Research Article: Increased Nucleosomes and Neutrophil Activation Link to Disease Progression in Patients with Scrub Typhus but Not Murine Typhus in Laos

Date Published: August 28, 2015

Publisher: Public Library of Science

Author(s): Daniel H. Paris, Femke Stephan, Ingrid Bulder, Diana Wouters, Tom van der Poll, Paul N. Newton, Nicholas P. J. Day, Sacha Zeerleder, Pamela L. C. Small.

Abstract: Cell-mediated immunity is essential in protection against rickettsial illnesses, but the role of neutrophils in these intracellular vasculotropic infections remains unclear. This study analyzed the plasma levels of nucleosomes, FSAP-activation (nucleosome-releasing factor), and neutrophil activation, as evidenced by neutrophil-elastase (ELA) complexes, in sympatric Lao patients with scrub typhus and murine typhus. In acute scrub typhus elevated nucleosome levels correlated with lower GCS scores, raised respiratory rate, jaundice and impaired liver function, whereas neutrophil activation correlated with fibrinolysis and high IL-8 plasma levels, a recently identified predictor of severe disease and mortality. Nucleosome and ELA complex levels were associated with a 4.8-fold and 4-fold increased risk of developing severe scrub typhus, beyond cut off values of 1,040 U/ml for nucleosomes and 275 U/ml for ELA complexes respectively. In murine typhus, nucleosome levels associated with pro-inflammatory cytokines and the duration of illness, while ELA complexes correlated strongly with inflammation markers, jaundice and increased respiratory rates. This study found strong correlations between circulating nucleosomes and neutrophil activation in patients with scrub typhus, but not murine typhus, providing indirect evidence that nucleosomes could originate from neutrophil extracellular trap (NET) degradation. High circulating plasma nucleosomes and ELA complexes represent independent risk factors for developing severe complications in scrub typhus. As nucleosomes and histones exposed on NETs are highly cytotoxic to endothelial cells and are strongly pro-coagulant, neutrophil-derived nucleosomes could contribute to vascular damage, the pro-coagulant state and exacerbation of disease in scrub typhus, thus indicating a detrimental role of neutrophil activation. The data suggest that increased neutrophil activation relates to disease progression and severe complications, and increased plasma levels of nucleosomes and ELA complexes represent independent risk factors for developing severe scrub typhus.

Partial Text: Typhus-like illnesses, represented by rickettsioses, leptospirosis, dengue and typhoid, pose a significant challenge to tropical infectious disease clinicians due to their non-specific clinical presentations and difficulties in laboratory diagnosis. Recent studies have revealed tropical rickettsioses as leading causes of treatable fevers in Southeast Asia [1–4]. Scrub typhus, caused by infection with Orientia tsutsugamushi, and murine typhus, caused by Rickettsia typhi, are the predominant species infecting humans in Asia, and probably represent the most frequent, neglected, severe but easily treatable diseases in the world [5,6].

Although the importance of cell-mediated adaptive immune response in host protection against scrub typhus and murine typhus is well established, the role of neutrophils in these intracellular infections remains unclear. Pathophysiological studies of surrogate markers for cell adhesion molecules, coagulation and inflammation including histopathological observations in patients with scrub typhus and murine typhus, have highlighted differential profiles for the two diseases at the hospital admission time point [11–13,17]. In this study we hypothesized that neutrophils could provide a differential contribution to disease severity in these diseases, and measured the plasma levels of nucleosomes, FSAP activation and neutrophil activation in sympatric patients with scrub typhus and murine typhus in Laos. Although raised levels of circulating nucleosomes and systemic neutrophil activation were found in patients with both forms of typhus compared to controls, the increase of both markers was significantly higher in scrub typhus than in murine typhus (Fig 1).



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