Complex Cytokine Responses in Imported Scrub Typhus Cases, Germany, 2010–2018

Abstract

Scrub typhus is a life-threatening zoonotic disease, which is caused by Orientia tsutsugamushi, an obligatory intracellular Gram-negative bacterium. It is transmitted by Leptotrombidium mites in endemic regions of Southeast Asia. So far, data on imported scrub typhus cases to non-endemic areas and immunological descriptions are rare. Eleven scrub typhus cases that had been diagnosed by the German National Reference Center for Tropical Pathogens between 2010 and 2018 were retrospectively reviewed for clinical symptoms, laboratory changes, and travel destinations. Patient sera were included if follow-up samples showed simultaneous seroconversion for IgM and IgG antibody responses by immunofluorescence assays or concurrence with the first serum sample. The median of seroconversion was week 2 after symptom onset. Cytokine levels were measured over time, demonstrating simultaneously upregulated major Th1, Th2, and Th17 cytokines in the acute phase of infection followed by normalization during convalescence. This study underlines the complex mixed cytokine response elicited by scrub typhus and highlights clinical and diagnostic aspects of imported infections with O. tsutsugamushi.

A time-course comparative clinical and immune response evaluation study between the human pathogenic Orientia tsutsugamushi strains: Karp and Gilliam in a rhesus macaque (Macaca mulatta) model

“…Upon O . tsutsugamushi infection, a “cytokine storm” is known to occur in a subgroup of patients with scrub typhus [ 16 , 26 ] and may be associated with severe complications [ 14 , 15 , 27 ]. A number of studies reported that IL-6, IL-8 [ 14 ], IL-10 [ 15 ], MCP-1 [ 14 ], MIP-1β [ 14 ] and TNF [ 15 , 17 , 43 ] serum levels correlate with disease severity.…”

“…Intradermal inoculation of CD-1 Swiss outbred mice (closely mimicking the natural infection route) revealed that Karp and Gilliam strains led to more severe disease than Kato and Woods strains [13] and that the intracellular cytokine signatures induced by the intradermal inoculation of Karp and Woods strains (non-lethal scrub typhus models) differed significantly from that induced by the intraperitoneal inoculation of Karp strain (lethal scrub typhus model) [10]. Available data from mouse and human studies suggest that in severe scrub typhus with an overwhelming pathogen load, the host immune system produces a strong inflammatory cytokine response, which associates with increased disease severity and complications [10,[14][15][16][17].…”

“…A recent study in Vietnam suggested that Karp strains were associated with clinically more severe human cases than Gilliam and Kato strain infections [25]. The pathogenesis of scrub typhus appears to be closely associated with the host inflammatory response-locally at the eschar, and systematically via cytokines, which play a key role in the pathology of scrub typhus [14][15][16]26]. High levels of several cytokines, including IL-6, IL-8, IL-10, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1 beta (MIP-1β), IFN-γ and TNF were reported during the acute phase of scrub typhus patients, and correlated with disease severity [14,17].…”