ALOX12 in human toxoplasmosis

William H. Witola, Susan Ruosu Liu, Alexandre Montpetit, Ruth Welti, Magali Hypolite, Mary Roth, Ying Zhou, Ernest Mui, Marie France Cesbron-Delauw, Gilbert J. Fournie, Pierre Cavailles, Cordelia Bisanz, Kenneth Boyer, Shawn Withers, A. Gwendolyn Noble, Charles N. Swisher, Peter T. Heydemann, Peter Rabiah, Stephen P. Muench, Rima McLeod

Research output: Research - peer-reviewArticle

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.

LanguageEnglish (US)
Pages2670-2679
Number of pages10
JournalInfection and Immunity
Volume82
Issue number7
DOIs
StatePublished - 2014
Externally publishedYes

Fingerprint

Toxoplasmosis
Genes
Hydroxyeicosatetraenoic Acids
Arachidonic Acid
Parasites
Cell Line
Arachidonate 12-Lipoxygenase
Congenital Toxoplasmosis
Dioxygenases
Lentivirus
Lipoxygenase
Eicosanoids
Toxoplasma
RNA Interference
Vasoconstriction
Catecholamines
Schizophrenia
Atherosclerosis
Cell Death
Alleles

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

Cite this

Witola, W. H., Liu, S. R., Montpetit, A., Welti, R., Hypolite, M., Roth, M., ... McLeod, R. (2014). ALOX12 in human toxoplasmosis. Infection and Immunity, 82(7), 2670-2679. DOI: 10.1128/IAI.01505-13

ALOX12 in human toxoplasmosis. / Witola, William H.; Liu, Susan Ruosu; Montpetit, Alexandre; Welti, Ruth; Hypolite, Magali; Roth, Mary; Zhou, Ying; Mui, Ernest; Cesbron-Delauw, Marie France; Fournie, Gilbert J.; Cavailles, Pierre; Bisanz, Cordelia; Boyer, Kenneth; Withers, Shawn; Gwendolyn Noble, A.; Swisher, Charles N.; Heydemann, Peter T.; Rabiah, Peter; Muench, Stephen P.; McLeod, Rima.

In: Infection and Immunity, Vol. 82, No. 7, 2014, p. 2670-2679.

Research output: Research - peer-reviewArticle

Witola, WH, Liu, SR, Montpetit, A, Welti, R, Hypolite, M, Roth, M, Zhou, Y, Mui, E, Cesbron-Delauw, MF, Fournie, GJ, Cavailles, P, Bisanz, C, Boyer, K, Withers, S, Gwendolyn Noble, A, Swisher, CN, Heydemann, PT, Rabiah, P, Muench, SP & McLeod, R 2014, 'ALOX12 in human toxoplasmosis' Infection and Immunity, vol 82, no. 7, pp. 2670-2679. DOI: 10.1128/IAI.01505-13
Witola WH, Liu SR, Montpetit A, Welti R, Hypolite M, Roth M et al. ALOX12 in human toxoplasmosis. Infection and Immunity. 2014;82(7):2670-2679. Available from, DOI: 10.1128/IAI.01505-13
Witola, William H. ; Liu, Susan Ruosu ; Montpetit, Alexandre ; Welti, Ruth ; Hypolite, Magali ; Roth, Mary ; Zhou, Ying ; Mui, Ernest ; Cesbron-Delauw, Marie France ; Fournie, Gilbert J. ; Cavailles, Pierre ; Bisanz, Cordelia ; Boyer, Kenneth ; Withers, Shawn ; Gwendolyn Noble, A. ; Swisher, Charles N. ; Heydemann, Peter T. ; Rabiah, Peter ; Muench, Stephen P. ; McLeod, Rima. / ALOX12 in human toxoplasmosis. In: Infection and Immunity. 2014 ; Vol. 82, No. 7. pp. 2670-2679
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