ALOX12in Human Toxoplasmosis

Abstract

ABSTRACTALOX12is a gene encoding arachidonate 12-lipoxygenase (12-LOX), a member of a nonheme lipoxygenase family of dioxygenases.ALOX12catalyzes 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 ofALOX12are associated with diseases including schizophrenia, atherosclerosis, and cancers, but the mechanisms have not been defined.Toxoplasma gondiiis 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 asToxo1is critical for susceptibility or resistance toT. gondiiinfection in rats. An orthologous gene region withALOX12centromeric is also present in humans. Here we report that the humanALOX12gene 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 downALOX12. InALOX12knockdown cells,ALOX12RNA expression decreased and levels of theALOX12substrate, arachidonic acid, increased.ALOX12knockdown attenuated the progression ofT. gondiiinfection and resulted in greater parasite burdens but decreased consequent late cell death of the human monocytic cell line. These findings suggest thatALOX12influences host responses toT. gondiiinfection in human cells.ALOX12has been shown in other studies to be important in numerous diseases. Here we demonstrate the critical roleALOX12plays inT. gondiiinfection in humans.