Document Detail


Sphingolipid degradation by Leishmania major is required for its resistance to acidic pH in the mammalian host.
MedLine Citation:
PMID:  21576322     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Wei Xu; Lijun Xin; Lynn Soong; Kai Zhang
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-05-16
Journal Detail:
Title:  Infection and immunity     Volume:  79     ISSN:  1098-5522     ISO Abbreviation:  Infect. Immun.     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-07-18     Completed Date:  2011-09-13     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  0246127     Medline TA:  Infect Immun     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3377-87     Citation Subset:  IM    
Affiliation:
Department of Biological Sciences, Texas Tech University, Lubbock, TX 79409, USA.
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MeSH Terms
Descriptor/Qualifier:
Acids / toxicity*
Animals
Cell Survival / drug effects
Female
Hydrogen-Ion Concentration
Leishmania major / drug effects*,  immunology,  metabolism,  pathogenicity*
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Sphingolipids / metabolism*
Stress, Physiological*
T-Lymphocytes / immunology
Virulence
Grant Support
ID/Acronym/Agency:
1R56AI081781/AI/NIAID NIH HHS; 5R01AI043003/AI/NIAID NIH HHS; 5R03AI076662/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Acids; 0/Sphingolipids
Comments/Corrections

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