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.
Immune-based diagnosis of Buruli ulcer disease (BUD) in children is difficult due to cross-reactivity between mycobacteria. We found that T-cell IFNγ/TNFαresponses against Mycobacterium (M.) ulcerans and M. tuberculosis (PPDMulc, PPDMtub) were different between children with BUD (n=27) and TB (n=20) but only ratios (PPDMtub/PPDMulc) discriminated the study groups efficiently.
Monocyte‐derived macrophages contribute centrally to immune protection in Mycobacterium tuberculosis infection and changes in monocyte phenotype characterize immunopathology in tuberculosis patients. Recent studies highlighted an important role of the plasma milieu in tuberculosis immunopathology. Here, we investigated monocyte pathology in patients with acute tuberculosis and determined tuberculosis plasma milieu effects on phenotype as well as cytokine signalling of reference monocytes. Patients with tuberculosis (n = 37) and asymptomatic contacts (controls n = 35) were recruited as part of a hospital‐based study in the Ashanti region of Ghana. Multiplex flow cytometry phenotyping of monocyte immunopathology was performed and effects of individual blood plasma samples on reference monocytes prior to and during treatment were characterized. Concomitantly, cell signalling pathways were analysed to elucidate underlying mechanisms of plasma effects on monocytes. Multiplex flow cytometry visualization characterized changes in monocyte subpopulations and detected higher expression of CD40, CD64 and PD‐L1 in monocytes from tuberculosis patients as compared to controls. Aberrant expression normalized during anti‐mycobacterial treatment and also CD33 expression decreased markedly. Notably, higher CD33, CD40 and CD64 expression was induced in reference monocytes when cultured in the presence of plasma samples from tuberculosis patients as compared to controls. STAT signalling pathways were affected by the aberrant plasma milieu and higher levels of STAT3 and STAT5 phosphorylation was found in tuberculosis plasma‐treated reference monocytes. Importantly, high pSTAT3 levels were associated with high CD33 expression and pSTAT5 correlated with CD40 as well as CD64 expression. These results suggested plasma milieu effects with potential implications on monocyte phenotype and function in acute tuberculosis.
Background Buruli ulcer disease (BUD) caused by Mycobacterium (M.) ulcerans is characterized by necrotic skin lesions. As for other mycobacterial infections, e.g., tuberculosis, the immune response is important for host protection. B-cells may play a role in antimycobacterial immunity but studies characterizing the B-cell repertoire and memory generation in BUD and during the course of treatment are scarce. Methods We investigated the adaptive immune cell repertoire in children with BUD and healthy matched controls by flow cytometry. Analyses prior to treatment, also in a study group of patients with tuberculosis, as well as three time points during BUD treatment (i.e., week 8, 16, and 32) were performed. In addition, BUD disease severity as well as treatment response were analysed for association with B-cell repertoire differences. Results Children with BUD had comparable total B- and T-cell proportions but differed largely in B-cell subsets. Memory B-cell (B mem) proportions were higher in children with BUD whereas regulatory B-cell (B reg) proportions were lower as compared to healthy controls and tuberculosis patients. Lower naïve (B naïve) and higher transitional B-cell (B trans) proportions characterized children with BUD in comparison with tuberculosis patients. Under treatment, B mem proportions decreased significantly whereas proportions of B reg and B naive increased concomitantly in children with BUD. Also, we found significant correlation between lesion size and B mem as well as B reg. However, we did not detect associations between treatment efficacy and B-cell proportions. Conclusions These results suggest a role of B-cell subsets in the immune response against M. ulcerans. Furthermore, changes in B-cell subset proportions may be used as markers for treatment monitoring in BUD.
Background Doxycycline is used for treatment of Mansonella (M.) perstans infection. Immune modulatory effects of both, M. perstans and doxycycline, have been described but long-term implications on host immune response are not defined. Here we determined multiple immune parameters of M. perstans infected individuals prior to and after doxycycline treatment to characterize doxycycline effects on host T-cell immunity. Methods Immune characterization of doxycycline-treated M. perstans infected individuals was performed as part of an open-label randomized clinical trial. Immune cell population phenotyping by flow cytometry and functional in vitro T-cell assays were performed at baseline, six months, and ‘long-term’ (18-24 months) after treatment start. Treatment efficacy, based on peripheral blood microfiliaria burden, was correlated with immune parameters and effects on immune response against concomitant Mycobacterium tuberculosis infection were determined. Results Immune population phenotyping indicated changes in functional T-cell responses after doxycycline treatment. Constitutive and superantigen induced T-cell activation and polarization towards T helper type (TH)1 phenotype at baseline declined after doxycycline treatment whereas low proportions of TH17 and TH1* cells at baseline increased significantly at follow-up. In accordance, long-term decline in antigen-specific TH1 responses against concomitant Mycobacterium tuberculosis infection was seen. Notably, only TH17 and TH1* changes after six months and TH17 at baseline were negatively correlated with M. perstans microfilaria burden or reduction whereas long-term changes were not associated with treatment efficacy. Conclusions We found long-term immune modulatory effects of doxycycline treatment leading to decreased constitutive T-cell activation, polarization towards TH17/TH1*, and impaired immune response against concomitant Mycobacterium tuberculosis infection.
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