Chlamydia pneumoniae has been postulated to cause systemic disease by infection of monocytes/macrophages and spread via the blood or lymphatics. To investigate how C. pneumoniae disseminates, the ability of the organism to infect murine macrophages in vivo and whether infection can be transferred via macrophages were determined. C. pneumoniae was detected by direct plating, isolation, and polymerase chain reaction in alveolar macrophages from intranasally inoculated mice and peritoneal macrophages from intraperitoneally inoculated mice. C. pneumoniae were also detected in peripheral blood mononuclear cells, but not plasma, of intranasally and intraperitoneally inoculated mice. When alveolar or peritoneal macrophages were adoptively transferred by intraperitoneal injection from infected to uninfected mice, C. pneumoniae DNA was detected by polymerase chain reaction in lung, thymus, spleen, and/or abdominal lymph nodes. These results demonstrate the ability of C. pneumoniae to infect macrophages in vivo and to disseminate systemically via infected macrophages by hematogenous and lymphatic routes.

Accumulating evidence supports an association between Chlamydia pneumoniae infection and atherosclerosis. To determine whether there is a causal relationship, the effects of chronic infection with C. pneumoniae on the development of atherosclerosis in apolipoprotein E (apoE)-deficient mice were evaluated. Eight-week-old male apoE-deficient mice were inoculated intranasally with C. pneumoniae three times, at 8, 9, and 10 weeks of age. The combined area of atherosclerotic lesions in the lesser curvature of the aortic arch was measured en face by computer-assisted morphometry. The lesion area was 2.4-fold greater (P=.05) at 16 weeks of age and 1.6-fold greater (P=.05) at 20 weeks of age in infected mice than in control mice. There were no differences in total plasma cholesterol levels between groups. This study demonstrates that C. pneumoniae infection accelerates the progression of atherosclerosis in the aortic arch of apoE-deficient mice.

Chlamydia pneumoniae have been demonstrated in atherosclerotic lesions but not in normal arteries. An animal model of both C. pneumoniae and atherosclerosis is needed to investigate the role of the organism in atherosclerosis. Apolipoprotein (apo) E-deficient transgenic mice, which spontaneously develop atherosclerosis, and C57BL/6J mice, which only develop atherosclerosis on an atherogenic diet, were evaluated. Following single and multiple intranasal inoculations of apoE-deficient transgenic mice, C. pneumoniae were detected in lung, aorta, and spleen for 20 weeks after inoculation in 25%-100% of mice. In the aorta, C. pneumoniae were detected within the atherosclerotic lesion. In C57BL/6J mice on a nonatherogenic diet, C. pneumoniae were detected in the aorta only 2 weeks after a single intranasal inoculation in 8% of mice. The persistence of C. pneumoniae in atheromas suggests a tropism of C. pneumoniae to the lesion. These mouse models should be useful for studying the pathogenic role of C. pneumoniae in atherosclerosis.

Atherosclerotic lesions are initiated and progress largely as a result of a chronic, fibroproliferative, inflammatory response. This review discusses how Chlamydia pneumoniae could conceivably contribute to this chronic inflammatory response and reports on recent in vivo and in vitro studies. In vivo studies in mice demonstrate that C. pneumoniae infection is disseminated to the artery wall following infection in the lung by alveolar macrophages. Recent in vitro studies show that infected U937 cells can directly transfer infection to endothelial cells and can indirectly increase the susceptibility of endothelial cells to C. pneumoniae infection. Loading of RAW 264.7 cells with modified forms of low-density lipoprotein increases the resistance of the cells to C. pneumoniae infection and also increases the susceptibility to the combined toxic effects of modified lipids and C. pneumoniae infection.

Seroepidemiologic studies have shown an association of Chlamydia pneumoniae antibody with atherosclerosis. Compelling additional evidence has accumulated, in that the organism has been found within atherosclerotic lesions throughout the arterial tree by multiple methods. C. pneumoniae has also been isolated from coronary and carotid atheromatous plaques. Although these studies support a potential role for C. pneumoniae in atherogenesis, confirmation of a causal relationship requires the use of animal models and intervention studies. We have focused on the evaluation of mouse models to address the hypothesis that, following upper respiratory tract infection, lung macrophages are infected, disseminate to the aorta, and alter the onset or progression of atherogenesis. ApoE-deficient knock-out and C57BU6J mice were used. The apoE-deficient mouse develops atherosclerotic lesions spontaneously on a regular diet in a time-and age-dependent manner. This knock-out strain was developed on the background of the C57BU6J mouse, which only develops atherosclerosis on a high-fauhigh-cholesterol diet. To investigate whether infected macrophages constitute a vehicle for dissemination of C. pneumoniae in vivo, mice were inoculated intranasally or intraperitoneally. The organism was detected in harvested alveolar and peritoneal macrophages at all time points following intranasal and intraperitoneal inoculations, respectively, and in peripheral blood mononuclear cells following inoculation by both routes. In another experiment, alveolar and peritoneal macrophages from intranasally and intraperitoneally inoculated mice were adoptively transferred by intraperitoneal injection to uninfected mice. Subsequently, C. pneumoniae was detected in lung, spleen, abdominal lymph nodes and/or thymus of recipient mice. In control experiments, UVinactivated C. pneumoniae DNA was not detected in alveolar or peritoneal macrophages beyond 5 min after inoculation in vivo. These cumulative results demonstrate that C. pneumoniae infects macrophages in vivo and that macrophages can serve as a vehicle for dissemination to other sites.To answer the question of whether the organism disseminates to and persists in the aorta, 8-week-old mice were infected intranasally. Following single or multiple inoculations in apoE-deficient mice, C. pneumoniae was detected in the lung and aorta for 20 weeks postinfection. In contrast, in C57BU6J mice, the organism did not persist in the aorta following a single intranasal inoculation, but could be detected up to 7 weeks postinfection in multiply inoculated mice. Significantly, in apoE-deficient mice with developed atherosclerotic lesions, the organism was found in foam cells within the lesions by immunocytochemical staining. These studies show that persistent C. pneumoniae infection occurs in atherosclerotic lesions in the aorta in the apoE-deficient knock-out mouse model. Infection of the aorta also occurred in C57BU6J mice but was more transient. Both models should be useful in studying the pathogenic role of C. pneumoni...

To elucidate sites of SRV‐2/W persistence, tissue DNA from three groups of naturally infected Macaca nemestrina was analyzed for provirus: vertically transmitted, viremic, seronegative macaques; horizontally transmitted, viremic, seronegative macaques, and nonviremic seropositive macaques. In viremic animals infected vertically, provirus was found in many tissues, whereas in those infected horizontally, proviral DNA was limited. In V–Ab+ macaques, provirus was detected in bone marrow and/or ileocecal junction, confirming the presence of provirus in V –Ab+ animals.

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