| 1. |
- Abate, Ebba, et al.
(författare)
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Asymptomatic Helminth Infection in Active Tuberculosis Is Associated with Increased Regulatory and Th-2 Responses and a Lower Sputum Smear Positivity
- 2015
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Ingår i: PLoS Neglected Tropical Diseases. - : PUBLIC LIBRARY SCIENCE. - 1935-2727 .- 1935-2735. ; 9:8
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Tidskriftsartikel (refereegranskat)abstract
- Background The impact of intestinal helminth infection on the clinical presentation and immune response during active tuberculosis (TB) infection is not well characterized. Our aim was to investigate whether asymptomatic intestinal helminth infection alters the clinical signs and symptoms as well as the cell mediated immune responses in patients with active TB.Methodology Consecutive, newly diagnosed TB patients and healthy community controls (CCs) were recruited in North-west Ethiopia. TB-score, body mass index and stool samples were analyzed. Cells from HIV-negative TB patients (HIV-/TB) and from CCs were analyzed for regulatory T-cells (Tregs) and cytokine responses using flow cytometry and ELISPOT, respectively.Results A significantly higher ratio of helminth co-infection was observed in TB patients without HIV (Helm+/HIV-/TB) compared to HIV negative CCs, (40% (121/306) versus 28% (85/306), p = 0.003). Helm+/HIV-/TB patients showed significantly increased IL-5 secreting cells compared to Helm-/HIV-/TB (37 SFU (IQR:13-103) versus 2 SFU (1-50); p = 0.02, n = 30). Likewise, levels of absolute Tregs (9.4 (3.2-16.7) cells/mu l versus 2.4 (1.1-4.0) cells/mu l; p = 0.041) and IL-10 secreting cells (65 SFU (7-196) versus 1 SFU (0-31); p = 0.014) were significantly higher in Helm+/HIV-/TB patients compared to Helm-/HIV-/TB patients. In a multivariate analysis, a lower rate of sputum smear positivity for acid fast bacilli, lower body temperature, and eosinophilia were independently associated with helminth infection in TB patients.Conclusions Asymptomatic helminth infection is associated with increased regulatory T-cell and Th2-type responses and a lower rate of sputum smear positivity. Further studies are warranted to investigate the clinical and immunological impact of helminth infection in TB patients.
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| 2. |
- Bewket, Gezahegn, et al.
(författare)
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Helminth species dependent effects on Th1 and Th17 cytokines in active tuberculosis patients and healthy community controls
- 2022
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Ingår i: PLoS Neglected Tropical Diseases. - : PUBLIC LIBRARY SCIENCE. - 1935-2727 .- 1935-2735. ; 16:8
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Tidskriftsartikel (refereegranskat)abstract
- Despite that the impact of different helminth species is not well explored, the current dogma states that helminths affect the Th1/Th2 balance which in turn affects the risk of tuberculosis (TB) reactivation and severity of disease. We investigated the influence of helminth species on cytokine profiles including IL-17A in TB patients and healthy community controls (CCs). In total, 104 newly diagnosed pulmonary TB patients and 70 HIV negative and Quanti-FERON negative CCs in Gondar, Ethiopia were included following helminth screening by stool microscopy. Plasma samples and ex vivo stimulation of peripheral blood mononuclear cells (PBMCs) with purified protein derivative (PPD) and Staphylococcus enterotoxin B (SEB) was used to determine cytokine profiles by cytometric bead array. In CCs, Ascaris lumbricoides or Schistosoma mansoni infections were associated with an impaired Th1-type response (IFN-gamma, IL-6 and TNF-alpha) in PBMCs mainly with SEB stimulations, whereas in TB patients only hookworm infection showed a similar pattern. Among CCs, the IL-17A response in PBMCs stimulated with SEB was higher only for S. mansoni, whereas in TB patients, the elevated systemic IL-17A plasma level was significantly suppressed in hookworm infected TB patients compared to patients without helminth coinfection. Following treatment of TB and helminth infection there was a general decrease in ex vivio IL-10 and TNF-alpha production in unstimulated, PPD or SEB stimulated PBMCs that was the most pronounced and significant in TB patients infected with S. mansoni, whereas the follow-up levels of IFN-gamma and IL-17A was significantly increased only in TB patients without helminth coinfection from PBMCs stimulated mainly with SEB. In summary, in addition to confirming helminth specific effects on the Th1/Th2 response before and after TB treatment, our novel finding is that IL-17A was impaired in helminth infected TB patients especially for hookworm, indicating a helminth species-specific immunoregulatory effect on IL-17A which needs to be further investigated.
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| 3. |
- Bewket, Gezahegn, et al.
(författare)
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Helminth species specific expansion and increased TNF-alpha production of non-classical monocytes during active tuberculosis
- 2021
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Ingår i: PLoS Neglected Tropical Diseases. - : Public Library of Science. - 1935-2727 .- 1935-2735. ; 15:3
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Tidskriftsartikel (refereegranskat)abstract
- Author summary Monocytes are important cells for the early innate immune response and play an integral part during inflammation and infection. Classical monocytes, the dominant monocyte subset during homeostasis and health, have been linked to efficient TB protection. Intermediate or non-classical monocytes have instead been associated with uncontrolled inflammation (TNF-alpha), cell death, and poor protection against Mycobacterium tuberculosis. In areas endemic for intestinal helminths, the immunoregulatory effects of monocytes may affect development or progression of TB disease. The role of monocyte subsets during helminth/TB coinfection have not been studied. In Gondar, Ethiopia, we show that in patients with helminth infection, a helminth species dependent expansion of non-classical monocytes is triggered, where Ascaris and hookworm had the strongest effect in coinfected pulmonary TB-patients. The increase in non-classical monocytes was mainly detected in coinfected patients with a low-to-intermediate disease severity. Only coinfection with helminths and TB induced an increased TNF-alpha response in monocytes. Thus, we found a helminth species-specific dysregulation of monocyte subset distribution and functionality in coinfected TB-patients which could affect TB pathogenesis. Both Mycobacterium tuberculosis infection and helminths may affect innate immune mechanisms such as differential effects on monocytes towards the non-classical and intermediate subsets that favor bacterial persistence. Our aim, was to investigate helminth species specific effects on the frequency and functional activity of monocyte subsets in patients with active tuberculosis and healthy subjects. HIV-negative patients with active pulmonary tuberculosis (PTB) and community controls (CCs) in Gondar, Ethiopia were screened for helminth infection by stool microscopy. Flow cytometric analysis of peripheral blood mononuclear cells (PBMCs) and ex vivo stimulation with purified protein derivative (PPD) and helminth antigens were used to characterize the distribution of monocyte subsets and their function. A total of 74 PTB patients and 57 CCs with and without helminth infection were included. Non-classical monocytes were increased in PTB patients with Ascaris and hookworm infection but not in Schistosoma-infected patients. Ascaris had the strongest effect in increasing the frequency of non-classical monocytes in both PTB patients and CCs, whereas PTB without helminth infection did not affect the frequency of monocyte subsets. There was a helminth specific increase in the frequency of TNF-alpha producing non-classical monocytes in hookworm infected PTB patients, both with and without PPD-stimulation. Low-to-intermediate TB disease severity associated with increased frequency of non-classical monocytes only for helminth-positive PTB patients, and the frequency of TNF-alpha producing monocytes were significantly higher in intermediate and non-classical monocytes of helminth positive PTB patients with an intermediate disease score. Helminth infection affected the frequency of monocyte subsets and function both in TB patients and controls which was helminth species dependent in TB patients. The clinical role of this potential immunomodulatory effect needs further study and may affect the response and protection to tuberculosis in areas where helminth infections are endemic.
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| 4. |
- Jidling, Carl, et al.
(författare)
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Screening for Chagas disease from the electrocardiogram using a deep neural network
- 2023
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Ingår i: PLoS Neglected Tropical Diseases. - : Public Library of Science (PLoS). - 1935-2727 .- 1935-2735. ; 17:7
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Tidskriftsartikel (refereegranskat)abstract
- Chagas disease (ChD) is a neglected tropical disease, and the diagnosis relies on blood testing of patients from endemic areas. However, there is no clear recommendation on how to select patients for testing in endemic regions. Since most cases of Chronic ChD are asymptomatic, the diagnostic rates are low, preventing patients from receiving adequate treatment.The Electrocardiogram (ECG) is a widely available, low-cost exam, often available in primary care settings. We present an Artificial intelligence (AI) model for automatically detecting ChD from the ECG. AI algorithms have allowed the detection of hidden conditions on the ECG and, to the best of our knowledge, this is the first study that does it for ChD. We utilize large cohorts of patients from the relevant population of all-comers in affected regions in Brazil to develop a model for ChD detection that is then validated on datasets with ground truth labels obtained directly from the patients’ serological status.Our findings demonstrate a promising AI-ECG-based model for discriminating patients with chronic Chagas cardiomyopathy (CCC). The capacity of detecting ChD patients without CCC is still limited. But we believe this can be improved with the addition of epidemiological questions, and that such models can become useful tools for pre-selecting patients for further testing.
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| 5. |
- Kiflie, Amare, et al.
(författare)
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Helminth species-specific effects on IFN-gamma producing T cells during active and latent tuberculosis
- 2023
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Ingår i: PLoS Neglected Tropical Diseases. - : PUBLIC LIBRARY SCIENCE. - 1935-2727 .- 1935-2735. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundInterferon-gamma (IFN-gamma) is a key cytokine inducing protective immune responses during tuberculosis (TB) infection. Helminth-induced immune responses may affect IFN-gamma production by T cells, although its connection with disease severity and immune recovery during treatment is unexplored. We investigated the species-specific effect of helminths on the IFN-gamma production by T cells in relation to disease severity during active and latent TB infection (LTBI). MethodsIn this study, 69 active pulmonary TB patients (PTB), 28 with LTBI and 66 healthy controls were included. Active TB was diagnosed using GenXpert MTB/RIF while QuantiFERON test (QFT) was used for the screening of healthy community controls (CCs) and for the diagnosis of LTBI. Helminth infection was identified by routine diagnosis whereas clinical disease severity was evaluated by the TB score. Intracellular IFN-gamma production of T cells in stimulated peripheral blood mononuclear cells (PBMCs) was analyzed by flow cytometry using TB antigens (PPD), the polyclonal T cell activator staphylococcal enterotoxin B (SEB), or medium as unstimulated control. ResultsHelminth infected CCs and LTBI subjects showed a significant reduction of IFN-gamma(+) CD4(+) T cells by PPD-stimulation compared to non-helminth infected control groups. The significant reduction in the frequency of IFN-gamma(+) T cells in both latent and active PTB patients following SEB stimulation was mostly attributed to Schistosoma mansoni infection, whereas Ascaris lumbricoides, Schistosoma mansoni, and hookworm infection contributed equally in CCs. Following anti-helminthic and anti-TB treatment for 2 months, the frequency of IFN-gamma(+) CD4 T cells in helminth coinfected PTB was restored to levels of helminth negative PTB before treatment. Helminth coinfected PTB patients with an intermediate and severe clinical course had reduced capacity for production of IFN-gamma(+) T cells compared to the corresponding non-helminth infected PTB. ConclusionWe found a reduction in IFN-gamma producing T cells by helminth coinfection which was restored following anti-helminthic treatment. This reduction was helminth species-dependent in an exploratory sub-analysis and correlated to increased disease severity. Author summaryProtective immunity against tuberculosis (TB) requires a Th-1 response with cytokines like TNF and IFN-gamma which plays a key role in the recruitment and activation of immune cells. Helminth infection, on the other hand, can lead to induction of regulatory T cells and a Th-2 skewed response decreasing IFN-gamma in T cells. Decreased Th-1 responses could favor reactivation of latent TB infection (LTBI), although the helminth species-specific effect on IFN-gamma(+)CD4(+) T cells and the link to TB disease severity in patients with active pulmonary TB (PTB) have not been fully investigated. Therefore, blood cells (PBMCs) from healthy controls, LTBI individuals, and PTB patients were used to evaluate the impact of different helminths on the frequency of IFN-gamma(+)CD4(+) T cells, in Gondar Ethiopia. Ascaris lumbricoides, Schistosoma mansoni, and hookworm infection in healthy controls contributed equally to decreasing the frequency of IFN-gamma(+)CD4(+) T cells, whereas in both LTBI and PTB patients S. mansoni coinfection had the greatest impact on reducing IFN-gamma producing capacity of T cells. Decreased IFN-gamma producing capacity of T cells was correlated with increased TB disease severity, only in helminth coinfected PTB patients, and anti-helminthic therapy restored the IFN-gamma producing capacity of T cells at the 2 months follow-up.
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