C-C Motif Ligand 7 (CCL7) and C-C Motif Chemokine Receptor 3 (CCR3) dysregulation in patients with scrub typhus and association with mortality.

Abstract

Scrub typhus, caused by Orientia tsutsugamushi involves infiltration of a mixture of perivascular lymphocytes and macrophages into affected organs. We investigated if this is characterized by chemokine dysregulation. mRNA expression of chemokines and receptors were screened in whole blood by cDNA microarray in a subgroup of patients and controls. Regulated transcripts were analyzed in plasma by enzyme immunoassays (chemokines) and in whole blood by qPCR (receptors) from scrub typhus patients (n=129), patients with similar febrile illness without Orentia tsutsugamushi infection (n=31) and healthy controls (n=31). (i) cDNA microarray identified dysregulation of the chemokines CCL18 and CCL23 and CCR3 receptor, in severe scrub typhus. (ii) Plasma CCL7, a ligand for CCR3, CCL18 and CCL23 were higher in scrub typhus patients, with a decline during follow-up. (iii) Conversely, mRNA levels of CCR3 and CCR8, the receptor for CCL18, were decreased in whole blood at hospital admission followed by an increase during follow-up. (iv) CCL7 was independently associated with disease severity. (v) Admission CCL7 levels were associated with short-time mortality. Our findings suggest CCL7 could represent a hitherto unknown pathogenic mediator in Orentia tsutsugamushi infection contributing to local and systemic inflammation.