Abstract
Orientia (O.) tsutsugamushi, the causative agent of scrub typhus, is a neglected, obligate intracellular bacterium that has a prominent tropism for monocytes and macrophages. Complications often involve the lung, where interstitial pneumonia is a typical finding. The severity of scrub typhus in humans has been linked to altered plasma concentrations of chemokines which are known to act as chemoattractants for myeloid cells. The trafficking and function of monocyte responses is critically regulated by interaction of the CC chemokine ligand 2 (CCL2) and its CC chemokine receptor CCR2. In a self-healing mouse model of intradermal infection with the human-pathogenic Karp strain of O. tsutsugamushi, we investigated the role of CCR2 on bacterial dissemination, development of symptoms, lung histology and monocyte subsets in blood and lungs. CCR2-deficient mice showed a delayed onset of disease and resolution of symptoms, higher concentrations and impaired clearance of bacteria in the lung and the liver, accompanied by a slow infiltration of interstitial macrophages into the lungs. In the blood, we found an induction of circulating monocytes that depended on CCR2, while only a small increase in Ly6Chi monocytes was observed in CCR2-/- mice. In the lung, significantly higher numbers of Ly6Chi and Ly6Clo monocytes were found in the C57BL/6 mice compared to CCR2-/- mice. Both wildtype and CCR2-deficient mice developed an inflammatory milieu as shown by cytokine and inos/arg1 mRNA induction in the lung, but with delayed kinetics in CCR2-deficient mice. Histopathology revealed that infiltration of macrophages to the parenchyma, but not into the peribronchial tissue, depended on CCR2. In sum, our data suggest that in Orientia infection, CCR2 drives blood monocytosis and the influx and activation of Ly6Chi and Ly6Clo monocytes into the lung, thereby accelerating bacterial replication and development of interstitial pulmonary inflammation.
Highlights
Scrub typhus is a mite-borne, neglected tropical infection caused by the obligate intracellular bacterium Orientia (O.) tsutsugamushi
Inflammatory monocytes, phenotyped as CD11b+ Ly6C+ Ly6Gin mice, have been implicated in the defense against bacterial, viral, fungal and protozoal pathogens. Their emigration from the bone marrow to the circulation is mediated by interaction of CC chemokine ligand 2 (CCL2) (MCP-1) with the chemokine receptor chemokine receptor 2 (CCR2) [14], which is highly expressed by CD11b+ Ly6C+ monocytes [47]
Guided by the observations that CCL2 (MCP-1) is strongly induced by O. tsutsugamushi [2,3,4], that Orientia is associated with monocytes or monocyte-like cells in eschar lesions and peripheral blood [1, 6] and grows within monocytes [10], we investigated the role of CCR2 in monocyte responses in a murine model of self-healing, i.d
Summary
Scrub typhus is a mite-borne, neglected tropical infection caused by the obligate intracellular bacterium Orientia (O.) tsutsugamushi. Transmission of O. tsutsugamushi during mite bites induces a cutaneous necrosis, the eschar [1], and is accompanied by undifferentiated fever in mild cases. O. tsutsugamushi has long been known to be a potent inducer of monocyte-related chemokines in humans and mice [2,3,4]. Robust evidence supports a macrophage/monocyte tropism for this pathogen in blood and tissue [1, 5, 6] and strong macrophage responses in infected tissues [7, 8]. O. tsutsugamushi infects and replicates in human blood-derived monocytes ex vivo, as it does in neutrophils [9, 10]
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