Intracellullar infections in the pathogenesis of vascular diseases; in vitro studies

Abstract

Various microorganisms are able to infect endothelial cells, hepatocytes, adipocytes and monocytes. Intracellular infection of these cells in vitro induces cellular dysfunction and initiates procoagulant activity, hypofibrinolysis, impaired cellular function, and inflammation, as reflected by increased expression of pro-inflammatory cytokines. There was a remarkable resemblance in how monocytes, hepatocytes, endothelial cells, and adipocytes reacted to infection, with the activation of processes that could be involved in atherogenesis. This suggests that not only direct infection of the vessel wall but also indirect infection by transmission of viruses to tissues elsewhere in the body may initiate a systemic inflammatory and procoagulant state. The results of the studies presented in this thesis suggest that intracellular infections have a causal role in the etiology of vascular diseases. We propose that intracellular microorganisms should be added to the list of factors that induce endothelial dysfunction and contribute to the development of atherosclerosis. We identified inflammation, procoagulant activity, and hypofibrinolysis to be major outcomes of intracellular infection of different types of cells. Our studies identified at least some of the mechanisms by which intracellular infections may contribute to the development of cardiovascular diseases. Chronic low-grade inflammation is a component of many diseases and is often seen in atherosclerosis, obesity, diabetes and the metabolic syndrome. The presence of inflammation is evidenced by elevated plasma concentrations of a variety of markers. Atherosclerosis begins in early life and progresses to cause severe adverse effects in adult life. This is a chronic multifactorial process and cannot be explained solely in terms of the traditional cardiovascular risk factors. Infections with a variety of microorganisms during lifetime are common and could be a direct cause of atherosclerosis. Infective progeny virus may invade cells involved in atherogenesis and disseminate to other cells. Intracellular infections in vivo may become latent or even persistent, but may still be capable of having a deleterious effect on cells. The cumulative effects of simultaneous infections at various sites and/or repetitive infections may contribute to the pathogenesis and progression of atherosclerosis. Influenza virus, Cytomegalovirus (CMV), and Chlamydia pneumoniae (Cp), in particular, have been associated with cardiovascular disorders. The role of infections in endothelial injury and vascular wall inflammation has been studied extensively but current data do not allow us to determine whether infection is a cause or a co-factor in atherogenesis. Animal and pathological studies probably provide the best evidence that infections have effects in vivo similar to those seen in atherosclerosis. In the in vitro studies presented in this thesis, we investigated which of the effects caused by these infections could account for the impairment of vascular function and atherogenesis. We infected endothelial cells, hepatocytes, adipocytes and monocytes and measured inflammatory parameters (IL-6, TNF-alpha) and fibrinolytic parameters (PAI-1) and coagulation factors in the infected culture supernatants. Infection consistently resulted in time and dose dependent inflammatory effects. In conclusion, we showed that various infections are able to trigger cellular responses involved in atherogenesis. We therefore propose a causal role for intracellular pathogens in the etiology of vascular diseases.