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. Key Points Decreased IL-7 receptor expression of monocytes from tuberculosis patients occurred. Impaired IL-7 response of monocytes in M. tuberculosis infection occurred. IL-7 promotes mycobacterial killing by macrophages in vitro. Visual Abstract

Background. According to the World Health Organization, neglected tropical diseases (NTDs) affect over two billion people worldwide. While the links between nutrition and many diseases have become clear over recent decades, NTDs have lagged behind and the linkage with nutrition is largely unknown. We conducted this systematic review with meta-analysis to determine the current knowledge on the association between NTDs and malnutrition. Methodology. PubMed, Embase, Scopus and African Journals Online databases were searched using predefined search terms. We included all original articles with a case–control design and at least one NTD. The studies had to compare nutritional parameters between infected cases and control participants. Articles that did not report original data were excluded. The quality of the studies was assessed using the Newcastle–Ottawa scale. Pooled estimates were conducted using the random effect model. The publication bias of the studies was determined by funnel plots. Q and I ² statistics were used to assess the heterogeneity of the studies. Results. After screening 1294 articles, only 16 qualified for the systematic review and 12 for meta-analysis. These predominately had a focus on soil-transmitted helminthiasis (ascariasis, hookworm diseases and trichuriasis) and schistosomiasis, with a minority concerning leishmaniasis and leprosy. Pooled estimates showed an association between intestinal parasites and stunting in children [odds ratio (OR) = 1.38, 95% confidence interval (CI): 1.14–1.66, I ² = 0%, tau² = 0]. We also identified a moderate association established between serum iron deficiency (OR = 4.67, 95% CI: 1.91–11.44, tau² = 0) and intestinal parasites. Conclusions/significance. Of the 20 NTDs, the links between diet and disease have been explored for only 4. There is a paucity of data from low- and middle-income countries and least-developed countries where the NTD burden is high. Therefore, more research into the role of malnutrition in NTDs other than intestinal parasites, leishmaniasis and leprosy is needed.

Bacterial components and cytokines induce IL-7 receptor (IL-7R alpha) expression in monocytes. Aberrant low IL-7R alpha expression of monocytes has been identified as a feature of tuberculosis immunopathology. Here, we investigated the mechanisms underlying IL-7R alpha regulation of monocytes and tuberculosis serum effects on IL-7R alpha expression. Serum samples from tuberculosis patients and healthy controls, cytokine candidates, and mycobacterial components were analyzed for in vitro effects on IL-7R alpha expression of primary monocytes, monocyte-derived macrophages (MDM), and monocyte cell lines. IL-7R alpha regulation during culture and the role of FoxO1 were characterized. In vitro activation-induced IL-7R alpha expression in human monocytes and serum samples from tuberculosis patients boosted IL-7R alpha expression. Although pathognomonic tuberculosis cytokines were not associated with serum effects, we identified cytokines (i.e., GM-CSF, IL-1 beta, TNF-alpha, IFN-gamma) that induced IL-7R alpha expression in monocytes and/or MDM comparable to mycobacterial components. Blocking of cytokine subsets (i.e., IL-1 beta/TNF-alpha in monocytes, GM-CSF in MDM) largely diminished IL-7R alpha expression induced by mycobacterial components. Finally, we showed that in vitro-induced IL-7R alpha 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-7R alpha expression in monocytes.

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 and intensity and may require additional investigations to augment current hookworm diagnostic techniques.

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.

Mycobacterium (M.) bovis BCG vaccination is recommended for healthy babies after birth in several countries with a high prevalence of tuberculosis, including Ghana. Previous studies showed that BCG vaccination prevents individuals from developing severe clinical manifestations of tuberculosis, but BCG vaccination effects on the induction of IFN-γ after M. tuberculosis infection have hardly been investigated. Here, we performed IFN-γ-based T-cell assays (i.e., IFN-γ Release Assay, IGRA; T-cell activation and maturation marker assay, TAM-TB) in children who had contact with index tuberculosis patients (contacts). These contacts were classified as either being BCG vaccinated at birth (n = 77) or non-BCG-vaccinated (n = 17) and were followed up at three timepoints for a period of one year to determine immune conversion after M. tuberculosis exposure and potential infection. At baseline and month 3, BCG-vaccinated contacts had significantly lower IFN-γ levels after stimulation with M. tuberculosis-specific proteins as compared to non-BCG-vaccinated contacts. This resulted in decreased proportions of positive IGRA results (BCG-vaccinated: 60% at baseline, 57% at month 3; non-BCG-vaccinated: 77% and 88%, respectively) at month 3. However, until month 12, immune conversion in BCG-vaccinated contacts led to balanced proportions in IGRA responders and IFN-γ expression between the study groups. TAM-TB assay analyses confirmed higher proportions of IFN-γ-positive T-cells in non-BCG-vaccinated contacts. Low proportions of CD38-positive M. tuberculosis-specific T-cells were only detected in non-BCG-vaccinated contacts at baseline. These results suggest that BCG vaccination causes delayed immune conversion as well as differences in the phenotype of M. tuberculosis-specific T-cells in BCG-vaccinated contacts of tuberculosis patients. These differences are immune biomarker candidates for protection against the development of severe clinical tuberculosis manifestations.