Altered monocyte differentiation and effector functions characterize immune pathogenesis of tuberculosis. IL-7 is an important factor for proliferation of T cells and impaired IL-7 sensitivity due to decreased IL-7 receptor α-chain (IL-7Rα) expression was found in patients with acute tuberculosis. Peripheral blood monocytes have moderate IL-7Rα expression and increased IL-7Rα levels were described for inflammatory diseases. In this study, we investigated a potential role of IL-7 and IL-7Rα expression for monocyte functions in tuberculosis. We analyzed the phenotype of monocytes in the blood from tuberculosis patients (n = 33), asymptomatic contacts of tuberculosis patients (contacts; n = 30), and healthy controls (n = 20) from Ghana by multicolor flow cytometry. Mycobacterial components were analyzed for their capacity to induce IL-7Rα expression in monocytes. Functional effects of monocyte to IL-7 were measured during signaling and by using an antimycobacterial in vitro kill assay. Monocytes were more frequent in peripheral blood from patients with tuberculosis and especially higher proportions of CD14+/CD16+ (M1/2) monocytes with increased PD-L1 expression characterized acute tuberculosis. IL-7Rα expression was decreased particularly on M1/2 monocytes from patients with tuberculosis and aberrant low expression IL-7Rα correlated with high PD-L1 levels. Constitutive low pSTAT5 levels of monocytes ex vivo and impaired IL-7 response confirmed functionally decreased monocyte IL-7 sensitivity of patients with tuberculosis. Mycobacteria and mycobacterial cell wall components induced IL-7 receptor expression in monocytes and IL-7 boosted mycobacterial killing by monocyte-derived macrophages in vitro. We demonstrated impaired monocyte IL-7 receptor expression as well as IL-7 sensitivity in tuberculosis with potential effects on antimycobacterial effector functions.
Bacterial components and cytokines induce IL‐7 receptor (IL‐7Rα) expression in monocytes. Aberrant low IL‐7Rα expression of monocytes has been identified as a feature of tuberculosis immunopathology. Here, we investigated the mechanisms underlying IL‐7Rα regulation of monocytes and tuberculosis serum effects on IL‐7Rα expression. Serum samples from tuberculosis patients and healthy controls, cytokine candidates, and mycobacterial components were analyzed for in vitro effects on IL‐7Rα expression of primary monocytes, monocyte‐derived macrophages (MDM), and monocyte cell lines. IL‐7Rα regulation during culture and the role of FoxO1 were characterized. In vitro activation‐induced IL‐7Rα expression in human monocytes and serum samples from tuberculosis patients boosted IL‐7Rα expression. Although pathognomonic tuberculosis cytokines were not associated with serum effects, we identified cytokines (i.e., GM‐CSF, IL‐1β, TNF‐α, IFN‐γ) that induced IL‐7Rα expression in monocytes and/or MDM comparable to mycobacterial components. Blocking of cytokine subsets (i.e., IL‐1β/TNF‐α in monocytes, GM‐CSF in MDM) largely diminished IL‐7Rα expression induced by mycobacterial components. Finally, we showed that in vitro‐induced IL‐7Rα expression was transient and dependent on constitutive FoxO1 expression in primary monocytes and monocyte cell lines. This study demonstrated the crucial roles of cytokines and constitutive FoxO1 expression for transient IL‐7Rα expression in monocytes.
Background Mycobacterium (M.) tuberculosis-caused immunopathology is characterized by aberrant expression of plasma cytokines in human tuberculosis. Disease severity and long-term anti-mycobacterial treatment are potentially influenced by immunopathology and normalization of plasma cytokine levels during therapy may indicate treatment efficacy and recovery. Study design and methods In this study, we analyzed the concentrations of selected plasma cytokines (i.e., IL-6, IP-10, IL-10, IL-22, IFNγ, GM-CSF, IL-8) and M. tuberculosis sputum burden in patients with tuberculosis (n = 76). Cytokine levels were compared to healthy contacts (n = 40) and changes under treatment were monitored (i.e., 6 and 16 weeks after treatment start). According to differences in M. tuberculosis sputum burden and conversion, tuberculosis patients were classified as paucibacillary as well as ‘rapid’ or ‘slow’ treatment responders. A subgroup of tuberculosis patients had fatal disease courses. Results Six of seven cytokines were significantly higher in tuberculosis patients as compared to contacts and four of these (i.e., IL-6, IP-10, IL-10, and IL-22) were detectable in the majority of tuberculosis patients. IL-6 showed the strongest discriminating capacity for tuberculosis disease and in combination with IL-10 concentrations efficiently classified paucibacillary tuberculosis cases as well as those with fatal disease outcome. In addition, IL-6 and IP-10 levels decreased significantly after 6 weeks of treatment and analyses of subgroups with differential treatment response showed delayed decline of IL-6 levels in slow treatment responders. Conclusions Combinations of different plasma cytokine (namely, IL-6, IL-10, and IP-10) efficiently classified tuberculosis patients with differential mycobacterial burden and especially IL-6 qualified as a biomarker candidate for early treatment response.
Purpose Human tuberculosis is characterized by immunopathology that affects T-cell phenotype and functions. Previous studies found impaired T-cell response to phytohemagglutinin (PHA) in patients with acute tuberculosis. However, the influence of disease severity, affected T-cell subsets, and underlying mechanisms remain elusive. Methods Here we investigated PHA-induced and antigen-specific T-cell effector cytokines in tuberculosis patients (n = 55) as well as in healthy asymptomatic contacts (n = 32) from Ghana. Effects of Mycobacterium (M.) tuberculosis sputum burden and treatment response were analyzed and compared during follow-up. Finally, cytokine characteristics of the aberrant plasma milieu in tuberculosis were analyzed as a potential cause for impaired PHA response. Results PHA-induced IFN-γ expression was significantly lower in sputum-positive tuberculosis patients as compared to both, contacts and paucibacillary cases, and efficiently discriminated the study groups. T-cell responses to PHA increased significantly early during treatment and this was more pronounced in tuberculosis patients with rapid treatment response. Analysis of alternative cytokines revealed distinct patterns and IL-22, as well as IL-10, showed comparable expression to IFN-γ in response to PHA. Finally, we found that high IL-6 plasma levels were strongly associated with impaired IFN-γ and IL-22 response to PHA. Conclusion We conclude that impaired T-cell response to PHA stimulation in acute tuberculosis patients (i) was potentially caused by the aberrant plasma milieu, (ii) affected differentially polarized T-cell subsets, (iii) normalized early during treatment. This study shed light on the mechanisms of impaired T-cell functions in tuberculosis and yielded promising biomarker candidates for diagnosis and monitoring of treatment response.
Background Plasmodium falciparum and Hookworm infections are prevalent in West Africa and they cause iron deficiency anemia and protein malnutrition in Children. Immune response of these parasites interact and their interactions could have repercussions on vaccine development and efficacy. The current goal of hookworm eradication lies on vaccination. We evaluated the effect of P. falciparum coinfection and albendazole treatment on naturally acquired antibody profile against hookworm L3 stage larvae antigen. Methods In a longitudinal study, 40 individuals infected with Necator americanus only, 63 participants infected with N. americanus and P. falciparum , and 36 nonendemic controls (NECs) were recruited. The study was done in the Kintampo North Metropolis of Ghana. Stool and blood samples were taken for laboratory analyses. Serum samples were obtained before hookworm treatment and 3 weeks after treatment. Results The malaria‐hookworm ( N. americanus and P. falciparum ) coinfected subjects had significantly higher levels of IgE ( β = 0.30, 95% CI = [0.12, 0.48], p = 0.023) and IgG3 ( β = 0.15, 95% CI = [0.02, 0.52], p = 0.004) compared to those infected with hookworm only ( N. americanus ). The N. americanus groups had significantly higher levels of IgG3 ( β = 0.39, 95% CI = [0.14–0.62], p = 0.002) compared to the control group. Similarly, N. americanus and P. falciparum coinfected participants had significantly higher levels of IgE ( β = 0.35, 95% CI = [0.70–0.39], p = 0.002) and IgG3 ( β = 0.54, 95% CI = [0.22–0.76], p = 0.002). Moreover, albendazole treatment led to a significant reduction in IgE, IgA, IgM, and IgG3 antibodies against hookworm L3 stage larvae ( p < 0.05) Conclusion P. falciparum is associated with improved IgE and IgG response against hookworm L3 stage larvae. Treatment with single dose of albendazole led to reduction in naturally acquired immune response against hookworm infection. Thus, P. falciparum infection may have a boosting effect on hookworm vaccine effectiveness.
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