Research Article: Interleukin (IL)-6 and IL-10 Are Up Regulated in Late Stage Trypanosoma brucei rhodesiense Sleeping Sickness

Date Published: June 19, 2015

Publisher: Public Library of Science

Author(s): Charles D. Kato, Vincent P. Alibu, Ann Nanteza, Claire M. Mugasa, Enock Matovu, Ricardo Toshio Fujiwara.

Abstract: BackgroundSleeping sickness due to Trypanosoma brucei rhodesiense has a wide spectrum of clinical presentations coupled with differences in disease progression and severity across East and Southern Africa. The disease progresses from an early (hemo-lymphatic) stage to the late (meningoencephalitic) stage characterized by presence of parasites in the central nervous system. We hypothesized that disease progression and severity of the neurological response is modulated by cytokines.MethodsA total of 55 sleeping sickness cases and 41 healthy controls were recruited passively at Lwala hospital, in Northern Uganda. A panel of six cytokines (IFN-γ, IL1-β, TNF-α, IL-6, TGF-β and IL-10) were assayed from paired plasma and cerebrospinal fluid (CSF) samples. Cytokine concentrations were analyzed in relation to disease progression, clinical presentation and severity of neurological responses.ResultsMedian plasma levels (pg/ml) of IFN-γ (46.3), IL-6 (61.7), TGF-β (8755) and IL-10 (256.6) were significantly higher in cases compared to controls (p< 0.0001). When early stage and late stage CSF cytokines were compared, IL-10 and IL-6 were up regulated in late stage patients and were associated with a reduction in tremors and cranioneuropathy. IL-10 had a higher staging accuracy with a sensitivity of 85.7% (95% CI, 63.7%-97%) and a specificity of 100% (95% CI, 39.8%-100%) while for IL-6, a specificity of 100% (95% CI, 47.8%-100%) gave a sensitivity of 83.3% (95% CI, 62.2%-95.3%).ConclusionOur study demonstrates the role of host inflammatory cytokines in modulating the progression and severity of neurological responses in sleeping sickness. We demonstrate here an up-regulation of IL-6 and IL-10 during the late stage with a potential as adjunct stage biomarkers. Given that both cytokines could potentially be elevated by other CNS infections, our findings should be further validated in a large cohort of patients including those with other inflammatory diseases such as cerebral malaria.

Partial Text: Human African Trypanosomiasis (HAT) or sleeping sickness is caused by extra-cellular protozoan parasites T. b. rhodesiense (East and Southern Africa) and T. b. gambiense (West and central Africa). Although an estimated 12.3 million people are at a risk of developing T. b. rhodesiense disease, the number of new cases has reduced for the past 4 years to below 200 cases per year (range 110–190) [1]. The disease progresses in two stages, the hemo-lymphatic or early stage is characterized by the proliferation of trypanosomes in blood and lymph. The second or late stage is characterized by invasion of trypanosomes in the central nervous system (CNS) and appears after weeks in the typically acute T. b. rhodesiense disease or months in the chronic T. b. gambiense HAT.

In this study we have carried out a comprehensive analysis of cytokines in T. b. rhodesiense HAT patients and analyzed them in light of disease stage, duration and severity. Sleeping sickness due to T. b. rhodesiense was previously described as an acute disease [31]. However, recent studies reporting a wide range of disease pathology with variation in severity and progression both within and across disease foci have started to emerge [3,4]. HAT patients in Uganda (Eastern Africa) were reported to suffer from a more acute disease compared to patients from Malawi (Southern Africa) [3]. Indeed, even when HAT pathology was compared in two geographically close foci in Uganda (Tororo and Soroti) significant differences in disease presentation and progression were noted [5]. This variation in HAT severity and progression has been proposed to be due to variation in host inflammatory cytokines in both human patients [3,5,32] and in experimental animals [11,27,33]. However, controversies still exist about the roles of specific cytokines in HAT progression [7].



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