Unravelling Human Trypanotolerance: IL8 is Associated with Infection Control whereas IL10 and TNFα Are Associated with Subsequent Disease Development

Abstract

In West Africa, Trypanosoma brucei gambiense, causing human African trypanosomiasis (HAT), is associated with a great diversity of infection outcomes. In addition to patients who can be diagnosed in the early hemolymphatic phase (stage 1) or meningoencephalitic phase (stage 2), a number of individuals can mount long-lasting specific serological responses while the results of microscopic investigations are negative (SERO TL+). Evidence is now increasing to indicate that these are asymptomatic subjects with low-grade parasitemia. The goal of our study was to investigate the type of immune response occurring in these “trypanotolerant” subjects. Cytokines levels were measured in healthy endemic controls (n = 40), stage 1 (n = 10), early stage 2 (n = 19), and late stage 2 patients (n = 23) and in a cohort of SERO TL+ individuals (n = 60) who were followed up for two years to assess the evolution of their parasitological and serological status. In contrast to HAT patients which T-cell responses appeared to be activated with increased levels of IL2, IL4, and IL10, SERO TL+ exhibited high levels of proinflammatory cytokines (IL6, IL8 and TNFα) and an almost absence of IL12p70. In SERO TL+, high levels of IL10 and low levels of TNFα were associated with an increased risk of developing HAT whereas high levels of IL8 predicted that serology would become negative. Further studies using high throughput technologies, hopefully will provide a more detailed view of the critical molecules or pathways underlying the trypanotolerant phenotype.

Systems analysis uncovers inflammatory Th/Tc17-driven modules during acute GVHD in monkey and human T cells

“…This module provided compelling evidence for inflammatory transcript enrichment in T cells during breakthrough acute disease, including the following inflammatory transcripts from the "Zhou_Inflammatory_response_FIMA_Up" gene set 44 : IL8, CCL20, CXCL3, CXCL1, PTX3, IL1b, IER3, CRISP3, G0S2, TLR2, PTGS2, CXCL2 (highlighted in Figure 6D black box), the first 6 of which have been linked to Th/Tc17-mediated inflammation in both preclinical models and in human disease. 45,46 The black module was also enriched for multiple other pathways of immune activation, including the KEGG and reactome "asthma," "signaling in the immune system," "GVHD" pathways as well as the KEGG "cytokine:cytokine receptor interaction" and "chemokine signaling" pathways ( Figure 6F; supplemental Table 8). …”

Trypanosoma brucei gambiense excreted/secreted factors impair lipopolysaccharide‐induced maturation and activation of human monocyte‐derived dendritic cells

“…For example, trypanotolerant patients have been characterized as having a marked inflammatory response with elevated levels of plasmatic IL8, IL6 and TNF‐α. For these patients, increase in IL‐10 levels and decrease in TNF‐α levels were markers of disease development during follow‐up . IL‐10 has been found to be essential for maintenance of the immunological balance between protective and pathological immune responses during HAT.…”

“…For these patients, increase in IL-10 levels and decrease in TNF-α levels were markers of disease development during follow-up. 29 IL-10 has been found to be essential for maintenance of the immunological balance between protective and pathological immune responses during HAT. It has been recently shown that other pathways may also contribute to maintain this immunological balance, such as IL-27 signalling.…”

An Overview of Trypanosoma brucei Infections: An Intense Host–Parasite Interaction

“…For example, in HAT caused by the gambiense strain (considered as invariably fatal), cases of self-cure in untreated patients have been described, although accurate diagnostic tools were not available at the time (revised by Jamonneau et al, 2012). In studies performed in mangrove areas of coastal Guinea, high levels of IL-10 and low levels of TNF-α have been associated with an increased risk to suffer HAT, whereas high levels of IL-8 were associated with disease control (Ilboudo et al, 2014). Recent data from patients that refused to receive chemotherapy and were monitored for periods from 5 to 15 years demonstrated parasite clearance, as observed using follow-up tools such as microscopy and polymerase chain reaction.…”