PLOS Neglected Tropical Diseases

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ISSN / EISSN : 1935-2735 / 1935-2735
Published by: Public Library of Science (PLoS) (10.1371)
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Yegnasew Takele, Emebet Adem, Susanne Ursula Franssen, Rebecca Womersley, Myrsini Kaforou, Michael Levin, Ingrid Müller, James Anthony Cotton,
PLOS Neglected Tropical Diseases, Volume 16; https://doi.org/10.1371/journal.pntd.0010544

Abstract:
Visceral leishmaniasis (VL) is a neglected tropical disease that causes substantial morbidity and mortality and is a growing health problem in Ethiopia, where this study took place. Most individuals infected with Leishmania donovani parasites will stay asymptomatic, but some develop VL that, if left untreated, is almost always fatal. This stage of the disease is associated with a profound immunosuppression, characterised by impaired production of Interferonγ (IFNγ), a cytokine that plays a key role in the control of Leishmania parasites, and high expression levels of an inhibitory receptor, programmed cell death 1 (PD1) on CD4+ T cells. Here, we tested the contribution of the interaction between the immune checkpoint PD1 and its ligand PDL-1 on the impaired production of IFNγ in VL patients. Our results show that in the blood of VL patients, not only CD4+, but also CD8+ T cells express high levels of PD1 at the time of VL diagnosis. Next, we identified PDL-1 expression on different monocyte subsets and neutrophils and show that PDL-1 levels were significantly increased in VL patients. PD1/PDL-1 inhibition resulted in significantly increased production of IFNγ, suggesting that therapy using immune checkpoint inhibitors might improve disease control in these patients.
Alexandra Zakharova, Amanda T. S. Albanaz, Fred R. Opperdoes, Ingrid Škodová-Sveráková, Diana Zagirova, Andreu Saura, Lˇubomíra Chmelová, Evgeny S. Gerasimov, Tereza Leštinová, Tomáš Bečvář, et al.
PLOS Neglected Tropical Diseases, Volume 16; https://doi.org/10.1371/journal.pntd.0010510

Abstract:
Leishmaniasis is a parasitic vector-borne disease caused by the protistan flagellates of the genus Leishmania. Leishmania (Viannia) guyanensis is one of the most common causative agents of the American tegumentary leishmaniasis. It has previously been shown that L. guyanensis strains that carry the endosymbiotic Leishmania RNA virus 1 (LRV1) cause more severe form of the disease in a mouse model than those that do not. The presence of the virus was implicated into the parasite’s replication and spreading. In this respect, studying the molecular mechanisms of cellular control of viral infection is of great medical importance. Here, we report ~30.5 Mb high-quality genome assembly of the LRV1-positive L. guyanensis M4147. This strain was turned into a model by establishing the CRISPR-Cas9 system and ablating the gene encoding phosphatidate phosphatase 2-like (PAP2L) protein. The orthologue of this gene is conspicuously absent from the genome of an unusual member of the family Trypanosomatidae, Vickermania ingenoplastis, a species with mostly bi-flagellated cells. Our analysis of the PAP2L-null L. guyanensis showed an increase in the number of cells strikingly resembling the bi-flagellated V. ingenoplastis, likely as a result of the disruption of the cell cycle, significant accumulation of phosphatidic acid, and increased virulence compared to the wild type cells.
Ji-Hoon Park, Min-Hee Kim, Edwin Sutanto, Seok-Won Na, , , Mohammed Mohieldien Abbas Elfaki, , , Sisay Getachew Alemu, et al.
PLOS Neglected Tropical Diseases, Volume 16; https://doi.org/10.1371/journal.pntd.0010492

Abstract:
Plasmodium vivax is the most widespread cause of human malaria. Recent reports of drug resistant vivax malaria and the challenge of eradicating the dormant liver forms increase the importance of vaccine development against this relapsing disease. P. vivax reticulocyte binding protein 1a (PvRBP1a) is a potential vaccine candidate, which is involved in red cell tropism, a crucial step in the merozoite invasion of host reticulocytes. As part of the initial evaluation of the PvRBP1a vaccine candidate, we investigated its genetic diversity and antigenicity using geographically diverse clinical isolates. We analysed pvrbp1a genetic polymorphisms using 202 vivax clinical isolates from six countries. Pvrbp1a was separated into six regions based on specific domain features, sequence conserved/polymorphic regions, and the reticulocyte binding like (RBL) domains. In the fragmented gene sequence analysis, PvRBP1a region II (RII) and RIII (head and tail structure homolog, 152–625 aa.) showed extensive polymorphism caused by random point mutations. The haplotype network of these polymorphic regions was classified into three clusters that converged to independent populations. Antigenicity screening was performed using recombinant proteins PvRBP1a-N (157–560 aa.) and PvRBP1a-C (606–962 aa.), which contained head and tail structure region and sequence conserved region, respectively. Sensitivity against PvRBP1a-N (46.7%) was higher than PvRBP1a-C (17.8%). PvRBP1a-N was reported as a reticulocyte binding domain and this study identified a linear epitope with moderate antigenicity, thus an attractive domain for merozoite invasion-blocking vaccine development. However, our study highlights that a global PvRBP1a-based vaccine design needs to overcome several difficulties due to three distinct genotypes and low antigenicity levels.
Mi Hee Seo, Choon-Mee Kim, , Na Ra Yun, Jung Wook Park, Jae Keun Chung
PLOS Neglected Tropical Diseases, Volume 16; https://doi.org/10.1371/journal.pntd.0010526

Abstract:
Background: Hemorrhagic fever with renal syndrome (HFRS) caused by hantaviruses is a frequently reported acute hemorrhagic fever in South Korea. These viruses are transmitted by various rodent species such as Apodemus agrarius. Methodology/Principal findings: To investigate hantavirus infection and seroprevalence in rodents, wild rodents were captured from two districts in the suburbs of Gwangju Metropolitan City from January 2016 to December 2018. Nested reverse-transcription polymerase chain reaction (RT-PCR) targeting the hantavirus-specific L segment and indirect immunofluorescence antibody (IFA) assay using Hantaan virus antigen slides were performed. A total of 585 wild rodents were captured—512 A. agrarius, 49 Crocidura lasiura, and 24 Myodes regulus. Nested RT-PCR was performed to examine the rate of hantavirus infection in wild rodents, and 1.88% (11/585) of all rodents, 1.17% (6/512) of A. agrarius, 6.12% (3/49) of C. lasiura, and 8.33% (2/24) of M. regulus tested positive. The nucleotide sequence analysis of the eleven PCR-positive products revealed that six PCR products showed over 85% sequence similarity with the Jeju virus, four showed over 99.7% similarity with the Hantaan virus, and one showed over 95.3% homology with the Imjin virus. Moreover, IgG antibodies against the Hantaan virus were detected in 6.15% (36/585) of all rodents, 6.8% (35/512) of A. agrarius, and 4.17% (1/24) of M. regulus. IgG antibodies were not detected in C. lasiura. Conclusions/Significance: Hantaviruses were detected in all three wild rodent species of A. agrarius, C. lasiura, and M. regulus captured in the suburbs of Gwangju Metropolitan City, South Korea, and it was demonstrated that they were various strains of hantaviruses such as the Hantaan, Jeju, and Imjin viruses.
, Wangjian Zhang, Shicheng Yu, Shao Lin,
PLOS Neglected Tropical Diseases, Volume 16; https://doi.org/10.1371/journal.pntd.0010470

Abstract:
Background: The association between the incidence of hand, foot, and mouth disease (HFMD) and ambient temperature has been well documented. Although the severity of symptoms is an important indicator of disease burden and varies significantly across cases, it usually was ignored in previous studies, potentially leading to biased estimates of the health impact of temperature. Methods: We estimated the disability-adjusted life year (DALY) by considering the severity of symptoms for each HFMD case reported during 2010–2012 in Guangdong and used distributed lag-nonlinear models to estimate the association between the daily average temperature and daily DALY of HFMD cases at the city-level. We investigated the potential effect modifiers on the pathway between temperature and DALY and pooled city-specific estimates to a provincial association using a meta-regression. The overall impact of temperature was further evaluated by estimates of DALYs that could be attributed to HFMD. Results: The overall cumulative effect of daily mean temperature on the DALY of HFMD showed an inverse-U shape, with the maximum effect estimated to be β = 0.0331 (95%CI: 0.0199–0.0463) DALY at 23.8°C. Overall, a total of 6.432 (95%CI: 3.942–8.885) DALYs (attributable fraction = 2.721%, 95%CI: 1.660–3.759%) could be attributed to temperature exposure. All the demographic subgroups had a similar trend as the main analysis, while the magnitude of the peak of the temperature impact tended to be higher among the males, those aged ≥3yrs or from the Pear-River Delta region. Additionally, the impact of temperature on DALY elevated significantly with the increasing population density, per capita GDP, and per capita green space in parks. Conclusions: Temperature exposure was associated with increased burden of HFMD nonlinearly, with certain groups such as boys and those from areas with greater population density being more vulnerable.
Xin Gao, Yong Yang, , Fengyan Xu, Yang Wang, Lei Liu, Yaming Yang, Mingyuan Liu, Xue Bai
PLOS Neglected Tropical Diseases, Volume 16; https://doi.org/10.1371/journal.pntd.0010528

Abstract:
Trichinella spiralis (T. spiralis) derived extracellular vesicles (EVs) have been proposed to play a key role in regulating the host immune responses. In this study, we provided the first investigation of EVs proteomics released by T. spiralis muscle larvae (ML). T. spiralis ML EVs (Ts-ML-EVs) were successfully isolated and characterized by transmission electron microscopy (TEM) and western blotting. Using liquid chromatograph mass spectrometer (LC-MS/MS) analysis, we identified 753 proteins in the Ts-ML-EVs proteome and annotated by gene ontology (GO). These proteins were enriched in different categories by GO, kyoto encyclopedia of genes and genomes (KEGG) and domain analysis. GO enrichment analysis indicated association of protein deglutathionylation, lysosomal lumen and serine-type endopeptidase inhibitor activity with proteins which may be helpful during parasite-host interaction. Moreover, KEGG enrichment analysis revealed involvement of Ts-ML-EVs proteins in other glycan degradation, complement and coagulation cascades, proteasome and various metabolism pathways. In addition, BALB/c mice were immunized by subcutaneous injection of purified Ts-ML-EVs. Ts-ML-EVs group demonstrated a 23.4% reduction in adult worms and a 43.7% reduction in ML after parasite challenge. Cellular and humoral immune responses induced by Ts-ML-EVs were detected, including the levels of specific antibodies (IgG, IgM, IgE, IgG1 and IgG2a) as well as cytokines (IL-12, IFN-γ, IL-4 and IL-10) in serum. The results showed that Ts-ML-EVs could induce a Th1/Th2 mixed immune response with Th2 predominant. This study revealed a potential role of Ts-ML-EVs in T. spiralis biology, particularly in the interaction with host. This work provided a critical step to against T. spiralis infection based on Ts-ML-EVs.
, Mahfuza Islam, , , Abul Kasham Shoab, Julia Rosenbaum, , , , Ayse Ercumen
PLOS Neglected Tropical Diseases, Volume 16; https://doi.org/10.1371/journal.pntd.0010495

Abstract:
Pit latrines are the most common latrine technology in rural Bangladesh, and untreated effluent from pits can directly contaminate surrounding aquifers. Sand barriers installed around the latrine pit can help reduce contamination but can also alter the decomposition of the fecal sludge and accelerate pit fill-up, which can counteract their benefits. We aimed to evaluate whether there was a difference in decomposition of fecal sludge and survival of soil-transmitted helminth (STH) ova among latrines where a 50-cm sand barrier was installed surrounding and at the bottom of the pit, compared to latrines without a sand barrier, in coastal Bangladesh. We assessed decomposition in latrine pits by measuring the carbon-nitrogen (C/N) ratio of fecal sludge. We enumerated Ascaris lumbricoides and Trichuris trichiura ova in the pit following 18 and 24 months of latrine use. We compared these outcomes between latrines with and without sand barriers using generalized linear models with robust standard errors to adjust for clustering at the village level. The C/N ratio in latrines with and without a sand barrier was 13.47 vs. 22.64 (mean difference: 9.16, 95% CI: 0.15, 18.18). Pits with sand barriers filled more quickly and were reportedly emptied three times more frequently than pits without; 27/34 latrines with sand barriers vs. 9/34 latrines without barriers were emptied in the previous six months. Most reported disposal methods were unsafe. Compared to latrines without sand barriers, latrines with sand barriers had significantly higher log10 mean counts of non-larvated A. lumbricoides ova (log10 mean difference: 0.35, 95% CI: 0.12, 0.58) and T. trichiura ova (log10 mean difference: 0.47, 95% CI: 0.20, 0.73). Larvated ova counts were similar for the two types of latrines for both A. lumbricoides and T. trichiura. Our findings suggest that sand barriers help contain helminth ova within the pits but pits with barriers fill up more quickly, leading to more frequent emptying of insufficiently decomposed fecal sludge. Further research is required on latrine technologies that can both isolate pathogens from the environment and achieve rapid decomposition.
Priscilla Y. L. Tng, Leonela Z. Carabajal Paladino, , Zach N. Adelman, Rennos Fragkoudis, Rob Noad,
PLOS Neglected Tropical Diseases, Volume 16; https://doi.org/10.1371/journal.pntd.0010548

Abstract:
Aedes aegypti and Ae. albopictus are the main vectors of mosquito-borne viruses of medical and veterinary significance. Many of these viruses have RNA genomes. Exogenously provided, e.g. transgene encoded, small RNAs could be used to inhibit virus replication, breaking the transmission cycle. We tested, in Ae. aegypti and Ae. albopictus cell lines, reporter-based strategies for assessing the ability of two types of small RNAs to inhibit a chikungunya virus (CHIKV) derived target. Both types of small RNAs use a Drosophila melanogaster pre-miRNA-1 based hairpin for their expression, either with perfect base-pairing in the stem region (shRNA-like) or containing two mismatches (miRNA-like). The pre-miRNA-1 stem loop structure was encoded within an intron; this allows co-expression of one or more proteins, e.g. a fluorescent protein marker tracking the temporal and spatial expression of the small RNAs in vivo. Three reporter-based systems were used to assess the relative silencing efficiency of ten shRNA-like siRNAs and corresponding miRNA-like designs. Two systems used a luciferase reporter RNA with CHIKV RNA inserted either in the coding sequence or within the 3’ UTR. A third reporter used a CHIKV derived split replication system. All three reporters demonstrated that while silencing could be achieved with both miRNA-like and shRNA-like designs, the latter were substantially more effective. Dcr-2 was required for the shRNA-like siRNAs as demonstrated by loss of inhibition of the reporters in Dcr-2 deficient cell lines. These positive results in cell culture are encouraging for the potential use of this pre-miRNA-1-based system in transgenic mosquitoes.
, , Parfait Djossou, Esaï Gimatal Anagonou, Gilbert Adjimon Ayélo, Anita Carolle Akpéédjé Wadagni, , Jean Gabin Houezo, Roch Christian Johnson
PLOS Neglected Tropical Diseases, Volume 16; https://doi.org/10.1371/journal.pntd.0010533

Abstract:
Introduction: In the absence of early treatment, leprosy, a neglected tropical disease, due to Mycobacterium leprae or Hansen Bacillus, causes irreversible grade 2 disability (G2D) numerous factors related to the individual, the community and the health care system are believed to be responsible for its late detection and management. This study aims to investigate the factors associated with belated screening for leprosy in Benin. Methods: This was a cross-sectional, descriptive, and analytical study conducted from January 1 to June 31, 2019, involving all patients and staff in leprosy treatment centers and public peripheral level health structures in Benin. The dependent variable of the study was the presence or not of G2D, reflecting late or early screening. We used a logistic regression model, at the 5% threshold, to find the factors associated with late leprosy screening. The fit of the final model was assessed with the Hosmer-Lemeshow test. Results: A number of 254 leprosy patients were included with a mean age of 48.24 ± 18.37 years. There was a male dominance with a sex ratio of 1.23 (140/114). The proportion of cases with G2D was 58.27%. Associated factors with its belated screening in Benin were (OR; 95%CI; p) the fear of stigma related to leprosy (8.11; 3.3–19.94; <0.001), multiple visits to traditional healers (5.20; 2.73–9.89; <0.001) and multiple visits to hospital practitioners (3.82; 2.01–7.27; <0.001). The unawareness of leprosy by 82.69% of the health workers so as the permanent decrease in material and financial resources allocated to leprosy control were identified as factors in link with the health system that helps explain this late detection. Conclusion: This study shows the need to implement strategies in the control programs to strengthen the diagnostic abilities of health workers, to improve the level of knowledge of the population on the early signs and symptoms of leprosy, to reduce stigmatization and to ban all forms of discrimination against leprosy patients.
, Emmanouil Logothetis, Daniel Engelman, Eirini Samiotaki-Logotheti, Spyros Pournaras, Ymkje Stienstra
PLOS Neglected Tropical Diseases, Volume 16; https://doi.org/10.1371/journal.pntd.0010153

Abstract:
Scabies is a global health concern disproportionately affecting vulnerable populations such as refugees and asylum seekers. Greece is a main point of entry in Europe for refugees, but epidemiological data on scabies in this population are scarce. We aimed to describe the epidemiology of scabies, including trends over the study period. Data were collected from June, 2016 to July, 2020, using the surveillance system of the Greek National Public Health Organization. Daily reports on scabies and other infectious diseases were submitted by staff at health centers for refugees/asylum seekers. Observed proportional morbidity for scabies was calculated using consultations for scabies as a proportion of total consultations. There were a total of 13118 scabies cases over the study period. Scabies was the third most frequently observed infectious disease in refugees/asylum seekers population after respiratory infections and gastroenteritis without blood in the stool. The scabies monthly observed proportional morbidity varied between 0.3% (August 2017) to 5.7% (January 2020). Several outbreaks were documented during the study period. The number of cases increased from October 2019 until the end of the study period, with a peak of 1663 cases in January 2020, related to an outbreak at one center. Spearman correlation test between the number of reported scabies cases and time confirmed an increasing trend (ρ = 0.67). Scabies is one of the most frequently reported infectious diseases by health care workers in refugee/asylum seekers centers in Greece. Observed proportional morbidity for scabies increased over time and there were several outbreaks. The current surveillance system with daily reports of the new cases effectively detects new cases in an early stage. Public health interventions, including mass drug administration, should be considered to reduce the burden of scabies in refugee/migrant populations. Scabies is a skin disease caused by the ectoparasitic mite Sarcoptes scabiei var. hominis. Most people with scabies have a diffuse and pruritic rash, while the most complicated forms of the infection can lead to bacterial infections and sepsis. Scabies is a global health concern and in 2017, the World Health Organization (WHO) added it to the portfolio of conditions prioritized by WHO’s Department of Control of Neglected Tropical Diseases. However, the prevalence of scabies among refugees residing in camps in Greece has not been thoroughly investigated. In this study, we wanted to obtain an overview of scabies epidemiology and identify trends over time. To do so, we analyzed data extracted from epidemiological reports submitted each week as part of the Greek National Public Health Organization. Our findings confirmed the high prevalence of scabies among refugees residing in the camps and identified a clear trend of significant increase over time. Public health interventions, like mass drug administration with ivermectin, could help restrain the dissemination of the disease and lower its burden among refugees.
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