is responsible for disease progression in mice. Within hours of infection L. mexicana induced the local recruitment of neutrophils, which ingested parasites and formed extracellular traps without markedly impairing parasite survival. We further showed that the L. mexicana-induced recruitment of neutrophils impaired the early recruitment of dendritic cells at the site of infection as observed by intravital 2-photon microscopy and flow cytometry analysis. Indeed, infection of neutropenic Genista mice and of mice depleted of neutrophils at the onset of infection demonstrated a prominent role for neutrophils in this process. Furthermore, an increase in monocyte-derived dendritic cells was also observed in draining lymph nodes of neutropenic mice, correlating with subsequent increased frequency of IFNγ-secreting T helper cells, and better parasite control leading ultimately to complete healing of the lesion. Altogether, these findings show that L. mexicana exploits neutrophils to block the induction of a protective immune response and impairs the control of lesion development. Our data thus demonstrate an unanticipated negative role for these innate immune cells in host defense, suggesting that in certain forms of cutaneous leishmaniasis, regulating neutrophil recruitment could be a strategy to promote lesion healing.",
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year = "2015",
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Hurrell, BP, Schuster, S, Grün, E, Coutaz, M, Williams, RA, Held, W, Malissen, B, Malissen, M, Yousefi, S, Simon, H-U, Müller, AJ & Tacchini-Cottier, F 2015, 'Rapid Sequestration of Leishmania mexicana by Neutrophils Contributes to the Development of Chronic Lesion' PLOS Pathogens, vol. 11, no. 5, e1004929. https://doi.org/10.1371/journal.ppat.1004929

Rapid Sequestration of Leishmania mexicana by Neutrophils Contributes to the Development of Chronic Lesion. / Hurrell, Benjamin P; Schuster, Steffen; Grün, Eva; Coutaz, Manuel; Williams, Roderick A; Held, Werner; Malissen, Bernard; Malissen, Marie; Yousefi, Shida; Simon, Hans-Uwe; Müller, Andreas J; Tacchini-Cottier, Fabienne.

In: PLOS Pathogens, Vol. 11, No. 5, e1004929, 05.2015.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Rapid Sequestration of Leishmania mexicana by Neutrophils Contributes to the Development of Chronic Lesion

AU - Hurrell, Benjamin P

AU - Schuster, Steffen

AU - Grün, Eva

AU - Coutaz, Manuel

AU - Williams, Roderick A

AU - Held, Werner

AU - Malissen, Bernard

AU - Malissen, Marie

AU - Yousefi, Shida

AU - Simon, Hans-Uwe

AU - Müller, Andreas J

AU - Tacchini-Cottier, Fabienne

PY - 2015/5

Y1 - 2015/5

N2 - The protozoan Leishmania mexicana parasite causes chronic non-healing cutaneous lesions in humans and mice with poor parasite control. The mechanisms preventing the development of a protective immune response against this parasite are unclear. Here we provide data demonstrating that parasite sequestration by neutrophils is responsible for disease progression in mice. Within hours of infection L. mexicana induced the local recruitment of neutrophils, which ingested parasites and formed extracellular traps without markedly impairing parasite survival. We further showed that the L. mexicana-induced recruitment of neutrophils impaired the early recruitment of dendritic cells at the site of infection as observed by intravital 2-photon microscopy and flow cytometry analysis. Indeed, infection of neutropenic Genista mice and of mice depleted of neutrophils at the onset of infection demonstrated a prominent role for neutrophils in this process. Furthermore, an increase in monocyte-derived dendritic cells was also observed in draining lymph nodes of neutropenic mice, correlating with subsequent increased frequency of IFNγ-secreting T helper cells, and better parasite control leading ultimately to complete healing of the lesion. Altogether, these findings show that L. mexicana exploits neutrophils to block the induction of a protective immune response and impairs the control of lesion development. Our data thus demonstrate an unanticipated negative role for these innate immune cells in host defense, suggesting that in certain forms of cutaneous leishmaniasis, regulating neutrophil recruitment could be a strategy to promote lesion healing.

AB - The protozoan Leishmania mexicana parasite causes chronic non-healing cutaneous lesions in humans and mice with poor parasite control. The mechanisms preventing the development of a protective immune response against this parasite are unclear. Here we provide data demonstrating that parasite sequestration by neutrophils is responsible for disease progression in mice. Within hours of infection L. mexicana induced the local recruitment of neutrophils, which ingested parasites and formed extracellular traps without markedly impairing parasite survival. We further showed that the L. mexicana-induced recruitment of neutrophils impaired the early recruitment of dendritic cells at the site of infection as observed by intravital 2-photon microscopy and flow cytometry analysis. Indeed, infection of neutropenic Genista mice and of mice depleted of neutrophils at the onset of infection demonstrated a prominent role for neutrophils in this process. Furthermore, an increase in monocyte-derived dendritic cells was also observed in draining lymph nodes of neutropenic mice, correlating with subsequent increased frequency of IFNγ-secreting T helper cells, and better parasite control leading ultimately to complete healing of the lesion. Altogether, these findings show that L. mexicana exploits neutrophils to block the induction of a protective immune response and impairs the control of lesion development. Our data thus demonstrate an unanticipated negative role for these innate immune cells in host defense, suggesting that in certain forms of cutaneous leishmaniasis, regulating neutrophil recruitment could be a strategy to promote lesion healing.

KW - Animals

KW - Cells, Cultured

KW - Chronic Disease

KW - Cytokines

KW - Dendritic Cells

KW - Flow Cytometry

KW - Leishmania mexicana

KW - Leishmaniasis, Cutaneous

KW - Mice

KW - Mice, Inbred BALB C

KW - Mice, Inbred C57BL

KW - Monocytes

KW - Neutrophil Infiltration

KW - Neutrophils

KW - RNA, Messenger

KW - Real-Time Polymerase Chain Reaction

KW - Reverse Transcriptase Polymerase Chain Reaction

U2 - 10.1371/journal.ppat.1004929

DO - 10.1371/journal.ppat.1004929

M3 - Article

VL - 11

JO - PLOS Pathogens

JF - PLOS Pathogens

SN - 1553-7366

IS - 5

M1 - e1004929

ER -