Sphingolipid degradation by Leishmania major is required for its resistance to acidic pH in the mammalian host

Wei Xu, Lijun Xin, Lynn Soong, Kai Zhang

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Leishmania parasites alternate between flagellated promastigotes in sand flies and nonflagellated amastigotes in mammals, causing a spectrum of serious diseases. To survive, they must resist the harsh conditions in phagocytes (including acidic pH, elevated temperature, and increased oxidative/nitrosative stress) and evade the immune response. Recent studies have highlighted the importance of sphingolipid (SL) metabolism in Leishmania virulence. In particular, we have generated a Leishmania major iscl- mutant which is deficient in SL degradation but grows normally as promastigotes in culture. Importantly, iscl- mutants cannot induce pathology in either immunocompetent or immunodeficient mice yet are able to persist at low levels. In this study, we investigated how the degradation of SLs might contribute to Leishmania infection. First, unlike wild-type (WT) L. major, iscl- mutants do not trigger polarized T cell responses in mice. Second, like WT parasites, iscl- mutants possess the ability to downregulate macrophage activation by suppressing the production of interleukin-12 (IL-12) and nitric oxide. Third, during the stationary phase, iscl- promastigotes were extremely vulnerable to acidic pH but not to other adverse conditions, such as elevated temperature and oxidative/nitrosative stress. In addition, inhibition of phagosomal acidification significantly improved iscl- survival in murine macrophages. Together, these findings indicate that SL degradation by Leishmania is essential for its adaption to the acidic environment in phagolysosomes but is not required for the suppression of host cell activation. Finally, our studies with iscl- mutant-infected mice suggest that having viable, persistent parasites is not sufficient to provide immunity against virulent Leishmania challenge.

Original languageEnglish (US)
Pages (from-to)3377-3387
Number of pages11
JournalInfection and Immunity
Volume79
Issue number8
DOIs
StatePublished - Aug 2011

Fingerprint

Leishmania major
Sphingolipids
Leishmania
Parasites
Oxidative Stress
Psychodidae
Phagosomes
Temperature
Macrophage Activation
Interleukin-12
Phagocytes
Virulence
Mammals
Immunity
Nitric Oxide
Down-Regulation
Macrophages
Pathology
T-Lymphocytes
Infection

ASJC Scopus subject areas

  • Immunology
  • Microbiology
  • Parasitology
  • Infectious Diseases

Cite this

Sphingolipid degradation by Leishmania major is required for its resistance to acidic pH in the mammalian host. / Xu, Wei; Xin, Lijun; Soong, Lynn; Zhang, Kai.

In: Infection and Immunity, Vol. 79, No. 8, 08.2011, p. 3377-3387.

Research output: Contribution to journalArticle

@article{ed7325c91a884c96a87c6fa34c74dd27,
title = "Sphingolipid degradation by Leishmania major is required for its resistance to acidic pH in the mammalian host",
abstract = "Leishmania parasites alternate between flagellated promastigotes in sand flies and nonflagellated amastigotes in mammals, causing a spectrum of serious diseases. To survive, they must resist the harsh conditions in phagocytes (including acidic pH, elevated temperature, and increased oxidative/nitrosative stress) and evade the immune response. Recent studies have highlighted the importance of sphingolipid (SL) metabolism in Leishmania virulence. In particular, we have generated a Leishmania major iscl- mutant which is deficient in SL degradation but grows normally as promastigotes in culture. Importantly, iscl- mutants cannot induce pathology in either immunocompetent or immunodeficient mice yet are able to persist at low levels. In this study, we investigated how the degradation of SLs might contribute to Leishmania infection. First, unlike wild-type (WT) L. major, iscl- mutants do not trigger polarized T cell responses in mice. Second, like WT parasites, iscl- mutants possess the ability to downregulate macrophage activation by suppressing the production of interleukin-12 (IL-12) and nitric oxide. Third, during the stationary phase, iscl- promastigotes were extremely vulnerable to acidic pH but not to other adverse conditions, such as elevated temperature and oxidative/nitrosative stress. In addition, inhibition of phagosomal acidification significantly improved iscl- survival in murine macrophages. Together, these findings indicate that SL degradation by Leishmania is essential for its adaption to the acidic environment in phagolysosomes but is not required for the suppression of host cell activation. Finally, our studies with iscl- mutant-infected mice suggest that having viable, persistent parasites is not sufficient to provide immunity against virulent Leishmania challenge.",
author = "Wei Xu and Lijun Xin and Lynn Soong and Kai Zhang",
year = "2011",
month = "8",
doi = "10.1128/IAI.00037-11",
language = "English (US)",
volume = "79",
pages = "3377--3387",
journal = "Infection and Immunity",
issn = "0019-9567",
publisher = "American Society for Microbiology",
number = "8",

}

TY - JOUR

T1 - Sphingolipid degradation by Leishmania major is required for its resistance to acidic pH in the mammalian host

AU - Xu, Wei

AU - Xin, Lijun

AU - Soong, Lynn

AU - Zhang, Kai

PY - 2011/8

Y1 - 2011/8

N2 - Leishmania parasites alternate between flagellated promastigotes in sand flies and nonflagellated amastigotes in mammals, causing a spectrum of serious diseases. To survive, they must resist the harsh conditions in phagocytes (including acidic pH, elevated temperature, and increased oxidative/nitrosative stress) and evade the immune response. Recent studies have highlighted the importance of sphingolipid (SL) metabolism in Leishmania virulence. In particular, we have generated a Leishmania major iscl- mutant which is deficient in SL degradation but grows normally as promastigotes in culture. Importantly, iscl- mutants cannot induce pathology in either immunocompetent or immunodeficient mice yet are able to persist at low levels. In this study, we investigated how the degradation of SLs might contribute to Leishmania infection. First, unlike wild-type (WT) L. major, iscl- mutants do not trigger polarized T cell responses in mice. Second, like WT parasites, iscl- mutants possess the ability to downregulate macrophage activation by suppressing the production of interleukin-12 (IL-12) and nitric oxide. Third, during the stationary phase, iscl- promastigotes were extremely vulnerable to acidic pH but not to other adverse conditions, such as elevated temperature and oxidative/nitrosative stress. In addition, inhibition of phagosomal acidification significantly improved iscl- survival in murine macrophages. Together, these findings indicate that SL degradation by Leishmania is essential for its adaption to the acidic environment in phagolysosomes but is not required for the suppression of host cell activation. Finally, our studies with iscl- mutant-infected mice suggest that having viable, persistent parasites is not sufficient to provide immunity against virulent Leishmania challenge.

AB - Leishmania parasites alternate between flagellated promastigotes in sand flies and nonflagellated amastigotes in mammals, causing a spectrum of serious diseases. To survive, they must resist the harsh conditions in phagocytes (including acidic pH, elevated temperature, and increased oxidative/nitrosative stress) and evade the immune response. Recent studies have highlighted the importance of sphingolipid (SL) metabolism in Leishmania virulence. In particular, we have generated a Leishmania major iscl- mutant which is deficient in SL degradation but grows normally as promastigotes in culture. Importantly, iscl- mutants cannot induce pathology in either immunocompetent or immunodeficient mice yet are able to persist at low levels. In this study, we investigated how the degradation of SLs might contribute to Leishmania infection. First, unlike wild-type (WT) L. major, iscl- mutants do not trigger polarized T cell responses in mice. Second, like WT parasites, iscl- mutants possess the ability to downregulate macrophage activation by suppressing the production of interleukin-12 (IL-12) and nitric oxide. Third, during the stationary phase, iscl- promastigotes were extremely vulnerable to acidic pH but not to other adverse conditions, such as elevated temperature and oxidative/nitrosative stress. In addition, inhibition of phagosomal acidification significantly improved iscl- survival in murine macrophages. Together, these findings indicate that SL degradation by Leishmania is essential for its adaption to the acidic environment in phagolysosomes but is not required for the suppression of host cell activation. Finally, our studies with iscl- mutant-infected mice suggest that having viable, persistent parasites is not sufficient to provide immunity against virulent Leishmania challenge.

UR - http://www.scopus.com/inward/record.url?scp=79961118829&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79961118829&partnerID=8YFLogxK

U2 - 10.1128/IAI.00037-11

DO - 10.1128/IAI.00037-11

M3 - Article

VL - 79

SP - 3377

EP - 3387

JO - Infection and Immunity

JF - Infection and Immunity

SN - 0019-9567

IS - 8

ER -