ALOX12 In Human Toxoplasmosis.
Résumé
: ALOX12 is a gene encoding arachidonate 12-lipoxygenase (12-LOX), a member of a non-heme lipoxygenase family of dioxygenases. ALOX12 catalyzes the addition of oxygen onto arachidonic acid producing 12-hydroperoxyeicosatetraenoic acid, 12-HPETE, which can be reduced to eicosanoid, 12-HETE. 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 without definition of mechanisms. 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. Herein, 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], rs434473 [P<0.038516]). A human monocytic cell line was genetically engineered using lentivirus RNA interference to knockdown ALOX12. In ALOX12 knockdown cells, ALOX12 RNA expression decreased and ALOX12 substrate, arachidonic acid, increased. ALOX12 knockdown attenuated progression of T. gondii infection and resulted in greater parasite burden, 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. Herein, we now demonstrate the critical role ALOX12 plays in T. gondii infection in humans.