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.

Efficacy and Safety of Antibiotics for Treatment of Scrub Typhus

“…However, a recent report identified some cases in South America, which is an area that had no previously documented scrub typhus cases. 5 So far, there is no available vaccine for O tsutsugamushi because of extensive antigenic diversity and a short duration of immune protection following immunity stimulated by naturally acquired scrub typhus infection. 12 , 49 Therefore, antibiotics are the only therapy for scrub typhus.…”

“…However, although almost 1 million new cases are reported every year, scrub typhus is regarded as a neglected tropical disease. 5 …”

“…Antibiotics have been used for scrub typhus treatment for many years and, with no vaccine available, are the only way to treat scrub typhus. 5 Thus, it is necessary to assess the antibiotics used in treatment. The most common antibiotics used for treatment are doxycycline, tetracyclines, chloramphenicol, and azithromycin, 13 but their efficacy is disputable.…”

Polarized lung inflammation and Tie2/angiopoietin-mediated endothelial dysfunction during severe Orientia tsutsugamushi infection

“…Sublethal O. tsutsugamushi infection studies in outbred Swiss CD-1 mice [19], as well as clinical studies of human patients [20], have shown significant elevation of endothelial activation markers (ICAM-1, VCAM-1, E-Selectin, etc.) in the serum of infected individuals; however, endothelium-focused analyses during in vivo infection remain largely unexplored [21]. Several studies have characterized the response and activation of MFs during O. tsutsugamushi infection [22,23].…”

Genome-Wide Association Study Identifies Eight Novel Loci for Susceptibility of Scrub Typhus and Highlights Immune-Related Signaling Pathways in Its Pathogenesis

“…Because scrub typhus is a Rickettsia disease, it is not surprising that several studies have noted Rickettsia-related innate immune response proteins [ 14 ]. In this context, an important study using the candidate gene approach has been performed to identify the pathogenesis of scrub typhus associated with molecular mechanisms [ 15 ].…”