Browsing by Author "Nutman, Thomas B."

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    Strongyloides stercoralis Infection in Solid Organ Transplant Patients Is Associated With Eosinophil Activation and Intestinal Inflammation: A Cross-sectional Study
    (Oxford University Press, 2020-12) Clark, Eva; Pritchard, Haley; Hemmige, Vagish; Restrepo, Alejandro; Bautista, Karla; Damania, Ashish; Ricciardi, Alessandra; Nutman, Thomas B.; Mejia, Rojelio; Medicine, School of Medicine
    Background: Strongyloidiasis can cause devastating morbidity and death in immunosuppressed patients. Identification of reliable biomarkers for strongyloidiasis in immunosuppressed patients is critical for the prevention of severe disease. Methods: In this cross-sectional study of solid organ transplant (SOT) candidates and recipients, we quantified Strongyloides-specific IgG to the recombinant NIE-Strongyloides antigen and/or to a soluble extract of S. stercoralis somatic antigens ("crude antigen") using enzyme-linked immunosorbent assays (ELISAs). We also measured peripheral eosinophilia, 4 different eosinophil granule proteins, and intestinal fatty acid-binding protein (IFABP). Results: We evaluated serum biomarkers in 149 individuals; 77 (52%) pre-SOT and 72 (48%) post-SOT. Four percent (6/149) tested positive by NIE ELISA and 9.6% (11/114) by crude antigen ELISA (overall seropositivity of 9.4% [14/149]). Seropositive patients had higher absolute eosinophil counts (AECs) than seronegative patients (P = .004). AEC was positively correlated to the levels of eosinophil granule proteins eosinophil cationic protein (ECP) and eosinophil peroxidase (EPO) (P < .05), while IFABP was positively related to the 2 other eosinophil granule proteins (major basic protein [MBP] and eosinophil-derived neurotoxin [EDN]; Spearman's r = 0.3090 and 0.3778, respectively; P < .05; multivariate analyses slopes = 0.70 and 2.83, respectively). Conclusions: This study suggests that, in SOT patients, strongyloidiasis triggers both eosinophilia and eosinophil activation, the latter being associated with intestinal inflammation. These data provide insight into the pathogenesis of S. stercoralis infection in the immunocompromised population at high risk of severe strongyloidiasis syndromes.
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    Systemic and cerebrospinal fluid immune and complement activation in Ugandan children and adolescents with long‐standing nodding syndrome: A case‐control study
    (Wiley, 2021-06) Ogwang, Rodney; Muhanguzi, Dennis; Mwikali, Kioko; Anguzu, Ronald; Kubofcik, Joe; Nutman, Thomas B.; Taylor, Mark; Newton, Charles R.; Vincent, Angela; Conroy, Andrea L.; Marsh, Kevin; Idro, Richard; Pediatrics, School of Medicine
    Objective: Nodding syndrome is a poorly understood epileptic encephalopathy characterized by a unique seizure type-head nodding-and associated with Onchocerca volvulus infection. We hypothesized that altered immune activation in the cerebrospinal fluid (CSF) and plasma of children with nodding syndrome may yield insights into the pathophysiology and progression of this seizure disorder. Method: We conducted a case-control study of 154 children (8 years or older) with long-standing nodding syndrome and 154 healthy age-matched community controls in 3 districts of northern Uganda affected by nodding syndrome. Control CSF samples were obtained from Ugandan children in remission from hematological malignancy during routine follow-up. Markers of immune activation and inflammation (cytokines and chemokines) and complement activation (C5a) were measured in plasma and CSF using ELISA or Multiplex Luminex assays. O volvulus infection was assessed by serology for anti-OV-16 IgG levels. Results: The mean (SD) age of the population was 15.1 (SD: 1.9) years, and the mean duration of nodding syndrome from diagnosis to enrollment was 8.3 (SD: 2.7) years. The majority with nodding syndrome had been exposed to O volvulus (147/154 (95.4%)) compared with community children (86/154 (55.8%)), with an OR of 17.04 (95% CI: 7.33, 45.58), P < .001. C5a was elevated in CSF of children with nodding syndrome compared to controls (P < .0001). The levels of other CSF markers tested were comparable between cases and controls after adjusting for multiple comparisons. Children with nodding syndrome had lower plasma levels of IL-10, APRIL, CCL5 (RANTES), CCL2, CXCL13, and MMP-9 compared with community controls (P < .05 for all; multiple comparisons). Plasma CRP was elevated in children with nodding syndrome compared to community children and correlated with disease severity. Significance: Nodding syndrome is associated with exposure to O. volvulus. Compared to controls, children with long-standing symptoms of nodding syndrome show evidence of complement activation in CSF and altered immune activation in plasma.
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    Transcriptomic evidence for modulation of host inflammatory responses during febrile Plasmodium falciparum malaria
    (SpringerNature, 2016-08-10) Tran, Tuan M.; Jones, Marcus B.; Ongoiba, Aissata; Bijker, Else M.; Schats, Remko; Venepally, Pratap; Skinner, Jeff; Doumbo, Safiatou; Quinten, Edwin; Visser, Leo G.; Whalen, Elizabeth; Presnell, Scott; O’Connell, Elise M.; Kayentao, Kassoum; Doumbo, Ogobara K.; Chaussabel, Damien; Lorenzi, Hernan; Nutman, Thomas B.; Ottenhoff, Tom H. M.; Haks, Mariëlle C.; Traore, Boubacar; Kirkness, Ewen F.; Sauerwein, Robert W.; Crompton, Peter D.; Department of Medicine, IU School of Medicine
    Identifying molecular predictors and mechanisms of malaria disease is important for understanding how Plasmodium falciparum malaria is controlled. Transcriptomic studies in humans have so far been limited to retrospective analysis of blood samples from clinical cases. In this prospective, proof-of-principle study, we compared whole-blood RNA-seq profiles at pre-and post-infection time points from Malian adults who were either asymptomatic (n = 5) or febrile (n = 3) during their first seasonal PCR-positive P. falciparum infection with those from malaria-naïve Dutch adults after a single controlled human malaria infection (n = 5). Our data show a graded activation of pathways downstream of pro-inflammatory cytokines, with the highest activation in malaria-naïve Dutch individuals and significantly reduced activation in malaria-experienced Malians. Newly febrile and asymptomatic infections in Malians were statistically indistinguishable except for genes activated by pro-inflammatory cytokines. The combined data provide a molecular basis for the development of a pyrogenic threshold as individuals acquire immunity to clinical malaria.