PLoS Neglected Tropical Diseases News

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Natural infections of <i>Pintomyia verrucarum</i> and <i>Pintomyia maranonensis</i> by <i>Leishmania (Viannia) peruviana</i> in the Eastern Andes of northern Peru

15 April 2021 - 2:00pm

by Hirotomo Kato, Chisato Seki, Makoto Kubo, Lizandro Gonzales-Cornejo, Abraham G. Caceres

The natural infection of sand flies by Leishmania was investigated in Andean areas located between the Central and Eastern Cordilleras of northern Peru where cutaneous leishmaniasis caused by Leishmania (Viannia) peruviana is endemic. Sand flies were captured at five locations along the Utcubamba River in the Department of Amazonas, and morphologically identified under a microscope. Among 422 female sand flies dissected, the most dominant species was Pintomyia verrucarum (320 flies), followed by Pi. maranonensis (83 flies), Pi. robusta (13 flies), and Lutzomyia castanea (6 flies). Genetic analysis of sand flies from these areas together with those from other areas revealed that individuals of Pi. verrucarum were closely related regardless of morphological variation of their spermathecae. On the other hand, individuals of Pi. maranonensis collected in the study area were distant from those of other areas with genetic distances over the intraspecific level but mostly below the interspecific level, suggesting the unique characteristics of sand flies in this area. The natural infection of sand flies by flagellate parasites was detected mainly in the hindgut of each one of Pi. verrucarum and Pi. maranonensis. Both parasite species were identified as L. (V.) peruviana based on cytochrome b and mannose phosphate isomerase gene analyses. In addition, parasite species obtained from the lesion of a patient with cutaneous leishmaniasis in the study area in this period was identified as L. (V.) peruviana. These results strongly suggest that Pi. verrucarum and Pi. maranonensis are responsible for the transmission of L. (V.) peruviana in these areas. This is the first report of the natural infection of Pi. maranonensis by L. (V.) peruviana.

<i>Orientia tsutsugamushi</i> modulates cellular levels of NF-κB inhibitor p105

15 April 2021 - 2:00pm

by Tanaporn Wangsanut, Katelynn R. Brann, Haley E. Adcox, Jason A. Carlyon


Scrub typhus is a neglected tropical disease that threatens more than one billion people. If antibiotic therapy is delayed, often due to mis- or late diagnosis, the case fatality rate can increase considerably. Scrub typhus is caused by the obligate intracellular bacterium, Orientia tsutsugamushi, which invades phagocytes and endothelial cells in vivo and diverse tissue culture cell types in vitro. The ability of O. tsutsugamushi to replicate in the cytoplasm indicates that it has evolved to counter eukaryotic host cell immune defense mechanisms. The transcription factor, NF-κB, is a tightly regulated initiator of proinflammatory and antimicrobial responses. Typically, the inhibitory proteins p105 and IκBα sequester the NF-κB p50:p65 heterodimer in the cytoplasm. Canonical activation of NF-κB via TNFα involves IKKβ-mediated serine phosphorylation of IκBα and p105, which leads to their degradation and enables NF-κB nuclear translocation. A portion of p105 is also processed into p50. O. tsutsugamushi impairs NF-κB translocation into the nucleus, but how it does so is incompletely defined.

Principal findings

Western blot, densitometry, and quantitative RT-PCR analyses of O. tsutsugamushi infected host cells were used to determine if the pathogen’s ability to inhibit NF-κB is linked to modulation of p105. Results demonstrate that p105 levels are elevated several-fold in O. tsutsugamushi infected HeLa and RF/6A cells with only a nominal increase in p50. The O. tsutsugamushi-stimulated increase in p105 is bacterial dose- and protein synthesis-dependent, but does not occur at the level of host cell transcription. While TNFα-induced phosphorylation of p105 serine 932 proceeds unhindered in infected cells, p105 levels remain elevated and NF-κB p65 is retained in the cytoplasm.


O. tsutsugamushi specifically stabilizes p105 to inhibit the canonical NF-κB pathway, which advances understanding of how it counters host immunity to establish infection.

An investigation of conventional microbial culture for the <i>Naja atra</i> bite wound, and the comparison between culture-based 16S Sanger sequencing and 16S metagenomics of the snake oropharyngeal bacterial microbiota

15 April 2021 - 2:00pm

by Yan-Chiao Mao, Han-Ni Chuang, Chien-Hung Shih, Han-Hsueh Hsieh, Yu-Han Jiang, Liao-Chun Chiang, Wen-Loung Lin, Tzu-Hung Hsiao, Po-Yu Liu

Naja atra is a major venomous snake found in Taiwan. The bite of this snake causes extensive wound necrosis or necrotizing soft tissue infection. Conventional microbial culture-based techniques may fail to identify potential human pathogens and render antibiotics ineffective in the management of wound infection. Therefore, we evaluated 16S Sanger sequencing and next-generation sequencing (NGS) to identify bacterial species in the oropharynx of N. atra. Using conventional microbial culture methods and the VITEK 2 system, we isolated nine species from snakebite wounds. On the basis of the 16S Sanger sequencing of bacterial clones from agar plates, we identified 18 bacterial species in the oropharynx of N. atra, including Morganella morganii, Proteus vulgaris, and Proteus mirabilis, which were also present in the infected bite wound. Using NGS of 16S metagenomics, we uncovered more than 286 bacterial species in the oropharynx of N. atra. In addition, the bacterial species identified using 16S Sanger sequencing accounted for only 2% of those identified through NGS of 16S metagenomics. The bacterial microbiota of the oropharynx of N. atra were modeled better using NGS of 16S metagenomics compared to microbial culture-based techniques. Stenotrophomonas maltophilia, Acinetobacter baumannii, and Proteus penneri were also identified in the NGS of 16S metagenomics. Understanding the bacterial microbiota that are native to the oropharynx of N. atra, in addition to the bite wound, may have additional therapeutic implications regarding empiric antibiotic selection for managing N. atra bites.

Deciphering the introduction and transmission of SARS-CoV-2 in the Colombian Amazon Basin

15 April 2021 - 2:00pm

by Nathalia Ballesteros, Marina Muñoz, Luz Helena Patiño, Carolina Hernández, Felipe González-Casabianca, Iván Carroll, Mauricio Santos-Vega, Jaime Cascante, Andrés Angel, Alejandro Feged-Rivadeneira, Mónica Palma-Cuero, Carolina Flórez, Sergio Gomez, Adriana van de Guchte, Zenab Khan, Jayeeta Dutta, Ajay Obla, Hala Alejel Alshammary, Ana S. Gonzalez-Reiche, Matthew M. Hernandez, Emilia Mia Sordillo, Viviana Simon, Harm van Bakel, Alberto Paniz-M, Juan David Ramírez


The SARS-CoV-2 pandemic has forced health authorities across the world to take important decisions to curtail its spread. Genomic epidemiology has emerged as a valuable tool to understand introductions and spread of the virus in a specific geographic location.

Methodology/Principal findings

Here, we report the sequences of 59 SARS-CoV-2 samples from inhabitants of the Colombian Amazonas department. The viral genomes were distributed in two robust clusters within the distinct GISAID clades GH and G. Spatial-temporal analyses revealed two independent introductions of SARS-CoV-2 in the region, one around April 1, 2020 associated with a local transmission, and one around April 2, 2020 associated with other South American genomes (Uruguay and Brazil). We also identified ten lineages circulating in the Amazonas department including the P.1 variant of concern (VOC).


This study represents the first genomic epidemiology investigation of SARS-CoV-2 in one of the territories with the highest report of indigenous community of the country. Such findings are essential to decipher viral transmission, inform on global spread and to direct implementation of infection prevention and control measures for this vulnerable population, especially, due to the recent circulation of one of the variants of concern (P.1) associated with major transmissibility and possible reinfections.

Preventive chemotherapy for the control of strongyloidiasis in school-age children: Estimating the ivermectin need

15 April 2021 - 2:00pm

by Donal Bisanzio, Antonio Montresor, Michael French, Richard Reithinger, Paola Rodari, Zeno Bisoffi, Dora Buonfrate


Strongyloides stercoralis is a soil-transmitted helminth (STH) that affects approximately 600 million people worldwide. Interventions targeting S. stercoralis have not been implemented yet. Specific treatment (ivermectin) could be included in already ongoing preventive chemotherapy (PC) campaigns targeting other STHs. The aim of this study was to estimate the quantity of ivermectin needed for an integrated STH/S. stercoralis control program.

Methododology/Principal findings

Our study estimates the number of school- age children (SAC) (the main focus of STH deworming campaigns) in need of PC with ivermectin. The normal approximation of the binomial distribution was adopted to calculate the hypothetical prevalence distribution in each endemic country. Considering prevalence thresholds for PC equal to 10%, 15%, and 20%, we estimated the number of SAC in need of treatment. We adjusted the estimates accounting for ivermectin distributed in lymphatic filariasis and onchocerciasis elimination programs and excluded from our calculation areas where Loa loa is endemic.The global number of SAC that should be targeted in PC campaigns was estimated at 283.9 M (95% CI: 163.4–368.8), 207.2 M (95% CI: 160.9–380.7), and 160.7 M (95% CI: 86.6–225.7) when the threshold for intervention was set to 10%, 15%, and 20%, respectively. India, China, Indonesia, Bangladesh, and Nigeria accounted for about 50% of the global SAC would have to be covered by PC intervention.


Our analysis may support endemic countries to evaluate the ivermectin quantity needed for integrating strongyloidiasis in the existing STH programs. These estimates might also show to generic drug manufacturers the size of the potential market for ivermectin and encourage its production.

Drug reformulation for a neglected disease. The NANOHAT project to develop a safer more effective sleeping sickness drug

15 April 2021 - 2:00pm

by Lisa Sanderson, Marcelo da Silva, Gayathri N. Sekhar, Rachel C. Brown, Hollie Burrell-Saward, Mehmet Fidanboylu, Bo Liu, Lea Ann Dailey, Cécile A. Dreiss, Chris Lorenz, Mark Christie, Shanta J. Persaud, Vanessa Yardley, Simon L. Croft, Margarita Valero, Sarah A. Thomas


Human African trypanosomiasis (HAT or sleeping sickness) is caused by the parasite Trypanosoma brucei sspp. The disease has two stages, a haemolymphatic stage after the bite of an infected tsetse fly, followed by a central nervous system stage where the parasite penetrates the brain, causing death if untreated. Treatment is stage-specific, due to the blood-brain barrier, with less toxic drugs such as pentamidine used to treat stage 1. The objective of our research programme was to develop an intravenous formulation of pentamidine which increases CNS exposure by some 10–100 fold, leading to efficacy against a model of stage 2 HAT. This target candidate profile is in line with drugs for neglected diseases inititative recommendations.


To do this, we evaluated the physicochemical and structural characteristics of formulations of pentamidine with Pluronic micelles (triblock-copolymers of polyethylene-oxide and polypropylene oxide), selected candidates for efficacy and toxicity evaluation in vitro, quantified pentamidine CNS delivery of a sub-set of formulations in vitro and in vivo, and progressed one pentamidine-Pluronic formulation for further evaluation using an in vivo single dose brain penetration study.

Principal Findings

Screening pentamidine against 40 CNS targets did not reveal any major neurotoxicity concerns, however, pentamidine had a high affinity for the imidazoline2 receptor. The reduction in insulin secretion in MIN6 β-cells by pentamidine may be secondary to pentamidine-mediated activation of β-cell imidazoline receptors and impairment of cell viability. Pluronic F68 (0.01%w/v)-pentamidine formulation had a similar inhibitory effect on insulin secretion as pentamidine alone and an additive trypanocidal effect in vitro. However, all Pluronics tested (P85, P105 and F68) did not significantly enhance brain exposure of pentamidine.


These results are relevant to further developing block-copolymers as nanocarriers, improving BBB drug penetration and understanding the side effects of pentamidine.

Comparative dissection of the peripheral olfactory system of the Chagas disease vectors <i>Rhodnius prolixus</i> and <i>Rhodnius brethesi</i>

15 April 2021 - 2:00pm

by Florencia Campetella, Rickard Ignell, Rolf Beutel, Bill S. Hansson, Silke Sachse

American trypanosomiasis, or Chagas disease, is transmitted by both domestic and sylvatic species of Triatominae which use sensory cues to locate their vertebrate hosts. Among them, odorants have been shown to play a key role. Previous work revealed morphological differences in the sensory apparatus of different species of Triatomines, but to date a comparative functional study of the olfactory system is lacking. After examining the antennal sensilla with scanning electronic microscopy (SEM), we compared olfactory responses of Rhodnius prolixus and the sylvatic Rhodnius brethesi using an electrophysiological approach. In electroantennogram (EAG) recordings, we first showed that the antenna of R. prolixus is highly responsive to carboxylic acids, compounds found in their habitat and the headspace of their vertebrate hosts. We then compared responses from olfactory sensory neurons (OSNs) housed in the grooved peg sensilla of both species, as these are tuned to these compounds using single-sensillum recordings (SSRs). In R. prolixus, the SSR responses revealed a narrower tuning breath than its sylvatic sibling, with the latter showing responses to a broader range of chemical classes. Additionally, we observed significant differences between these two species in their response to particular volatiles, such as amyl acetate and butyryl chloride. In summary, the closely related, but ecologically differentiated R. prolixus and R. brethesi display distinct differences in their olfactory functions. Considering the ongoing rapid destruction of the natural habitat of sylvatic species and the likely shift towards environments shaped by humans, we expect that our results will contribute to the design of efficient vector control strategies in the future.

Correction: A next generation vaccine against human rabies based on a single dose of a chimpanzee adenovirus vector serotype C

13 April 2021 - 2:00pm

by Federico Napolitano, Rossella Merone, Adele Abbate, Virginia Ammendola, Emma Horncastle, Francesca Lanzaro, Marialuisa Esposito, Alessandra Maria Contino, Roberta Sbrocchi, Andrea Sommella, Joshua D. Duncan, Joseph Hinds, Richard A. Urbanowicz, Armin Lahm, Stefano Colloca, Antonella Folgori, Jonathan K. Ball, Alfredo Nicosia, Benjamin Wizel, Stefania Capone, Alessandra Vitelli

Correction: <i>Anopheles sundaicus</i> complex and the presence of <i>Anopheles epiroticus</i> in Indonesia

13 April 2021 - 2:00pm

by Din Syafruddin, Yulia E. Lestari, Dendi H. Permana, Puji B. S. Asih, Brandyce St. Laurent, Siti Zubaidah, Ismail E. Rozi, Sully Kosasih, Shinta, Supratman Sukowati †, Lukman Hakim, Edhi Haryanto, Wibowo Mangunwardoyo, Michael J. Bangs, Neil F. Lobo

Correction: Role of microglia in the dissemination of Zika virus from mother to fetal brain

13 April 2021 - 2:00pm

by Pei Xu, Chao Shan, Tiffany J. Dunn, Xuping Xie, Hongjie Xia, Junling Gao, Javier Allende Labastida, Zou Jing, Paula P. Villarreal, Caitlin R. Schlagal, Yongjia Yu, Gracie Vargas, Shannan L. Rossi, Nikos Vasilakis, Pei-Yong Shi, Scott C. Weaver, Ping Wu

Crimean-Congo hemorrhagic fever virus antibody prevalence in Mauritanian livestock (cattle, goats, sheep and camels) is stratified by the animal’s age

12 April 2021 - 2:00pm

by Ansgar Schulz, Yahya Barry, Franziska Stoek, Aliou Ba, Jana Schulz, Mohamed L. Haki, Miriam A. Sas, Baba A. Doumbia, Peter Kirkland, Mohamed Y. Bah, Martin Eiden, Martin H. Groschup

Crimean-Congo hemorrhagic fever virus (CCHFV) is one of the most widespread zoonotic arthropod-borne viruses in many parts of Africa, Europe and Asia. It belongs to the family of Nairoviridae in the genus of Orthonairovirus. The main reservoir and vector are ticks of the genus Hyalomma. Livestock animals (such as cattle, small ruminants and camels) develop a viremias lasting up to two weeks with absence of clinical symptoms, followed by seroconversion. This study was carried out to assess risk factors that affect seroprevalence rates in different species. In total, 928 livestock animal samples (cattle = 201; sheep = 247; goats = 233; camels = 247) from 11 out of 13 regions in Mauritania were assayed for CCHFV-specific immunoglobulin G (IgG) antibodies using enzyme-linked immunosorbent assays (ELISA) (including a novel indirect camel-IgG-specific CCHFV ELISA). Inconclusive results were resolved by an immunofluorescence assay (IFA). A generalized linear mixed-effects model (GLMM) was used to draw conclusions about the impact of certain factors (age, species, sex and region) which might have influenced the CCHFV antibody status of surveyed animals. In goats and sheep, about 15% of the animals were seropositive, whereas in cattle (69%) and camels (81%), the prevalence rate was significantly higher. On average, cattle and camels were up to twice to four times older than small ruminants. Interestingly, the seroprevalence in all species was directly linked to the age of the animals, i.e. older animals had significantly higher seroprevalence rates than younger animals. The highest CCHFV seroprevalence in Mauritania was found in camels and cattle, followed by small ruminants. The large proportion of positive animals in cattle and camels might be explained by the high ages of the animals. Future CCHFV prevalence studies should at least consider the age of surveyed animals in order to avoid misinterpretations.

Seroprevalence of chikungunya virus infection among HIV-infected adults in French Caribbean Islands of Martinique and Guadeloupe in 2015: A cross-sectional study

9 April 2021 - 2:00pm

by Elodie Curlier, Laurence Fagour, Cécile Herrmann-Storck, Adrien Staelen, Ingrid Vingadassalom, Sébastien Breurec, Sylvie Abel, Sandrine Pierre-François, Janick Jean-Marie, Cédric Laouénan, Raymond Césaire, Bruno Hoen, André Cabié


In 2014, a first outbreak of chikungunya hit the Caribbean area where chikungunya virus (CHIKV) had never circulated before.

Methodology/Principal findings

We conducted a cross-sectional study to measure the seroprevalence of CHIKV immediately after the end of the 2014 outbreak in HIV-infected people followed up in two clinical cohorts at the University hospitals of Guadeloupe and Martinique. Study patients were identified during the first months of 2015 and randomly selected to match the age and sex distribution of the general population in the two islands. They were invited to complete a survey that explored the symptoms consistent with chikungunya they could have developed during 2014 and to have a blood sample drawn for CHIKV serology.The study population consisted of 377 patients (198 in Martinique and 179 in Guadeloupe, 178 men and 199 women), 182 of whom reported they had developed symptoms consistent with chikungunya. CHIKV serology was positive in 230 patients, which accounted for an overall seroprevalence rate of 61% [95%CI 56–66], with only 153 patients who reported symptoms consistent with chikungunya. Most frequent symptoms included arthralgia (94.1%), fever (73.2%), myalgia (53.6%), headache (45.8%), and skin rash (26.1%).


This study showed that the seroprevalence of CHIKV infection was 61% after the 2014 outbreak, with one third of asymptomatic infections.

Trial registration NCT 02553369.

Characterization and functional analysis of the proteins Prohibitin 1 and 2 in <i>Trypanosoma cruzi</i>

8 April 2021 - 2:00pm

by Ana K. Ibarrola-Vannucci, Luis M. De Pablos, Lissette Retana-Moreira, Alberto Cornet-Gómez, Teresa Cruz-Bustos, Alejandro G. Schijman, José L. Ramírez, Susana Vílchez, Antonio Osuna


Chagas disease is the third most important neglected tropical disease. There is no vaccine available, and only two drugs are generally prescribed for the treatment, both of which with a wide range of side effects. Our study of T. cruzi PHBs revealed a pleiotropic function in different stages of the parasite, participating actively in the transformation of the non-infective replicative epimastigote form into metacyclic trypomastigotes and also in the multiplication of intracellular amastigotes.

Methodology/principal findings

To obtain and confirm our results, we applied several tools and techniques such as electron microscopy, immuno-electron microscopy, bioinformatics analysis and molecular biology. We transfected T. cruzi clones with the PHB genes, in order to overexpress the proteins and performed a CRISPR/Cas9 disruption to obtain partially silenced PHB1 parasites or completely silenced PHB2 parasites. The function of these proteins was also studied in the biology of the parasite, specifically in the transformation rate from non-infective forms to the metacyclic infective forms, and in their capacity of intracellular multiplication.


This research expands our understanding of the functions of PHBs in the life cycle of the parasite. It also highlights the protective role of prohibitins against ROS and reveals that the absence of PHB2 has a lethal effect on the parasite, a fact that could support the consideration of this protein as a possible target for therapeutic action.

<i>Aedes aegypti dyspepsia</i> encodes a novel member of the SLC16 family of transporters and is critical for reproductive fitness

7 April 2021 - 2:00pm

by Hitoshi Tsujimoto, Michelle A. E. Anderson, Heather Eggleston, Kevin M. Myles, Zach N. Adelman

As a key vector for the major arthropod-borne viruses (arboviruses), such as dengue, Zika and chikungunya, control of Aedes aegypti represents a major challenge in public health. Bloodmeal acquisition is necessary for the reproduction of vector mosquitoes and pathogen transmission. Blood contains potentially toxic amounts of iron while it provides nutrients for mosquito offspring; disruption of iron homeostasis in the mosquito may therefore lead to novel control strategies. We previously described a potential iron exporter in Ae. aegypti after a targeted functional screen of ZIP (zinc-regulated transporter/Iron-regulated transporter-like) and ZnT (zinc transporter) family genes. In this study, we performed an RNAseq-based screen in an Ae. aegypti cell line cultured under iron-deficient and iron-excess conditions. A subset of differentially expressed genes were analyzed via a cytosolic iron-sensitive dual-luciferase reporter assay with several gene candidates potentially involved in iron transport. In vivo gene silencing resulted in significant reduction of fecundity (egg number) and fertility (hatch rate) for one gene, termed dyspepsia. Silencing of dyspepsia reduced the induction of ferritin expression in the midgut and also resulted in delayed/impaired excretion and digestion. Further characterization of this gene, including a more direct confirmation of its substrate (iron or otherwise), could inform vector control strategies as well as to contribute to the field of metal biology.

Correction: CXCR3 chemokine receptor contributes to specific CD8<sup>+</sup> T cell activation by pDC during infection with intracellular pathogens

7 April 2021 - 2:00pm

by Camila Pontes Ferreira, Leonardo Moro Cariste, Isaú Henrique Noronha, Danielle Fernandes Durso, Joseli Lannes-Vieira, Karina Ramalho Bortoluci, Daniel Araki Ribeiro, Douglas Golenbock, Ricardo Tostes Gazzinelli, José Ronnie Carvalho de Vasconcelos