PLoS Neglected Tropical Diseases News

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Immunomodulatory drug methotrexate used to treat patients with chronic inflammatory rheumatisms post-chikungunya does not impair the synovial antiviral and bone repair responses

3 August 2018 - 9:00pm

by Yosra Bedoui, Claude Giry, Marie-Christine Jaffar-Bandjee, Jimmy Selambarom, Pascale Guiraud, Philippe Gasque

Chikungunya virus (CHIKV) is a mosquito-transmitted RNA alphavirus causing major outbreaks of infectious chronic inflammatory rheumatisms (CIR). Recently, methotrexate (MTX), a disease modifying anti-rheumatic drug has been used successfully to treat patients suffering from rheumatoid-like arthritis post-CHIK but its immunomodulatory activity in the context of viral persistence has been a matter of concerns. We herein used a model of primary human synovial fibroblasts (HSF) and the synthetic molecule polyriboinosinic:polyribocytidylic acid (PIC) to mimic chronic infectious settings in the joints of CHIKV infected patients. The innate antiviral immune and inflammatory responses were investigated in response to MTX used at the therapeutic concentration of 1 μM. We found that MTX did not affect cellular viability as indicated by the LDH release assay. By quantitative RT-PCR, we observed that HSF responded robustly to PIC by increasing ISG15 and IFNβ mRNA levels. Furthermore, PIC upregulated the mRNA expression of two of the major pattern recognition receptors, RIG-I and MDA5 involved in the innate immune detection of viral RNA. MTX did not impact the antiviral response of PIC on ISG15, IFNβ, RIG-I and MDA5 mRNA expressions. MTX alone or combined with PIC did not affect the expression of proinflammatory CCL2 and CXCL8 chemokines. PIC strongly upregulated the mRNA and protein expression of osteoclastogenic factors (IL-6, GM-CSF but not RANKL). Critically, MTX treatment alone or combined with PIC did not affect the expression of all three tested osteoclastogenic cytokines. We found that MTX alone did not increase the capacity of CHIKV to infect and replicate in HSF. In conclusion, our study argues for a beneficial effect of MTX to treat CIR post-CHIKV given that it does not critically impact the antiviral, the proinflammatory and the bone tissue remodeling responses of synovial cells.

Infection of epididymal epithelial cells and leukocytes drives seminal shedding of Zika virus in a mouse model

2 August 2018 - 9:00pm

by Erin M. McDonald, Nisha K. Duggal, Jana M. Ritter, Aaron C. Brault

While primarily a mosquito-borne virus, Zika virus (ZIKV; genus Flavivirus in the Flaviviridae family) is capable of being sexually transmitted. Thirty to fifty percent of men with confirmed ZIKV infection shed ZIKV RNA in their semen, and prolonged viral RNA shedding in semen can occur for more than 6 months. The cellular reservoir of ZIKV in semen is unknown, although spermatozoa have been shown to contain ZIKV RNA and antigen. Yet, spermatozoa are not a requisite for sexual transmission, as at least one case of ZIKV sexual transmission involved a vasectomized man. To determine the cellular reservoirs of ZIKV in semen, an established animal model of sexual transmission was used. The majority of virus detected in the seminal fluid of infected mice during the peak timing of sexual transmission was from the supernatant fraction, suggesting cell-free ZIKV may be largely responsible for sexual transmission. However, some ZIKV RNA was cell-associated. In the testes and epididymides of infected mice, intracellular staining of ZIKV RNA was more pronounced in spermatogenic precursors (spermatocytes and spermatogonia) than in spermatids. Visualization of intracellular negative strand ZIKV RNA demonstrated ZIKV replication intermediates in leukocytes, immature spermatids and epididymal epithelial cells in the male urogenital tract. Epididymal epithelial cells were the principal source of negative-strand ZIKV RNA during the peak timing of sexual transmission potential, indicating these cells may be the predominant source of infectious cell-free ZIKV in seminal fluid. These data promote a more complete understanding of sexual transmission of ZIKV and will inform further model development for future studies on persistent ZIKV RNA shedding.

Cs1, a <i>Clonorchis sinensis</i>-derived serodiagnostic antigen containing tandem repeats and a signal peptide

2 August 2018 - 9:00pm

by Na Cheng, Xue-Nian Xu, Yan Zhou, Yu-Ting Dong, Yi-Fang Bao, Bin Xu, Wei Hu, Zheng Feng


Clonorchiasis, caused by the liver fluke Clonorchis sinensis, remains a serious public health issue in Asia, especially in China, and its relationship with cholangiocarcinoma has highlighted the importance of C. sinensis infection. Proteins containing tandem repeats (TRs) are found in a variety of parasites and, as targets of B-cell responses, are valuable for the serodiagnosis of parasite infections. Here, we identified a novel C. sinensis-specific antigen, Cs1, containing TRs, and investigated its diagnostic value, other immunological properties, and tissue distribution.

Methodology/Principal findings

A partial Cs1 cDNA sequence was cloned by screening an adult C. sinensis cDNA expression library. The full-length Cs1 cDNA was obtained by 5′ rapid amplification of cDNA ends. The deduced Cs1 protein consists of a signal peptide and five TRs of 21 amino acids. The recombinant Cs1 (rCs1) was constructed and purified. rCs1 showed higher sensitivity (94.3%) and specificity (94.4%) than the C. sinensis excretory–secretory products (ESPs) according to ELISA of 114 serum samples. Native Cs1 was identified in C. sinensis ESPs and crude antigens of adult C. sinensis by western blotting using an anti-rCs1 monoclonal antibody. ELISA of recombinant peptides of different Cs1 regions demonstrated that the TR region was immunodominant in Cs1. Immunohistochemistry and confocal microscopy revealed that Cs1 is located in a granule-like structure surrounding the acetabulum of C. sinensis adults that has not previously been described.


We identified a novel C. sinensis-specific TR protein, Cs1, which is an antigen of high serological significance, compared with C. sinensis ESPs. The deduced features of Cs1 show a unique structure containing TRs and a signal peptide and the TR region is immunodominant in Cs1. This provides a basis for targeted screens of other antigens. The novel structure in which Cs1 is located also deserves further investigation.

Simulation of population dynamics of <i>Bulinus globosus</i>: Effects of environmental temperature on production of <i>Schistosoma haematobium</i> cercariae

2 August 2018 - 9:00pm

by Chester Kalinda, Moses J. Chimbari, William E. Grant, Hsiao-Hsuan Wang, Julius N. Odhiambo, Samson Mukaratirwa


Temperature is an important factor that influences the biology and ecology of intermediate host (IH) snails and the schistosome parasites they transmit. Although temperature shifts due to climate change has been predicted to affect the life history traits of IH snails and parasite production, the mechanisms of how this may affect parasite abundance and disease risks are still not clear.

Materials and methods

Using data from laboratory and field experiments, we developed a deterministic compartmental simulation model based on difference equations using a weekly time step that represented the life cycle of Bulinus globosus. We simulated snail population dynamics and the associated production of cercariae assuming current environmental temperatures as well as projected temperature increases of 1 °C and 2 °C.


The model generated snail fecundity and survival rates similar to those observed in the laboratory and also produced reasonable snail population dynamics under seasonally varying temperatures representative of generally favorable environmental conditions. Simulated relative abundances of both snails and cercariae decreased with increasing environmental temperatures, with maximum snail abundances decreased by 14% and 27%, and maximum cercariae productions decreased by 8% and 17%, when temperatures were increased by 1 °C and 2 °C, respectively.


The results indicate that future rise in temperature due to climate change may alter the abundance of B. globosus and impact on the prevalence of schistosomiasis. Furthermore, increased temperatures may not linearly influence the abundance of S. haematobium. These results may have important implications for schistosomiasis control programmes in view of temperature driven changes in the life history traits of B. globosus and S. haematobium. Our study recommends that the use of deterministic models incorporating the effects of temperature on the life history traits of IH snails would be vital in understanding the potential impact of climate change on schistosomiasis incidences and prevalence.

Evaluation of the rSP03B sero-strip, a newly proposed rapid test for canine exposure to <i>Phlebotomus perniciosus</i>, vector of <i>Leishmania infantum</i>

2 August 2018 - 9:00pm

by Laura Willen, Pascal Mertens, Petr Volf


Canine leishmaniasis (CanL) is a zoonotic disease, caused by Leishmania infantum and transmitted by Phlebotomus perniciosus in the Mediterranean basin. Previously, an ELISA based on the P. perniciosus salivary protein SP03B was proposed as a valid tool to screen for canine exposure to sand fly bites across regions endemic for CanL. Although this approach is useful in laboratory settings, a practical tool for immediate application in the field is needed. In this study we propose the rSP03B sero-strip, the first immunochromatographic test (ICT) in the field of vector exposure able to rapidly screen dogs living in endemic areas for the presence of P. perniciosus and to aid in the evaluation of vector control programs.

Methodology/Principal findings

The ICT was prepared using the bacterially expressed recombinant protein rSP03B as antigen. For test optimization, pre-immune sera from non-bitten laboratory-bred Beagles were used as negative controls. In order to validate the test, sera from laboratory-bred Beagles experimentally exposed to P. perniciosus bites were used as positive controls. Additionally, all samples were tested by ELISA using whole salivary gland homogenate (SGH) and the rSP03B protein as antigen. An almost perfect degree of agreement was found between the ICT and the SGH-ELISA. Furthermore, the newly proposed rSP03B sero-strip showed a sensitivity of 100% and a specificity of 86.79%.


We developed a simple and rapid ICT based on the P. perniciosus rSP03B salivary protein, able to replace the standard ELISA used in previous studies. Our rSP03B sero-strip showed to be highly sensitive and specific in the detection of antibodies (IgG) against P. perniciosus saliva. In the future, this test can be employed during large-scale epidemiological studies of CanL in the Mediterranean area to evaluate the efficacy of vector control programs.

The impact of the Ebola virus disease (EVD) epidemic on agricultural production and livelihoods in Liberia

2 August 2018 - 9:00pm

by Tsegaye T. Gatiso, Isabel Ordaz-Németh, Trokon Grimes, Menladi Lormie, Clement Tweh, Hjalmar S. Kühl, Jessica Junker

There is unequivocal evidence in the literature that epidemics adversely affect the livelihoods of individuals, households and communities. However, evidence in the literature is dominated by the socioeconomic impacts of HIV/AIDS and malaria, while evidence on the impact of the Ebola virus disease (EVD) on households’ livelihoods remains fragmented and scant. Our study investigates the effect of the EVD epidemic on the livelihoods of Liberian households using the Sustainable Livelihood Framework (SLF). The study also explores the effect of the EVD epidemic on agricultural production and productive efficiency of farm households using Spatial Stochastic Frontier Analysis (SSFA). We collected data from 623 households across Liberia in 2015, using a systematic random sampling design. Our results indicated that the annual income of sample households from communities where EVD occurred did not differ from the annual income of households from communities where EVD did not occur. Nonetheless, the majority of sample households reported a decrease in their income, compared to their income in the year before the survey. This suggests that the impact of the EVD epidemic might not only have been limited to communities directly affected by the epidemic, but also it may have indirectly affected communities in areas where EVD was not reported. We also found that the community-level incidence of EVD negatively affected crop production of farm households, which may have exacerbated the problem of food insecurity throughout the country. Moreover, we found that the EVD epidemic weakened the society’s trust in Liberian institutions. In a nutshell, our results highlight that epidemics, such as the recent EVD outbreak, may have long-lasting negative effects on the livelihoods of a society and their effect may extend beyond the communities directly affected by the epidemics. This means that the nation’s recovery from the impact of the epidemic would be more challenging, and the social and economic impacts of the epidemic may extend well beyond the end of the health crisis.

Precision mapping: An innovative tool and way forward to shrink the map, better target interventions, and accelerate toward the elimination of schistosomiasis

2 August 2018 - 9:00pm

by Louis-Albert Tchuem Tchuenté, J. Russell Stothard, David Rollinson, Jutta Reinhard-Rupp

Potential novel tick-borne Colpodella species parasite infection in patient with neurological symptoms

2 August 2018 - 9:00pm

by Jia-Fu Jiang, Rui-Ruo Jiang, Qiao-Cheng Chang, Yuan-Chun Zheng, Bao-Gui Jiang, Yi Sun, Na Jia, Ran Wei, Hong-Bo Liu, Qiu-Bo Huo, Hong Wang, Michael E. von Fricken, Wu-Chun Cao

The importance of dog population contact network structures in rabies transmission

1 August 2018 - 9:00pm

by Mirjam Laager, Céline Mbilo, Enos Abdelaziz Madaye, Abakar Naminou, Monique Léchenne, Aurélie Tschopp, Service Kemdongarti Naïssengar, Timo Smieszek, Jakob Zinsstag, Nakul Chitnis

Canine rabies transmission was interrupted in N’Djaména, Chad, following two mass vaccination campaigns. However, after nine months cases resurged with re-establishment of endemic rabies transmission to pre-intervention levels. Previous analyses investigated district level spatial heterogeneity of vaccination coverage, and dog density; and importation, identifying the latter as the primary factor for rabies resurgence. Here we assess the impact of individual level heterogeneity on outbreak probability, effectiveness of vaccination campaigns and likely time to resurgence after a campaign. Geo-located contact sensors recorded the location and contacts of 237 domestic dogs in N’Djaména over a period of 3.5 days. The contact network data showed that urban dogs are socially related to larger communities and constrained by the urban architecture. We developed a network generation algorithm that extrapolates this empirical contact network to networks of large dog populations and applied it to simulate rabies transmission in N’Djaména. The model predictions aligned well with the rabies incidence data. Using the model we demonstrated, that major outbreaks are prevented when at least 70% of dogs are vaccinated. The probability of a minor outbreak also decreased with increasing vaccination coverage, but reached zero only when coverage was near total. Our results suggest that endemic rabies in N’Djaména may be explained by a series of importations with subsequent minor outbreaks. We show that highly connected dogs hold a critical role in transmission and that targeted vaccination of such dogs would lead to more efficient vaccination campaigns.

MyD88 activation in cardiomyocytes contributes to the heart immune response to acute <i>Trypanosoma cruzi</i> infection with no effect on local parasite control

1 August 2018 - 9:00pm

by Danni Yohani Santana, Rafael Moysés Salgado, Marina Fevereiro, Rogério Silva do Nascimento, Raissa Fonseca, Niels Olsen Saraiva Câmara, Sabrina Epiphanio, Cláudio Romero Farias Marinho, Maria Luiza Barreto-Chaves, Maria Regina D’ Império-Lima, José M. Álvarez

Cardiomyopathy is the most serious consequence of Chagas disease, a neglected human disorder caused by Trypanosoma cruzi infection. Because T. cruzi parasites invade cardiomyocytes, we sought to investigate whether these cells recognize the parasite in vivo by receptors signaling through the MyD88 adaptor, which mediates the activation pathway of most Toll-like receptors (TLRs) and IL-1/IL-18 receptors, and influence the development of acute cardiac pathology. First, we showed that HL-1 cardiac muscle cell line expresses MyD88 gene and protein at resting state and after T. cruzi infection. To evaluate the role in vivo of MyD88 expression in cardiomyocytes, we generated Mer+MyD88flox+/+ mice in which tamoxifen treatment is expected to eliminate the MyD88 gene exclusively in cardiomyocytes. This Cre-loxP model was validated by both PCR and western blot analysis; tamoxifen treatment of Mer+MyD88flox+/+ mice resulted in decreased MyD88 gene and protein expression in the heart, but not in the spleen, while had no effect on littermates. The elimination of MyD88 in cardiomyocytes determined a lower increase in CCL5, IFNγ and TNFα gene transcription during acute infection by T. cruzi parasites of the Y strain, but it did not significantly modify heart leukocyte infiltration and parasitism. Together, our results show that cardiomyocytes can sense T. cruzi infection through MyD88-mediated molecular pathways and contribute to the local immune response to the parasite. The strong pro-inflammatory response of heart-recruited leukocytes may overshadow the effects of MyD88 deficiency in cardiomyocytes on the local leukocyte recruitment and T. cruzi control during acute infection.

An attenuated replication-competent chikungunya virus with a fluorescently tagged envelope

31 July 2018 - 9:00pm

by Jing Jin, Michael B. Sherman, Daniel Chafets, Nuntana Dinglasan, Kai Lu, Tzong-Hae Lee, Lars-Anders Carlson, Marcus O. Muench, Graham Simmons


Chikungunya virus (CHIKV) is the most common alphavirus infecting humans worldwide, causing acute and chronically debilitating arthralgia at a great economic expense.

Methodology/Principal findings

To facilitate our study of CHIKV, we generated a mCherry tagged replication-competent chimeric virus, CHIKV 37997-mCherry. Single particle cryoEM demonstrated icosahedral organization of the chimeric virus and the display of mCherry proteins on virus surface. CHIKV 37997-mCherry is attenuated in both IFNαR knockout and wild-type mice. Strong anti-CHIKV and anti-mCherry antibody responses were induced in CHIKV 37997-mCherry infected mice.


Our work suggests that chimeric alphaviruses displaying foreign antigen can serve as vaccines against both aphaviruses and other pathogens and diseases.

Understanding perceptions on 'Buruli' in northwestern Uganda: A biosocial investigation

30 July 2018 - 9:00pm

by Georgina Pearson


An understudied disease, little research thus far has explored responses to Buruli ulcer and quests for therapy from biosocial perspective, despite reports that people seek biomedical treatment too late.

Methods and findings

Taking an inductive approach and drawing on long-term ethnographic fieldwork in 2013–14, this article presents perspectives on this affliction of people living and working along the River Nile in northwest Uganda. Little is known biomedically about its presence, yet ‘Buruli’, as it is known locally, was and is a significant affliction in this region. Establishing a biosocial history of ‘Buruli’, largely obscured from biomedical perspectives, offers explanations for contemporary understandings, perceptions and practices.


We must move beyond over-simplifying and problematising ‘late presentation for treatment’ in public health, rather, develop biosocial approaches to understanding quests for therapy that take into account historical and contemporary contexts of health, healing and illness. Seeking to understand the context in which healthcare decisions are made, a biosocial approach enables greater depth and breadth of insight into the complexities of global and local public health priorities such as Buruli ulcer.

Ecological niche modelling and predicted geographic distribution of <i>Lutzomyia cruzi</i>, vector of <i>Leishmania infantum</i> in South America

30 July 2018 - 9:00pm

by Everton Falcão de Oliveira, Eunice Aparecida Bianchi Galati, Alessandra Gutierrez de Oliveira, Elizabeth Ferreira Rangel, Bruno Moreira de Carvalho

In some transmission foci of Leishmania infantum in Brazil, Lutzomyia cruzi could be considered the main vector of this pathogen. In addition, L. cruzi is a permissive vector of L. amazonensis. Its geographical distribution seems to be restricted and limited to Cerrado and Pantanal biomes, which includes some areas in Brazil and Bolivia. Considering that predicting the distribution of the species involved in transmission cycles is an effective approach for assessing human disease risk, this study aims to predict the spatial distribution of L. cruzi using a multiscale ecological niche model based in both climate and habitat variables. Ecological niche modelling was used to identify areas in South America that are environmentally suitable for this particular vector species, but its presence is not recorded. Vector occurrence records were compiled from the literature, museum collections and Brazilian Health Departments. Bioclimatic variables, altitude, and land use and cover were used as predictors in five ecological niche model algorithms: BIOCLIM, generalised linear model (logistic regression), maximum entropy, random forests, and support vector machines. The vector occurs in areas where annual mean temperature values range from 21.76°C to 26.58°C, and annual total precipitation varies from 1005 mm and 2048 mm. Urban areas were most present around capture locations. The potential distribution area of L. cruzi according to the final ecological niche model spans Brazil and Bolivia in patches of suitable habitats inside a larger climatically favourable area. The bigger portion of this suitable area is located at Brazilian States of Mato Grosso do Sul and Mato Grosso. Our findings identified environmentally suitable areas for L. cruzi in regions without its known occurrence, so further field sampling of sand flies is recommended, especially in southern Goiás State, Mato Grosso do Sul (borders with Mato Grosso, São Paulo and Minas Gerais); and in Bolivian departments Santa Cruz and El Beni.

Differing epidemiological dynamics of Chikungunya virus in the Americas during the 2014-2015 epidemic

30 July 2018 - 9:00pm

by Yi Tan, Brett E. Pickett, Susmita Shrivastava, Lionel Gresh, Angel Balmaseda, Paolo Amedeo, Lihui Hu, Vinita Puri, Nadia B. Fedorova, Rebecca A. Halpin, Matthew P. LaPointe, Marshall R. Cone, Lea Heberlein-Larson, Laura D. Kramer, Alexander T. Ciota, Aubree Gordon, Reed S. Shabman, Suman R. Das, Eva Harris

Chikungunya virus (CHIKV) has been detected sporadically since the 1950s and includes three distinct co-circulating genotypes. In late 2013, the Asian genotype of CHIKV was responsible for the Caribbean outbreak (CO) that rapidly became an epidemic throughout the Americas. There is a limited understanding of the molecular evolution of CHIKV in the Americas during this epidemic. We sequenced 185 complete CHIKV genomes collected mainly from Nicaragua in Central America and Florida in the United States during the 2014–2015 Caribbean/Americas epidemic. Our comprehensive phylogenetic analyses estimated the epidemic history of the Asian genotype and the recent Caribbean outbreak (CO) clade, revealed considerable genetic diversity within the CO clade, and described different epidemiological dynamics of CHIKV in the Americas. Specifically, we identified multiple introductions in both Nicaragua and Florida, with rapid local spread of viruses in Nicaragua but limited autochthonous transmission in Florida in the US. Our phylogenetic analysis also showed phylogeographic clustering of the CO clade. In addition, we identified the significant amino acid substitutions that were observed across the entire Asian genotype during its evolution and examined amino acid changes that were specific to the CO clade. Deep sequencing analysis identified specific minor variants present in clinical specimens below-consensus levels. Finally, we investigated the association between viral phylogeny and geographic/clinical metadata in Nicaragua. To date, this study represents the largest single collection of CHIKV complete genomes during the Caribbean/Americas epidemic and significantly expands our understanding of the emergence and evolution of CHIKV CO clade in the Americas.

Comparing the effectiveness of different strains of <i>Wolbachia</i> for controlling chikungunya, dengue fever, and zika

30 July 2018 - 9:00pm

by Ling Xue, Xin Fang, James M. Hyman

Once Aedes aegypti and Aedes albopictus mosquitoes that spread Chikungunya virus, dengue virus, and Zika virus are infected with Wolbachia, they have reduced egg laying rates, reduced transmission abilities, and shorter lifespans. Since most infected mosquitoes are only infectious in the last few days of their lives, shortening a mosquito’s lifespan by a day or two can greatly reduce their abilities to spread mosquito-borne viral diseases, such as Chikungunya, dengue fever, and Zika. We developed a mathematical model to compare the effectiveness of the wMel and wAlbB strains of Wolbachia for controlling the spread of these viruses. The differences among the diseases, mosquitoes, and Wolbachia strains are captured by the model parameters for the mosquito-human transmission cycle. Moreover, the model accounts for the behavior changes of infectious population created by differences in the malaise caused by these viruses. We derived the effective and basic reproduction numbers for the model that are used to estimate the number of secondary infections from the infectious populations. In the same density of Wolbachia-free Aedes aegypti or Aedes albopictus mosquitoes, we observed that wMel and wAlbB strains of Wolbachia can reduce the transmission rates of these diseases effectively.