title: ALOX12 in human toxoplasmosis.
abstract: ALOX12 is a gene encoding arachidonate 12-lipoxygenase (12-LOX), a member of a nonheme lipoxygenase family of dioxygenases. ALOX12 catalyzes the addition of oxygen to arachidonic acid, producing 12-hydroperoxyeicosatetraenoic acid (12-HPETE), which can be reduced to the eicosanoid 12-HETE (12-hydroxyeicosatetraenoic acid). 12-HETE acts in diverse cellular processes, including catecholamine synthesis, vasoconstriction, neuronal function, and inflammation. Consistent with effects on these fundamental mechanisms, allelic variants of ALOX12 are associated with diseases including schizophrenia, atherosclerosis, and cancers, but the mechanisms have not been defined. Toxoplasma gondii is an apicomplexan parasite that causes morbidity and mortality and stimulates an innate and adaptive immune inflammatory reaction. Recently, it has been shown that a gene region known as Toxo1 is critical for susceptibility or resistance to T. gondii infection in rats. An orthologous gene region with ALOX12 centromeric is also present in humans. Here we report that the human ALOX12 gene has susceptibility alleles for human congenital toxoplasmosis (rs6502997 [P, <0.000309], rs312462 [P, <0.028499], rs6502998 [P, <0.029794], and rs434473 [P, <0.038516]). A human monocytic cell line was genetically engineered using lentivirus RNA interference to knock down ALOX12. In ALOX12 knockdown cells, ALOX12 RNA expression decreased and levels of the ALOX12 substrate, arachidonic acid, increased. ALOX12 knockdown attenuated the progression of T. gondii infection and resulted in greater parasite burdens but decreased consequent late cell death of the human monocytic cell line. These findings suggest that ALOX12 influences host responses to T. gondii infection in human cells. ALOX12 has been shown in other studies to be important in numerous diseases. Here we demonstrate the critical role ALOX12 plays in T. gondii infection in humans.
authors.affiliation: Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, Illinois, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Witola
authors.affiliation: Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Susan Ruosu
authors.initials: SR
authors.lastname: Liu
authors.affiliation: McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Montpetit
authors.affiliation: Kansas Lipidomics Research Center, Division of Biology, Kansas State University, Manhattan, Kansas, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Welti
authors.affiliation: Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, Illinois, USA Laboratoire Adaptation et Pathogenie des Micro-Organismes, CNRS UMR 5163, Université Joseph Fourier Grenoble 1, Institut Jean Roget, Grenoble, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Hypolite
authors.affiliation: Kansas Lipidomics Research Center, Division of Biology, Kansas State University, Manhattan, Kansas, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Roth
authors.affiliation: Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Ernest
authors.initials: E
authors.lastname: Mui
authors.affiliation: Laboratoire Adaptation et Pathogenie des Micro-Organismes, CNRS UMR 5163, Université Joseph Fourier Grenoble 1, Institut Jean Roget, Grenoble, France.
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Cesbron-Delauw
authors.affiliation: INSERM, U563, and University Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: Gilbert J
authors.initials: GJ
authors.lastname: Fournie
authors.affiliation: Laboratoire Adaptation et Pathogenie des Micro-Organismes, CNRS UMR 5163, Université Joseph Fourier Grenoble 1, Institut Jean Roget, Grenoble, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Cavailles
authors.affiliation: Laboratoire Adaptation et Pathogenie des Micro-Organismes, CNRS UMR 5163, Université Joseph Fourier Grenoble 1, Institut Jean Roget, Grenoble, France.
authors.forename: Cordelia
authors.initials: C
authors.lastname: Bisanz
authors.affiliation: Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, Illinois, USA Rush University and Medical Center, Chicago, Illinois, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Boyer
authors.affiliation: Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Shawn
authors.initials: S
authors.lastname: Withers
authors.affiliation: Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, Illinois, USA Northwestern Lurie Children's Hospital and Medical Center, Chicago, Illinois, USA.
authors.forename: A Gwendolyn
authors.initials: AG
authors.lastname: Noble
authors.affiliation: Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, Illinois, USA Northwestern Lurie Children's Hospital and Medical Center, Chicago, Illinois, USA.
authors.forename: Charles N
authors.initials: CN
authors.lastname: Swisher
authors.affiliation: Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, Illinois, USA Rush University and Medical Center, Chicago, Illinois, USA.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Heydemann
authors.affiliation: Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, Illinois, USA Northshore University Health System, Evanston, Illinois, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Rabiah
authors.affiliation: School of Biomedical Sciences, University of Leeds, Leeds, England, United Kingdom.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Muench
authors.affiliation: Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, Illinois, USA Department of Pediatrics (Infectious Diseases), Toxoplasmosis Center, Institute of Genomics, Genetics and Systems Biology, CHeSS (Affiliate), and The College, Committees on Molecular Medicine, Immunology and Global Health, The University of Chicago, Chicago, Illinois, USA rmcleod@uchicago.edu.
authors.forename: Rima
authors.initials: R
authors.lastname: McLeod
mesh_terms: D000483:Alleles; D001092:Arachidonate 12-Lipoxygenase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D015331:Cohort Studies; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D014644:Genetic Variation; D006801:Humans; D008297:Male; D009000:Monocytes / Q000378:metabolism / Q000469:parasitology; D010957:Plasmids / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D014125:Toxoplasmosis, Congenital / Q000235:genetics* / Q000276:immunology / Q000469:parasitology
chemical_list: D016207:Cytokines; D034741:RNA, Small Interfering; D016718:Arachidonic Acid; D001092:Arachidonate 12-Lipoxygenase; C476558:ALOX12 protein, human; D020170:Caspase 1