title: Expression profiling of Sudanese visceral leishmaniasis patients pre- and post-treatment with sodium stibogluconate.
abstract: Visceral leishmaniasis (VL) in Sudan caused by Leishmania donovani is fatal in susceptible individuals if untreated. Treatment with sodium stibogluconate (SSG) leads to post-kala-azar dermal leishmaniasis (PKDL) in 58% of patients. Here, Affymetrix microarrays were used to identify genes differentially expressed in lymph nodes (N=9 paired samples) pre- and post-treatment with SSG. Using the Bioconductor package limma, 438 genes from 28 869 post-quality-control probe sets were differentially expressed (Pnominal≤.02) post- vs pretreatment. Canonical pathway analysis using Ingenuity Pathway Analysis™ identified "role of nuclear factor of activated T-cell in regulation of immune response" (Pnominal=1.35×10-5; PBH-adjusted=4.79×10-3), "B-cell development" (Pnominal=2.04×10-4; PBH-adjusted=.024), "Fcγ receptor-mediated phagocytosis in macrophages and monocytes" (Pnominal=2.04×10-4; PBH-adjusted=.024) and "OX40 signalling" (Pnominal=2.82×10-4; PBH-adjusted=.025) as pathways differentially regulated post- vs pretreatment. Major network hub genes included TP53, FN1, MYC, BCL2, JUN, SYK, RUNX2, MMP1 and ACTA2. Top endogenous upstream regulators included IL-7 (P=2.28×10-6), TNF (P=4.26×10-6), Amyloid Precursor Protein (P=4.23×10-5) and SPI1/PI.1 (P=1.17×10-7). Top predicted chemical drug regulators included the flavonoid genistein (P=4.56×10-7) and the quinoline alkaloid camptothecin (P=5.14×10-5). These results contribute to our understanding of immunopathology associated with VL and response to SSG treatment. Further replication could identify novel therapeutic strategies that improve on SSG treatment and reduce the likelihood of progression to PKDL.
authors.affiliation: Institute of Endemic Disease, University of Khartoum, Khartoum, Sudan.|Central Laboratory, Ministry of Higher Education and Scientific Research, Khartoum, Sudan.
authors.forename: M A M
authors.initials: MAM
authors.lastname: Salih
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: M
authors.initials: M
authors.lastname: Fakiola
authors.affiliation: Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: P A
authors.initials: PA
authors.lastname: Lyons
authors.affiliation: Institute of Endemic Disease, University of Khartoum, Khartoum, Sudan.
authors.forename: B M
authors.initials: BM
authors.lastname: Younis
authors.affiliation: Institute of Endemic Disease, University of Khartoum, Khartoum, Sudan.
authors.forename: A M
authors.initials: AM
authors.lastname: Musa
authors.affiliation: Institute of Endemic Disease, University of Khartoum, Khartoum, Sudan.
authors.forename: A M
authors.initials: AM
authors.lastname: Elhassan
authors.affiliation: Telethon Kids Institute, The University of Western Australia, Subiaco, WA, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Anderson
authors.affiliation: Telethon Kids Institute, The University of Western Australia, Subiaco, WA, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Syn
authors.affiliation: Institute of Endemic Disease, University of Khartoum, Khartoum, Sudan.
authors.forename: M E
authors.initials: ME
authors.lastname: Ibrahim
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK.|Telethon Kids Institute, The University of Western Australia, Subiaco, WA, Australia.
authors.forename: J M
authors.identifier: http://orcid.org/0000-0002-0784-7277
authors.initials: JM
authors.lastname: Blackwell
authors.affiliation: Institute of Endemic Disease, University of Khartoum, Khartoum, Sudan.|Department of Biology, Taibah University, Kingdom of Saudi Arabia.
authors.forename: H S
authors.initials: HS
authors.lastname: Mohamed
mesh_terms: D000293:Adolescent; D000967:Antimony Sodium Gluconate / Q000627:therapeutic use*; D000981:Antiprotozoal Agents / Q000627:therapeutic use*; D002648:Child; D005260:Female; D006801:Humans; D007893:Leishmania donovani; D016773:Leishmaniasis, Cutaneous / Q000276:immunology; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology; D008297:Male; D013397:Sudan; D059467:Transcriptome / Q000187:drug effects*; D055815:Young Adult
chemical_list: D000981:Antiprotozoal Agents; D000967:Antimony Sodium Gluconate
keywords: RNA expression; Sudan; bioconductor; ingenuity pathway analysis; microarray; sodium stibogluconate; visceral leishmaniasis