Effect of Chlamydia pneumoniae on Cellular ATP Content in Mouse Macrophages: Role of Toll-Like Receptor 2

Abstract

Chlamydiae are obligate intracellular gram-negative bacteria and are dependent on the host cell for ATP. Thus, chlamydial infection may alter the intracellular levels of ATP and affect all energy-dependent processes within the cell. We have shown that both live C. pneumoniae and inactivated C. pneumoniae induce markers of cell death prior to completion of the bacterial growth cycle. As depletion of ATP could account for the observed increase in cell death, the effects of C. pneumoniae on ATP concentrations within mouse macrophages were investigated. Live, heat-killed, and UV-inactivated C. pneumoniae cultures (at multiplicities of infection [MOIs] of 0.01, 0.1, and 1.0) were incubated with mouse bone marrow macrophages isolated from C57BL/6J mice and mice deficient in Toll-like receptors. Treatment of the macrophages with both live and inactivated C. pneumoniae increased the ATP content of the cells. In cells infected with live C. pneumoniae, the increase was inversely proportional to the MOI. In cells treated with inactivated C. pneumoniae, the increase in ATP content was smaller than that induced by infection with live organisms and was proportional to the MOI. The increase in ATP content early in the developmental cycle was independent of the growth of C. pneumoniae, while sustained induction required live organisms. The capacity of C. pneumoniae to increase the ATP content was ablated in macrophages deficient in expression of either Toll-like receptor 2 or the Toll-like receptor accessory protein MyD88. In contrast, no effect was observed in macrophages lacking expression of Toll-like receptor 4.Chlamydia pneumoniae is a human respiratory pathogen that causes a wide spectrum of respiratory diseases (13) and may be a risk factor for immunoreactive disorders, such as adult onset asthma (6), reactive airway disease in children (5), and arthritis (2). C. pneumoniae infection has also been associated with an increased risk of cardiovascular disease, and the organism is found within macrophage-and smooth muscle cell-derived foam cells in atherosclerotic lesions (10). The association between C. pneumoniae and cardiovascular disease has been further supported by studies with animal models (for a review see reference 3). In previous studies, we investigated the hypothesis that C. pneumoniae infection of foam cells could increase atherosclerotic plaque instability by contributing to foam cell death. These studies demonstrated that C. pneumoniae induced cell death in mouse macrophages by a caspase-independent mechanism (K.Yaraei, L. A. Campbell, C.-C. Kuo, and M. E. Rosenfeld, Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother., abstr. B-1668, 2003). C. pneumoniae infection induced neither formation of the mitochondrial transition pore nor DNA fragmentation. Because chlamydiae are obligate intracellular parasites that are dependent on the host cell for obtaining ATP, one possible mechanism by which C. pneumoniae could induce cell death is by depletion of intracellular ATP. Interestingly, several reports have demo...

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