ALOX12 in Human Toxoplasmosis

ALOX12is a gene encoding arachidonate 12- lipoxygenase(12-LOX), a member of a nonheme lipoxygenasefamily 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 of ALOX12are 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 ALOX12centromeric is also present in humans. Here we report that the human ALOX12gene 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 lentivirusRNA interference to knock down ALOX12. In ALOX12knockdown cells, ALOX12RNA expression decreased and levels of the ALOX12substrate, arachidonic acid, increased. ALOX12knockdown 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 ALOX12influences host responses to T. gondii infection in human cells. ALOX12has been shown in other studies to be important in numerous diseases. Here we demonstrate the critical role ALOX12plays in T. gondii infection in humans.