| 1. |
- 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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| 2. |
- 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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| 3. |
- Burgert-Brucker, Clara R., et al.
(författare)
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Risk factors associated with failing pre-transmission assessment surveys (pre-TAS) in lymphatic filariasis elimination programs : Results of a multi-country analysis
- 2020
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Ingår i: PLoS Neglected Tropical Diseases. - : Public Library of Science (PLoS). - 1935-2727 .- 1935-2735. ; 14:6
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Tidskriftsartikel (refereegranskat)abstract
- Achieving elimination of lymphatic filariasis (LF) as a public health problem requires a minimum of five effective rounds of mass drug administration (MDA) and demonstrating low prevalence in subsequent assessments. The first assessments recommended by the World Health Organization (WHO) are sentinel and spot-check sites-referred to as pre-transmission assessment surveys (pre-TAS)-in each implementation unit after MDA. If pre-TAS shows that prevalence in each site has been lowered to less than 1% microfilaremia or less than 2% antigenemia, the implementation unit conducts a TAS to determine whether MDA can be stopped. Failure to pass pre-TAS means that further rounds of MDA are required. This study aims to understand factors influencing pre-TAS results using existing programmatic data from 554 implementation units, of which 74 (13%) failed, in 13 countries. Secondary data analysis was completed using existing data from Bangladesh, Benin, Burkina Faso, Cameroon, Ghana, Haiti, Indonesia, Mali, Nepal, Niger, Sierra Leone, Tanzania, and Uganda. Additional covariate data were obtained from spatial raster data sets. Bivariate analysis and multilinear regression were performed to establish potential relationships between variables and the pre-TAS result. Higher baseline prevalence and lower elevation were significant in the regression model. Variables statistically significantly associated with failure (p-value <= 0.05) in the bivariate analyses included baseline prevalence at or above 5% or 10%, use of Filariasis Test Strips (FTS), primary vector of Culex, treatment with diethylcarbamazine-albendazole, higher elevation, higher population density, higher enhanced vegetation index (EVI), higher annual rainfall, and 6 or more rounds of MDA. This paper reports for the first time factors associated with pre-TAS results from a multi-country analysis. This information can help countries more effectively forecast program activities, such as the potential need for more rounds of MDA, and prioritize resources to ensure adequate coverage of all persons in areas at highest risk of failing pre-TAS.
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| 4. |
- Guery, Romain, et al.
(författare)
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Clinical diversity and treatment results in tegumentary leishmaniasis : A European clinical report in 459 patients
- 2021
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Ingår i: PLoS Neglected Tropical Diseases. - : Public Library of Science (PLoS). - 1935-2727 .- 1935-2735. ; 15:10
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Tidskriftsartikel (refereegranskat)abstract
- Background Cutaneous leishmaniasis (CL) is frequent in travellers and can involve oro-nasal mucosae. Clinical presentation impacts therapeutic management. Methodology Demographic and clinical data from 459 travellers infected in 47 different countries were collected by members of the European LeishMan consortium. The infecting Leishmania species was identified in 198 patients. Principal findings Compared to Old World CL, New World CL was more frequently ulcerative (75% vs 47%), larger (3 vs 2cm), less frequently facial (17% vs 38%) and less frequently associated with mucosal involvement (2.7% vs 5.3%). Patients with mucosal lesions were older (58 vs 30 years) and more frequently immunocompromised (37% vs 3.5%) compared to patients with only skin lesions. Young adults infected in Latin America with L. braziliensis or L. guyanensis complex typically had an ulcer of the lower limbs with mucosal involvement in 5.8% of cases. Typically, infections with L. major and L. tropica acquired in Africa or the Middle East were not associated with mucosal lesions, while infections with L. infantum, acquired in Southern Europe resulted in slowly evolving facial lesions with mucosal involvement in 22% of cases. Local or systemic treatments were used in patients with different clinical presentations but resulted in similarly high cure rates (89% vs 86%). Conclusion/Significance CL acquired in L. infantum-endemic European and Mediterranean areas displays unexpected high rates of mucosal involvement comparable to those of CL acquired in Latin America, especially in immunocompromised patients. When used as per recommendations, local therapy is associated with high cure rates.
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| 5. |
- Ha, Tuyen V., et al.
(författare)
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Spatial distribution of Culex mosquito abundance and associated risk factors in Hanoi, Vietnam
- 2021
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Ingår i: PLoS Neglected Tropical Diseases. - : Public Library of Science (PLoS). - 1935-2727 .- 1935-2735. ; 15:6
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Tidskriftsartikel (refereegranskat)abstract
- Japanese encephalitis (JE) is the major cause of viral encephalitis (VE) in most AsianPacific countries. In Vietnam, there is no nationwide surveillance system for JE due to lack of medical facilities and diagnoses. Culex tritaeniorhynchus, Culex vishnui, and Culex quin-quefasciatus have been identified as the major JE vectors in Vietnam. The main objective of this study was to forecast a risk map of Culex mosquitoes in Hanoi, which is one of the most densely populated cities in Vietnam. A total of 10,775 female adult Culex mosquitoes were collected from 513 trapping locations. We collected temperature and precipitation information during the study period and its preceding month. In addition, the other predictor variables (e.g., normalized difference vegetation index [NDVI], land use/land cover and human population density), were collected for our analysis. The final model selected for estimating the Culex mosquito abundance included centered rainfall, quadratic term rainfall, rice cover ratio, forest cover ratio, and human population density variables. The estimated spatial distribution of Culex mosquito abundance ranged from 0 to more than 200 mosquitoes per 900m2. Our model estimated that 87% of the Hanoi area had an abundance of mosquitoes from 0 to 50, whereas approximately 1.2% of the area showed more than 150 mosquitoes, which was mostly in the rural/peri-urban districts. Our findings provide better insight into understanding the spatial distribution of Culex mosquitoes and its associated environmental risk factors. Such information can assist local clinicians and public health policymakers to identify potential areas of risk for JE virus. Risk maps can be an efficient way of raising public awareness about the virus and further preventive measures need to be considered in order to prevent outbreaks and onwards transmission of JE virus.
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| 6. |
- 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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| 7. |
- Khalil, Hussein
(författare)
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Poverty, sanitation, and Leptospira transmission pathways in residents from four Brazilian slums
- 2021
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Ingår i: PLoS Neglected Tropical Diseases. - : Public Library of Science (PLoS). - 1935-2727 .- 1935-2735. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Author summaryGlobally, more than 1 billion residents live in urban slums, where inadequate sanitation increases the spread of pathogens and their animal hosts. Leptospirosis is a globally distributed bacterial disease, and in urban areas the bacteria is spread by brown rats. Humans become infected upon exposure to water or soil/mud that was contaminated with the urine of infected rats. In four urban slums in the city of Salvador, Brazil, we used a range of individual, socioeconomic, and environmental variables to understand how they influence to one another and define o leptospirosis exposure in residents. Poverty and sanitation influenced the degree to which residents were exposed to sewer water and mud. Further, we found that while residents tried to improve the physical environment near their household, living in an area with poor sanitation mean that their infection risk remained high. This work highlight the importance of socioeconomic and environmental factors in determining disease risk, and suggests that governmental interventions should focus on improving sanitation changes in the poorest parts of the community.Residents of urban slums suffer from a high burden of zoonotic diseases due to individual, socioeconomic, and environmental factors. We conducted a cross-sectional sero-survey in four urban slums in Salvador, Brazil, to characterize how poverty and sanitation contribute to the transmission of rat-borne leptospirosis. Sero-prevalence in the 1,318 participants ranged between 10.0 and 13.3%. We found that contact with environmental sources of contamination, rather than presence of rat reservoirs, is what leads to higher risk for residents living in areas with inadequate sanitation. Further, poorer residents may be exposed away from the household, and ongoing governmental interventions were not associated with lower transmission risk. Residents at higher risk were aware of their vulnerability, and their efforts improved the physical environment near their household, but did not reduce their infection chances. This study highlights the importance of understanding the socioeconomic and environmental determinants of risk, which ought to guide intervention efforts.
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| 8. |
- 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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| 9. |
- Laurent, Timothée, et al.
(författare)
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The organization of double-stranded RNA in the chikungunya virus replication organelle
- 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
- Alphaviruses are mosquito-borne, positive-sense single-stranded RNA viruses. Amongst the alphaviruses, chikungunya virus is notable as a large source of human illness, especially in tropical and subtropical regions. When they invade a cell, alphaviruses generate dedicated organelles for viral genome replication, so-called spherules. Spherules form as outward-facing buds at the plasma membrane, and it has recently been shown that the thin membrane neck that connects this membrane bud with the cytoplasm is guarded by a two-megadalton protein complex that contains all the enzymatic functions necessary for RNA replication. The lumen of the spherules contains a single copy of the negative-strand template RNA, present in a duplex with newly synthesized positive-sense RNA. Less is known about the organization of this double-stranded RNA as compared to the protein components of the spherule. Here, we analyzed cryo-electron tomograms of chikungunya virus spherules in terms of the organization of the double-stranded RNA replication intermediate. We find that the double-stranded RNA has a shortened apparent persistence length as compared to unconstrained double-stranded RNA. Around half of the genome is present in either of five conformations identified by subtomogram classification, each representing a relatively straight segment of ~25–32 nm. Finally, the RNA occupies the spherule lumen at a homogeneous density, but has a preferred orientation to be perpendicular to a vector pointing from the membrane neck towards the spherule center. Taken together, this analysis lays another piece of the puzzle of the highly coordinated alphavirus genome replication.
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| 10. |
- Lindahl, Johanna
(författare)
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A systematic review and meta-analysis of the aetiological agents of non-malarial febrile illnesses in Africa
- 2022
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Ingår i: PLoS Neglected Tropical Diseases. - 1935-2727 .- 1935-2735. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe awareness of non-malarial febrile illnesses (NMFIs) has been on the rise over the last decades. Therefore, we undertook a systematic literature review and meta-analysis of causative agents of non-malarial fevers on the African continent.MethodologyWe searched for literature in African Journals Online, EMBASE, PubMed, Scopus, and Web of Science databases to identify aetiologic agents that had been reported and to determine summary estimates of the proportional morbidity rates (PMr) associated with these pathogens among fever patients.FindingsA total of 133 studies comprising 391,835 patients from 25 of the 54 African countries were eligible. A wide array of aetiologic agents were described with considerable regional differences among the leading agents. Overall, bacterial pathogens tested from blood samples accounted for the largest proportion. The summary estimates from the meta-analysis were low for most of the agents. This may have resulted from a true low prevalence of the agents, the failure to test for many agents or the low sensitivity of the diagnostic methods applied. Our meta-regression analysis of study and population variables showed that diagnostic methods determined the PMr estimates of typhoidal Salmonella and Dengue virus. An increase in the PMr of Klebsiella spp. infections was observed over time. Furthermore, the status of patients as either inpatient or outpatient predicted the PMr of Haemophilus spp. infections.ConclusionThe small number of epidemiological studies and the variety of NMFI agents on the African continent emphasizes the need for harmonized studies with larger sample sizes. In particular, diagnostic procedures for NMFIs should be standardized to facilitate comparability of study results and to improve future meta-analyses. Reliable NMFI burden estimates will inform regional public health strategies.
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