ALOX12 in Human Toxoplasmosis

Abstract

jALOX12 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.

Mammalian lipoxygenases and their biological relevance

“…The human ALOX12 gene has susceptibility alleles for human congenital toxoplasmosis and RNAi-mediated expression knockdown of this gene attenuated progression of T. gondii infection [398]. These data implicate ALOX12 in host defense against T. gondii but the underlying molecular mechanisms remain unclear.…”

Toxoplasma gondii infection in the context of the risk of schizophrenia development

“…The infection is usually asymptomatic and is characterized by the formation of inactive cysts with bradyzoites located in the tissues. However, in individuals with reduced immunity or congenital infection, toxoplasmosis may develop into a very severe form (24).…”

Toxoplasma gondii and Schizophrenia: A Relationship That Is Not Ruled Out

“…Thus, it has been demonstrated that a critical role in human congenital T. gondii infection is played by the ALOX12 gene, which encodes arachidonate 5-lipoxygenase enzyme, which is involved in fatty acid metabolism and has been related to schizophrenia, at least in a Korean population [190,191]. HLA-related genes such as SGK1 on chromosome 6, which plays a role in regulating different brain functions [192] and mediates the effects of cortisol on hippocampal neurogenesis [193], have a modulating effect on some infectious agents, including T. gondii, consistent with the proposition that parasitization may modify the risk of schizophrenia [187].…”