Possible Pivotal Role of T. gondii infection in the Pathogenesis of Atherosclerosis

Joseph Prandota

Abstract


Cardiovascular diseases such as atherosclerosis, atherothrombosis, coronary artery disease and stroke are the main causes of death worldwide. Atherosclerosis is a chronic, progressive immunoinflammatory and fibroproliferative disease of medium and large sized arteries with increased blood lipoprotein/cholesterol and their disposition in the arterial wall, important TH1 type proinflammatory reaction, and thrombogenic status. Elevated plasma levels of proinflammatory cytokines have been demonstrated in patients with established atherosclerotic disease, and therefore it is believed that cytokines are key players in all stages of disease and have a profound influence on the pathogenesis of the disease. Several authors suggested that the number of different pathogens, including T. gondii, may promote synergistic inflammatory responses that are capable of triggering and exacerbating atherosclerotic process. Latent chronic T. gondii infection may be a frequent cause of vascular endothelial cell dysfunction because this pathogen attacks all nucleated cells, and endothelium cells have enhanced susceptibility to infection with T. gondii tachyzoites. Oxidative stress characteristic for atherosclerosis may be caused by the host infection with the parasite. T. gondii is unable to synthesize sterol and acquires cholesterol from the host LDL receptor pathway. The accumulation of foamy transformed macrophages in the aortic intima characteristic for atherosclerotic lesion is due to acyl-CoA:cholesterol acyltransferase 1 and 2 (ACAT1 and ACAT2) increased expression in macrophages and other cells infected with T. gondii. ACAT2 is crucial in foam cell formation and development of atherosclerosis. The parasite also expresses two cholesteryl ester(CE)-synthesizing enzymes TgACAT1 and TgACAT2 that contribute to the CEs formation for storage in lipid bodies, but at the same time ACAT and CEs play a crucial role in replication of the pathogen. It must be emphasized that the increased expression of ACAT1 and ACAT2 normally present in macrophages may thus be further enhanced by the superimposing TgACAT1 and TgACA2 activities available in the host cells infected with T. gondii. In addition, proinflammatory cytokines increase foam cell formation and latent chronic T. gondii infection persistently generates these biomediators and thus play an important role in foam cell biogenesis. Patients with atherosclerosis had increased plasma levels of TGF-b and this cytokine increased T. gondii replication in the host cells, and participated in development of fibrotic changes in atherosclerotic lesions. Atherogenesis involved platelets activation with subsequent serotonin release. Hyperserotoninemia was also reported in autistic and mentally retarded children, and recently, a significantly higher seroprevalence of chronic toxoplasmosis was found in autistic children as compared with controls. T. gondii infection caused also increased leptin levels, and a marked association between T gondii seropositivity and obesity has been demonstrated. Cysteine cathepsins (Cat) play an important role of in foam cell formation and generation of amyloid in atherosclerotic arteries. Infection of vascular endothelial cells with T. gondii tachyzoites provide an additional source of cysteine cathepsins superimposing on the enzymes normally present in host cells, because the parasite expresses few members of the cathepsins, such as CatL-like, CatB-like, and CatC-like proteases. Finally, vitamin D exerted beneficial effects in both atherosclerosis and T. gondii infection, especially that it improved host immunity and decreased proliferation of T. gondii tachyzoites in macrophages and reduced tissue pathology caused by the pathogen. All together, it seems that latent chronic toxoplasmosis play a pivotal but so far neglected role in the pathogenesis of atherosclerosis.


Keywords


atherosclerosis; T. gondii infection; proinflammatory cytokines; ACAT1; ACAT2; cysteine proteases; foam cells; oxidative stress; vitamin D

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