title: Increased Nucleosomes and Neutrophil Activation Link to Disease Progression in Patients with Scrub Typhus but Not Murine Typhus in Laos.
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.
authors: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine & Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Microbiology Laboratory, Mahosot Hospital, Vientiane, Lao PDR.
authors: Daniel H
authors: DH
authors: Paris
authors: Sanquin Research, Department of Immunopathology, Amsterdam, The Netherlands.
authors: Femke
authors: F
authors: Stephan
authors: Sanquin Research, Department of Immunopathology, Amsterdam, The Netherlands.
authors: Ingrid
authors: I
authors: Bulder
authors: Sanquin Research, Department of Immunopathology, Amsterdam, The Netherlands.
authors: Diana
authors: D
authors: Wouters
authors: Department of Vascular Medicine and Centre for Experimental and Molecular Medicine (CEMM), Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors: Tom
authors: T
authors: van der Poll
authors: Centre for Tropical Medicine & Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Microbiology Laboratory, Mahosot Hospital, Vientiane, Lao PDR.
authors: Paul N
authors: PN
authors: Newton
authors: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine & Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors: Nicholas P J
authors: NP
authors: Day
authors: Sanquin Research, Department of Immunopathology, Amsterdam, The Netherlands; Department of Hematology, Academic Medical Centre, Amsterdam, The Netherlands.
authors: Sacha
authors: S
authors: Zeerleder
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D006801:Humans; D007812:Laos / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D018375:Neutrophil Activation / Q000276:immunology*; D009707:Nucleosomes / Q000502:physiology*; D012612:Scrub Typhus / Q000453:epidemiology / Q000276:immunology*; D012698:Serologic Tests; D014437:Typhus, Endemic Flea-Borne / Q000453:epidemiology / Q000276:immunology*; D055815:Young Adult
chemical_list: D009707:Nucleosomes