KEGG   PATHWAY: ocu05140
ocu05140                    Pathway                                
Leishmaniasis - Oryctolagus cuniculus (rabbit)
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.
Human Diseases; Infectious disease: parasitic
Pathway map
ocu05140  Leishmaniasis

Oryctolagus cuniculus (rabbit) [GN:ocu]
100009578  TLR2; toll like receptor 2 [KO:K10159]
100009497  TLR4; toll like receptor 4 [KO:K10160]
100340811  MYD88; myeloid differentiation primary response 88 [KO:K04729]
100354743  IRAK1; interleukin 1 receptor associated kinase 1 [KO:K04730] [EC:]
100341605  IRAK4; interleukin 1 receptor associated kinase 4 [KO:K04733] [EC:]
100343190  TRAF6; TNF receptor associated factor 6 [KO:K03175] [EC:]
100343571  MAP3K7; mitogen-activated protein kinase kinase kinase 7 [KO:K04427] [EC:]
100358246  TAB1; TGF-beta activated kinase 1 (MAP3K7) binding protein 1 [KO:K04403]
100342249  TAB2; TGF-beta activated kinase 1/MAP3K7 binding protein 2 [KO:K04404]
100359283  NFKBIB; NFKB inhibitor beta [KO:K02581]
100357341  NFKBIA; NFKB inhibitor alpha [KO:K04734]
100349426  NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
100009250  IL1A; interleukin 1 alpha [KO:K04383]
100008990  IL1B; interleukin 1 beta [KO:K04519]
100349007  IL12A; interleukin 12A [KO:K05406]
100354852  IL12B; interleukin 12B [KO:K05425]
100009088  TNF; tumor necrosis factor [KO:K03156]
100302454  IL4; interleukin 4 [KO:K05430]
100008833  NOS2; nitric oxide synthase 2 [KO:K13241] [EC:]
100008701  IL10; interleukin 10 [KO:K05443]
103345451  transforming growth factor beta-1 [KO:K13375]
108175468  transforming growth factor beta-1-like [KO:K13375]
100352552  transforming growth factor beta-1 [KO:K13375]
100352810  transforming growth factor beta-1 [KO:K13375]
103345452  transforming growth factor beta-1-like [KO:K13375]
100352301  transforming growth factor beta-1 [KO:K13375]
100353067  transforming growth factor beta-1 [KO:K13375]
103345448  transforming growth factor beta-1 [KO:K13375]
100008645  TGFB1; transforming growth factor beta-1 [KO:K13375]
100009371  TGFB2; transforming growth factor beta 2 [KO:K13376]
100358982  TGFB3; transforming growth factor beta 3 [KO:K13377]
100144334  CR1; complement C3b/C4b receptor 1 (Knops blood group) [KO:K04011]
100351865  ITGAM; integrin alpha-M [KO:K06461]
100339049  ITGB2; integrin subunit beta 2 [KO:K06464]
100009097  IGGC; Ig gamma chain C region [KO:K06856]
103345968  uncharacterized LOC103345968 [KO:K06856]
103345969  uncharacterized LOC103345969 [KO:K06856]
103345989  IGH; Ig heavy chain V-III region 23 [KO:K06856]
103347021  Ig heavy chain Mem5-like [KO:K06856]
100353656  uncharacterized LOC100353656 [KO:K06856]
103347220  IGHM; uncharacterized LOC103347220 [KO:K06856]
103346899  uncharacterized LOC103346899 [KO:K06856]
100351810  uncharacterized LOC100351810 [KO:K06856]
100353328  Ig heavy chain V-II region SESS [KO:K06856]
103347112  uncharacterized LOC103347112 [KO:K06856]
100352996  IGHM; Ig heavy chain V-III region 23 [KO:K06856]
100358696  high affinity immunoglobulin gamma Fc receptor I [KO:K06498]
100338413  FCGR2A; Fc fragment of IgG receptor IIa [KO:K06472]
100338913  low affinity immunoglobulin gamma Fc region receptor III-B-like [KO:K06463]
100337909  low affinity immunoglobulin gamma Fc region receptor III-B [KO:K06463]
100346103  ITGA4; integrin subunit alpha 4 [KO:K06483]
100008898  ITGB1; integrin subunit beta 1 [KO:K05719]
100009248  PTGS2; prostaglandin-endoperoxide synthase 2 [KO:K11987] [EC:]
100037719  PRKCB; protein kinase C beta [KO:K19662] [EC:]
100008803  NCF1; neutrophil cytosolic factor 1 [KO:K08011]
100008802  NCF2; neutrophil cytosolic factor 2 [KO:K08010]
100009359  NCF4; neutrophil cytosolic factor 4 [KO:K08012]
100008801  CYBB; cytochrome b-245 beta polypeptide [KO:K21421] [EC:1.-.-.-]
100008800  CYBA; p22-phox [KO:K08009]
100347345  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
100348561  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
100340952  ELK1; ELK1, ETS transcription factor [KO:K04375]
100338345  FOS; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379]
100008856  JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448]
100338341  EIF5A; eukaryotic translation initiation factor 5A [KO:K04448]
100350614  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:]
103346035  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:]
100344161  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:]
100341695  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:]
100008602  IFNG; interferon gamma [KO:K04687]
100341787  IFNGR1; interferon gamma receptor 1 [KO:K05132]
100338854  IFNGR2; interferon gamma receptor 2 [KO:K05133]
100352594  JAK1; Janus kinase 1 [KO:K11217] [EC:]
100358134  JAK2; Janus kinase 2 [KO:K04447] [EC:]
100343893  STAT1; signal transducer and activator of transcription 1 [KO:K11220]
100328929  RLA-DR-ALPHA; major histocompatibility complex, class II, DR alpha [KO:K06752]
100348904  RLA-DRB1; HLA class II histocompatibility antigen, DRB1-8 beta chain [KO:K06752]
100349408  HLA class II histocompatibility antigen, DRB1-1 beta chain [KO:K06752]
100349667  HLA class II histocompatibility antigen, DRB1-1 beta chain [KO:K06752]
100350656  RLA-DRB1; HLA class II histocompatibility antigen, DRB1-4 beta chain [KO:K06752]
100350168  Orcu-DRB; HLA class II histocompatibility antigen, DRB1-4 beta chain [KO:K06752]
100343144  Orcu-DQA; SLA class II histocompatibility antigen, DQ haplotype D alpha chain [KO:K06752]
100351163  RLA-DQB; HLA class II histocompatibility antigen, DQ beta 1 chain [KO:K06752]
100351416  HLA class II histocompatibility antigen, DO beta chain [KO:K06752]
100341358  RLA class II histocompatibility antigen, DP beta chain [KO:K06752]
100352927  RLA class II histocompatibility antigen, DP alpha-1 chain [KO:K06752]
100352672  HLA class II histocompatibility antigen, DO alpha chain [KO:K06752]
100355948  RLA-DMB; histocompatibility antigen DM heterodimer light chain-like [KO:K06752]
100352415  RLA-DMA; histocompatibility antigen DM heterodimer heavy chain-like [KO:K06752]
100009158  MARCKSL1; MARCKS like 1 [KO:K13536]
100008677  EEF1A2; eukaryotic translation elongation factor 1 alpha 2 [KO:K03231]
100009189  EEF1A1; eukaryotic translation elongation factor 1 alpha 1 [KO:K03231]
100348648  PTPN6; protein tyrosine phosphatase, non-receptor type 6 [KO:K05697] [EC:]
C00076  Calcium cation
C00195  N-Acylsphingosine
C00219  Arachidonate
C00533  Nitric oxide
C00584  Prostaglandin E2
C02737  Phosphatidylserine
Cunningham AC
Parasitic adaptive mechanisms in infection by leishmania.
Exp Mol Pathol 72:132-41 (2002)
Nandan D, Knutson KL, Lo R, Reiner NE
Exploitation of host cell signaling machinery: activation of macrophage phosphotyrosine phosphatases as a novel mechanism of molecular microbial pathogenesis.
J Leukoc Biol 67:464-70 (2000)
Nandan D, Reiner NE
Attenuation of gamma interferon-induced tyrosine phosphorylation in mononuclear phagocytes infected with Leishmania donovani: selective inhibition of signaling through Janus kinases and Stat1.
Infect Immun 63:4495-500 (1995)
Nandan D, Lo R, Reiner NE
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.
Infect Immun 67:4055-63 (1999)
Reiner NE
Altered cell signaling and mononuclear phagocyte deactivation during intracellular infection.
Immunol Today 15:374-81 (1994)
Nandan D, Reiner NE
Leishmania donovani engages in regulatory interference by targeting macrophage protein tyrosine phosphatase SHP-1.
Clin Immunol 114:266-77 (2005)
Kima PE
The amastigote forms of Leishmania are experts at exploiting host cell processes to establish infection and persist.
Int J Parasitol 37:1087-96 (2007)
Forget G, Gregory DJ, Olivier M
Proteasome-mediated degradation of STAT1alpha following infection of macrophages with Leishmania donovani.
J Biol Chem 280:30542-9 (2005)
Cameron P, McGachy A, Anderson M, Paul A, Coombs GH, Mottram JC, Alexander J, Plevin R
Inhibition of lipopolysaccharide-induced macrophage IL-12 production by Leishmania mexicana amastigotes: the role of cysteine peptidases and the NF-kappaB signaling pathway.
J Immunol 173:3297-304 (2004)
Tuon FF, Amato VS, Bacha HA, Almusawi T, Duarte MI, Amato Neto V
Toll-like receptors and leishmaniasis.
Infect Immun 76:866-72 (2008)
Kropf P, Freudenberg N, Kalis C, Modolell M, Herath S, Galanos C, Freudenberg M, Muller I
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.
J Leukoc Biol 76:48-57 (2004)
Feng GJ, Goodridge HS, Harnett MM, Wei XQ, Nikolaev AV, Higson AP, Liew FY
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.
J Immunol 163:6403-12 (1999)
Olivier M, Gregory DJ, Forget G
Subversion mechanisms by which Leishmania parasites can escape the host immune response: a signaling point of view.
Clin Microbiol Rev 18:293-305 (2005)
Matte C, Maion G, Mourad W, Olivier M
Leishmania donovani-induced macrophages cyclooxygenase-2 and prostaglandin E2 synthesis.
Parasite Immunol 23:177-84 (2001)
Ghosh S, Bhattacharyya S, Sirkar M, Sa GS, Das T, Majumdar D, Roy S, Majumdar S
Leishmania donovani suppresses activated protein 1 and NF-kappaB activation in host macrophages via ceramide generation: involvement of extracellular signal-regulated kinase.
Infect Immun 70:6828-38 (2002)
Bogdan C, Rollinghoff M
The immune response to Leishmania: mechanisms of parasite control and evasion.
Int J Parasitol 28:121-34 (1998)
Blanchette J, Abu-Dayyeh I, Hassani K, Whitcombe L, Olivier M
Regulation of macrophage nitric oxide production by the protein tyrosine phosphatase Src homology 2 domain phosphotyrosine phosphatase 1 (SHP-1).
Immunology 127:123-33 (2009)
Alexander J, Satoskar AR, Russell DG
Leishmania species: models of intracellular parasitism.
J Cell Sci 112 Pt 18:2993-3002 (1999)
Denkers EY, Butcher BA
Sabotage and exploitation in macrophages parasitized by intracellular protozoans.
Trends Parasitol 21:35-41 (2005)
Lodge R, Diallo TO, Descoteaux A
Leishmania donovani lipophosphoglycan blocks NADPH oxidase assembly at the phagosome membrane.
Cell Microbiol 8:1922-31 (2006)
de Freitas Balanco JM, Moreira ME, Bonomo A, Bozza PT, Amarante-Mendes G, Pirmez C, Barcinski MA
Apoptotic mimicry by an obligate intracellular parasite downregulates macrophage microbicidal activity.
Curr Biol 11:1870-3 (2001)
Kane MM, Mosser DM
Leishmania parasites and their ploys to disrupt macrophage activation.
Curr Opin Hematol 7:26-31 (2000)
de Almeida MC, Vilhena V, Barral A, Barral-Netto M
Leishmanial infection: analysis of its first steps. A review.
Mem Inst Oswaldo Cruz 98:861-70 (2003)
ocu00590  Arachidonic acid metabolism
ocu04010  MAPK signaling pathway
ocu04020  Calcium signaling pathway
ocu04120  Ubiquitin mediated proteolysis
ocu04145  Phagosome
ocu04610  Complement and coagulation cascades
ocu04620  Toll-like receptor signaling pathway
ocu04630  JAK-STAT signaling pathway
ocu04666  Fc gamma R-mediated phagocytosis
KO pathway

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