Scrub Typhus Pathogenesis: Innate Immune Response and Lung Injury During Orientia tsutsugamushi Infection

Abstract

Scrub typhus is an understudied, potentially lethal disease caused by infection with Orientia tsutsugamushi. Despite causing an estimated 1 million cases per year and an increasing global presence, mechanisms of scrub typhus pathogenesis remain unclear. One of the most life-threatening conditions that can arise in scrub typhus patients is acute respiratory distress syndrome (ARDS). The development of ARDS is a complex process; some of its pathological hallmarks, including prolonged recruitment of inflammatory immune cells to the lung and vasculature damage, have been observed in humans and/or animal models of O. tsutsugamushi infection. Although different cell types and mechanisms may contribute to ARDS development during O. tsutsugamushi infection, this review highlights our current evidence of pulmonary endothelial activation and damage, the potential roles of neutrophils and macrophages in the lung, and the knowledge gaps in this field. Continued investigation of the lung microenvironment and cellular interactions will help elucidate disease pathogenesis and possible treatment during scrub typhus.

Keywords: Orientia tsutsugamushi; acute respiratory distress syndrome; endothelial cell; macrophage; neutrophil; scrub typhus.

Figure 1

Pulmonary inflammation and ARDS development during scrub typhus. Activation of pulmonary endothelial cells via direct infection with O. tsutsugamushi (green circles) or by interaction with inflammatory cytokines leads to the release of Ang2 and upregulation of adhesion molecules. Endothelial activation results in recruitment of neutrophils and macrophages, which can in turn secrete chemokines for further immune cell recruitment (i.e., CXCL1, CXCL2, and CXCL8). Infection of endothelial cells coupled with continued recruitment of inflammatory immune cells results in breakdown of the endothelial barrier, pleural effusion, and pulmonary edema seen in severe scrub typhus patients. Activation of recruited neutrophils and macrophages contributes to the inflammatory pulmonary environment.