KEGG   PATHWAY: hsa05140Help
Entry
hsa05140                    Pathway                                

Name
Leishmaniasis - Homo sapiens (human)
Description
Leishmania is an intracellular protozoan parasite of macrophages that causes visceral, mucosal, and cutaneous diseases. The parasite is transmitted to humans by sandflies, where they survive and proliferate intracellularly by deactivating the macrophage. Successful infection of Leishmania is achieved by alteration of signaling events in the host cell, leading to enhanced production of the autoinhibitory molecules like TGF-beta and decreased induction of cytokines such as IL12 for protective immunity. Nitric oxide production is also inhibited. In addition, defective expression of major histocompatibility complex (MHC) genes silences subsequent T cell activation mediated by macrophages, resulting in abnormal immune responses.
Class
Human Diseases; Infectious disease: parasitic
BRITE hierarchy
Pathway map
hsa05140  Leishmaniasis
hsa05140

Ortholog table
Disease
H00359  Leishmaniasis
Organism
Homo sapiens (human) [GN:hsa]
Gene
7097  TLR2; toll like receptor 2 [KO:K10159]
7099  TLR4; toll like receptor 4 [KO:K10160]
4615  MYD88; MYD88 innate immune signal transduction adaptor [KO:K04729]
3654  IRAK1; interleukin 1 receptor associated kinase 1 [KO:K04730] [EC:2.7.11.1]
51135  IRAK4; interleukin 1 receptor associated kinase 4 [KO:K04733] [EC:2.7.11.1]
7189  TRAF6; TNF receptor associated factor 6 [KO:K03175] [EC:2.3.2.27]
6885  MAP3K7; mitogen-activated protein kinase kinase kinase 7 [KO:K04427] [EC:2.7.11.25]
10454  TAB1; TGF-beta activated kinase 1 (MAP3K7) binding protein 1 [KO:K04403]
23118  TAB2; TGF-beta activated kinase 1 (MAP3K7) binding protein 2 [KO:K04404]
4793  NFKBIB; NFKB inhibitor beta [KO:K02581]
4792  NFKBIA; NFKB inhibitor alpha [KO:K04734]
4790  NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
5970  RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]
3552  IL1A; interleukin 1 alpha [KO:K04383]
3553  IL1B; interleukin 1 beta [KO:K04519]
3592  IL12A; interleukin 12A [KO:K05406]
3593  IL12B; interleukin 12B [KO:K05425]
7124  TNF; tumor necrosis factor [KO:K03156]
3565  IL4; interleukin 4 [KO:K05430]
4843  NOS2; nitric oxide synthase 2 [KO:K13241] [EC:1.14.13.39]
3586  IL10; interleukin 10 [KO:K05443]
7040  TGFB1; transforming growth factor beta 1 [KO:K13375]
7042  TGFB2; transforming growth factor beta 2 [KO:K13376]
7043  TGFB3; transforming growth factor beta 3 [KO:K13377]
718  C3; complement C3 [KO:K03990]
1378  CR1; complement C3b/C4b receptor 1 (Knops blood group) [KO:K04011]
3684  ITGAM; integrin subunit alpha M [KO:K06461]
3689  ITGB2; integrin subunit beta 2 [KO:K06464]
102723407  IGH; immunoglobulin heavy variable 4-38-2-like [KO:K06856]
2209  FCGR1A; Fc fragment of IgG receptor Ia [KO:K06498]
2212  FCGR2A; Fc fragment of IgG receptor IIa [KO:K06472]
9103  FCGR2C; Fc fragment of IgG receptor IIc (gene/pseudogene) [KO:K16824]
2214  FCGR3A; Fc fragment of IgG receptor IIIa [KO:K06463]
2215  FCGR3B; Fc fragment of IgG receptor IIIb [KO:K06463]
3676  ITGA4; integrin subunit alpha 4 [KO:K06483]
3688  ITGB1; integrin subunit beta 1 [KO:K05719]
5743  PTGS2; prostaglandin-endoperoxide synthase 2 [KO:K11987] [EC:1.14.99.1]
5579  PRKCB; protein kinase C beta [KO:K19662] [EC:2.7.11.13]
653361  NCF1; neutrophil cytosolic factor 1 [KO:K08011]
4688  NCF2; neutrophil cytosolic factor 2 [KO:K08010]
4689  NCF4; neutrophil cytosolic factor 4 [KO:K08012]
1536  CYBB; cytochrome b-245 beta chain [KO:K21421] [EC:1.-.-.-]
1535  CYBA; cytochrome b-245 alpha chain [KO:K08009]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
2002  ELK1; ETS transcription factor ELK1 [KO:K04375]
2353  FOS; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379]
3725  JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448]
5600  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
6300  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
5603  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
1432  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
3458  IFNG; interferon gamma [KO:K04687]
3459  IFNGR1; interferon gamma receptor 1 [KO:K05132]
3460  IFNGR2; interferon gamma receptor 2 [KO:K05133]
3716  JAK1; Janus kinase 1 [KO:K11217] [EC:2.7.10.2]
3717  JAK2; Janus kinase 2 [KO:K04447] [EC:2.7.10.2]
6772  STAT1; signal transducer and activator of transcription 1 [KO:K11220]
3108  HLA-DMA; major histocompatibility complex, class II, DM alpha [KO:K06752]
3109  HLA-DMB; major histocompatibility complex, class II, DM beta [KO:K06752]
3111  HLA-DOA; major histocompatibility complex, class II, DO alpha [KO:K06752]
3112  HLA-DOB; major histocompatibility complex, class II, DO beta [KO:K06752]
3113  HLA-DPA1; major histocompatibility complex, class II, DP alpha 1 [KO:K06752]
3115  HLA-DPB1; major histocompatibility complex, class II, DP beta 1 [KO:K06752]
3117  HLA-DQA1; major histocompatibility complex, class II, DQ alpha 1 [KO:K06752]
3118  HLA-DQA2; major histocompatibility complex, class II, DQ alpha 2 [KO:K06752]
3119  HLA-DQB1; major histocompatibility complex, class II, DQ beta 1 [KO:K06752]
3122  HLA-DRA; major histocompatibility complex, class II, DR alpha [KO:K06752]
3123  HLA-DRB1; major histocompatibility complex, class II, DR beta 1 [KO:K06752]
3125  HLA-DRB3; major histocompatibility complex, class II, DR beta 3 [KO:K06752]
3126  HLA-DRB4; major histocompatibility complex, class II, DR beta 4 [KO:K06752]
3127  HLA-DRB5; major histocompatibility complex, class II, DR beta 5 [KO:K06752]
65108  MARCKSL1; MARCKS like 1 [KO:K13536]
5777  PTPN6; protein tyrosine phosphatase non-receptor type 6 [KO:K05697] [EC:3.1.3.48]
Compound
C00076  Calcium cation
C00195  N-Acylsphingosine
C00219  Arachidonate
C00533  Nitric oxide
C00584  Prostaglandin E2
C02737  Phosphatidylserine
Reference
  Authors
Cunningham AC
  Title
Parasitic adaptive mechanisms in infection by leishmania.
  Journal
Exp Mol Pathol 72:132-41 (2002)
DOI:10.1006/exmp.2002.2418
Reference
  Authors
Nandan D, Knutson KL, Lo R, Reiner NE
  Title
Exploitation of host cell signaling machinery: activation of macrophage phosphotyrosine phosphatases as a novel mechanism of molecular microbial pathogenesis.
  Journal
J Leukoc Biol 67:464-70 (2000)
DOI:10.1002/jlb.67.4.464
Reference
PMID:7591091
  Authors
Nandan D, Reiner NE
  Title
Attenuation of gamma interferon-induced tyrosine phosphorylation in mononuclear phagocytes infected with Leishmania donovani: selective inhibition of signaling through Janus kinases and Stat1.
  Journal
Infect Immun 63:4495-500 (1995)
Reference
  Authors
Nandan D, Lo R, Reiner NE
  Title
Activation of phosphotyrosine phosphatase activity attenuates mitogen-activated protein kinase signaling and inhibits c-FOS and nitric oxide synthase expression in macrophages infected with Leishmania donovani.
  Journal
Infect Immun 67:4055-63 (1999)
Reference
PMID:7916951
  Authors
Reiner NE
  Title
Altered cell signaling and mononuclear phagocyte deactivation during intracellular infection.
  Journal
Immunol Today 15:374-81 (1994)
DOI:10.1016/0167-5699(94)90176-7
Reference
  Authors
Nandan D, Reiner NE
  Title
Leishmania donovani engages in regulatory interference by targeting macrophage protein tyrosine phosphatase SHP-1.
  Journal
Clin Immunol 114:266-77 (2005)
DOI:10.1016/j.clim.2004.07.017
Reference
  Authors
Kima PE
  Title
The amastigote forms of Leishmania are experts at exploiting host cell processes to establish infection and persist.
  Journal
Int J Parasitol 37:1087-96 (2007)
DOI:10.1016/j.ijpara.2007.04.007
Reference
  Authors
Forget G, Gregory DJ, Olivier M
  Title
Proteasome-mediated degradation of STAT1alpha following infection of macrophages with Leishmania donovani.
  Journal
J Biol Chem 280:30542-9 (2005)
DOI:10.1074/jbc.M414126200
Reference
  Authors
Cameron P, McGachy A, Anderson M, Paul A, Coombs GH, Mottram JC, Alexander J, Plevin R
  Title
Inhibition of lipopolysaccharide-induced macrophage IL-12 production by Leishmania mexicana amastigotes: the role of cysteine peptidases and the NF-kappaB signaling pathway.
  Journal
J Immunol 173:3297-304 (2004)
DOI:10.4049/jimmunol.173.5.3297
Reference
  Authors
Tuon FF, Amato VS, Bacha HA, Almusawi T, Duarte MI, Amato Neto V
  Title
Toll-like receptors and leishmaniasis.
  Journal
Infect Immun 76:866-72 (2008)
DOI:10.1128/IAI.01090-07
Reference
  Authors
Kropf P, Freudenberg N, Kalis C, Modolell M, Herath S, Galanos C, Freudenberg M, Muller I
  Title
Infection of C57BL/10ScCr and C57BL/10ScNCr mice with Leishmania major reveals a role for Toll-like receptor 4 in the control of parasite replication.
  Journal
J Leukoc Biol 76:48-57 (2004)
DOI:10.1189/jlb.1003484
Reference
  Authors
Feng GJ, Goodridge HS, Harnett MM, Wei XQ, Nikolaev AV, Higson AP, Liew FY
  Title
Extracellular signal-related kinase (ERK) and p38 mitogen-activated protein (MAP) kinases differentially regulate the lipopolysaccharide-mediated induction of inducible nitric oxide synthase and IL-12 in macrophages: Leishmania phosphoglycans subvert macrophage IL-12 production by targeting ERK MAP kinase.
  Journal
J Immunol 163:6403-12 (1999)
Reference
  Authors
Olivier M, Gregory DJ, Forget G
  Title
Subversion mechanisms by which Leishmania parasites can escape the host immune response: a signaling point of view.
  Journal
Clin Microbiol Rev 18:293-305 (2005)
DOI:10.1128/CMR.18.2.293-305.2005
Reference
  Authors
Matte C, Maion G, Mourad W, Olivier M
  Title
Leishmania donovani-induced macrophages cyclooxygenase-2 and prostaglandin E2 synthesis.
  Journal
Parasite Immunol 23:177-84 (2001)
DOI:10.1046/j.1365-3024.2001.00372.x
Reference
  Authors
Ghosh S, Bhattacharyya S, Sirkar M, Sa GS, Das T, Majumdar D, Roy S, Majumdar S
  Title
Leishmania donovani suppresses activated protein 1 and NF-kappaB activation in host macrophages via ceramide generation: involvement of extracellular signal-regulated kinase.
  Journal
Infect Immun 70:6828-38 (2002)
DOI:10.1128/IAI.70.12.6828-6838.2002
Reference
PMID:9504340
  Authors
Bogdan C, Rollinghoff M
  Title
The immune response to Leishmania: mechanisms of parasite control and evasion.
  Journal
Int J Parasitol 28:121-34 (1998)
DOI:10.1016/S0020-7519(97)00169-0
Reference
  Authors
Blanchette J, Abu-Dayyeh I, Hassani K, Whitcombe L, Olivier M
  Title
Regulation of macrophage nitric oxide production by the protein tyrosine phosphatase Src homology 2 domain phosphotyrosine phosphatase 1 (SHP-1).
  Journal
Immunology 127:123-33 (2009)
DOI:10.1111/j.1365-2567.2008.02929.x
Reference
  Authors
Alexander J, Satoskar AR, Russell DG
  Title
Leishmania species: models of intracellular parasitism.
  Journal
J Cell Sci 112 Pt 18:2993-3002 (1999)
Reference
  Authors
Denkers EY, Butcher BA
  Title
Sabotage and exploitation in macrophages parasitized by intracellular protozoans.
  Journal
Trends Parasitol 21:35-41 (2005)
DOI:10.1016/j.pt.2004.10.004
Reference
  Authors
Lodge R, Diallo TO, Descoteaux A
  Title
Leishmania donovani lipophosphoglycan blocks NADPH oxidase assembly at the phagosome membrane.
  Journal
Cell Microbiol 8:1922-31 (2006)
DOI:10.1111/j.1462-5822.2006.00758.x
Reference
  Authors
de Freitas Balanco JM, Moreira ME, Bonomo A, Bozza PT, Amarante-Mendes G, Pirmez C, Barcinski MA
  Title
Apoptotic mimicry by an obligate intracellular parasite downregulates macrophage microbicidal activity.
  Journal
Curr Biol 11:1870-3 (2001)
DOI:10.1016/S0960-9822(01)00563-2
Reference
  Authors
Kane MM, Mosser DM
  Title
Leishmania parasites and their ploys to disrupt macrophage activation.
  Journal
Curr Opin Hematol 7:26-31 (2000)
Reference
  Authors
de Almeida MC, Vilhena V, Barral A, Barral-Netto M
  Title
Leishmanial infection: analysis of its first steps. A review.
  Journal
Mem Inst Oswaldo Cruz 98:861-70 (2003)
DOI:10.1590/S0074-02762003000700001
KO pathway
ko05140   

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