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.

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 and Aim: Human hookworm disease caused by Ancylostoma duodenale and Necator americanus is a serious public health problem. Hookworm infection activates eosinophil-mediated tissue inflammatory responses, involving the production of the eosinophil-specific chemokine (eotaxin), recruitment of eosinophils, secretion of the cationic protein, and production of antiparasite immunoglobulin E (IgE). We investigated eosinophil-mediated immune response as markers (CCL11, eosinophil cationic protein [ECP], and IgE) for detecting hookworm infection.Methods: This case-control study was carried out in hookworm endemic areas within the Kintampo North Municipality.Forty hookworm-positive subjects and 36 apparently healthy individuals were recruited as cases and controls, respectively.Stool samples were collected for hookworm detection by the Kato-Katz technique and speciation by polymerase chain reaction. Approximately, 5 ml of intravenous blood was used to obtain plasma for the immunological assays.Results: Of eosinophil-mediated immune response markers studied, ECP and CCL11 were significantly higher among hookworm patients compared to controls.Increasing CCL11 (β = −0.81, p = 0.015) was associated with a significant decrease hookworm intensity. However, increasing eosinophil count (β = 0.62, p = 0.027) was associated with significant increase in hookworm intensity. In receiver operator characteristics analysis, ECP could significantly detect hookworm infection with a very high area under the curve (AUC) (AUC = 0.97, p < 0.0001). At a cutoff of 39.05, ECP was the best eosinophil-mediated immune response marker for detecting hookworm infection with a sensitivity of 97.2%, specificity of 87.8%, a positive predictive value of 89.7%, and a negative predictive value of 96.6%. Conclusion:ECP best predicts eosinophil-mediated immune response for detecting hookworm infection, while CCL11 and eosinophil count better predict the intensity of hookworm. Moreover, the ECP level is a good indicator of hookworm infection