PLOS Neglected Tropical Diseases

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ISSN / EISSN : 19352735 / 19352735
Current Publisher: Public Library of Science (PLoS) (10.1371)
Total articles ≅ 7,375
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Kun-Hsien Tsai, Lo-Hsuan Chung, Chia-Hao Chien, Yu-Jung Tung, Hsin-Yi Wei, Tsai-Ying Yen, Pei-Yun Shu, Hsi-Chieh Wang
PLOS Neglected Tropical Diseases, Volume 13; doi:10.1371/journal.pntd.0007728

Abstract:Human granulocytic anaplasmosis, a tick-borne infection caused by Anaplasma phagocytophilum, has received scant attention, while scrub typhus, a mite-transmitted disease caused by Orientia tsutsugamushi, is the most common rickettsiosis in Taiwan. The clinical presentations of both diseases are characterized by undifferentiated fever, headache and malaise. Moreover, both pathogens have been detected in small mammals that serve as hosts for chiggers and ticks in the wild. The objective of the present study was to investigate whether human granulocytic anaplasmosis occurs in Taiwan. Blood samples from 274 patients suspected of having scrub typhus in Kinmen, an offshore island of Taiwan, in 2011 and 2012 were retrospectively examined by immunofluorescence assays. IgG antibodies reactive with Anaplasma phagocytophilum was found in 31.8% (87/274) of the patients. Paired serology identified 3 patients with human granulocytic anaplasmosis and 8 patients with coinfection with O. tsutsugamushi and A. phagocytophilum. Laboratory tests showed that elevated serum ALT/AST, creatinine, and BUN levels were observed in patients with anaplasmosis and coinfection, but elevated serum CRP levels, thrombocytopenia, and anemia were only observed in coinfected patients. PCR detected A. phagocytophilum 16S rDNA and p44/msp2 in 2 patients. The phylogenetic analysis suggested that the replicons of the 16S rDNA shared high sequence similarity with the reference sequences in the Korea, USA, Japan, and China. The amplicons of p44/msp2 were close to those of the human variants identified in the USA and Japan. Our findings indicated that A. phagocytophilum infection was prevalent but unrecognized in Taiwan. Human granulocytic anaplasmosis is a tick-borne rickettsial infection caused by Anaplasma phagocytophilum. Although most cases resolve readily, life-threatening complications can occur without prompt antibiotic treatment. The major difficulty in diagnosing human granulocytic anaplasmosis is due to the nonspecific nature of the symptoms. Given that scrub typhus is the most frequently reported rickettsial disease in Taiwan and shares similar early clinical signs with anaplasmosis, we retrospectively examined blood samples from patients with suspected diagnoses of scrub typhus in 2011 and 2012. While serological evidence of potential past exposure was found in as many as 31.8% (87/274) of the patients, current or recent anaplasmosis was supported by seroconversion in 11 patients, including 8 patients coinfected with scrub typhus. Anaplasma phagocytophilum DNA was detected in acute phase samples, and the amplified fragments were phylogenetically close to those of variants in the Korea, the USA, Japan, and China. Herein, for the first time, we confirmed the presence of human granulocytic anaplasmosis in Taiwan. By reporting coinfections with anaplasmosis and scrub typhus, the study further highlighted the health risk of increasing contact with wild rodents.
Angamuthu Selvapandiyan, Simon L. Croft, Suman Rijal, Hira L. Nakhasi, Nirmal K. Ganguly
PLOS Neglected Tropical Diseases, Volume 13; doi:10.1371/journal.pntd.0007616

Lucinda Hazell, Laura Braun, Michael R. Templeton
PLOS Neglected Tropical Diseases, Volume 13; doi:10.1371/journal.pntd.0007777

Abstract:Helminthiases are a group of disabling neglected tropical diseases that affect billions of people worldwide. Current control methods use preventative chemotherapy but reinfection is common and an inter-sectoral approach is required if elimination is to be achieved. Household and community scale water treatment can be used to provide a safe alternative water supply for contact activities, reducing exposure to WASH (water, sanitation, and hygiene) -related helminths. With the introduction of ultraviolet light emitting diodes (UV-C LEDs), ultraviolet (UV) disinfection could be a realistic option for water treatment in low-income regions in the near future, to provide safe alternative water supplies for drinking and contact activities such as handwashing, bathing, and laundry, but currently there is no guidance for the use of UV or solar disinfection against helminths. A qualitative systematic review of existing literature was carried out to establish which WASH-related helminths are more susceptible to UV disinfection and identify gaps in research to inform future studies. The search included all species that can infect humans and can be transmitted through water or wastewater. Five online databases were searched and results were categorized based on the UV source: sunlight and solar simulators, UV-A and UV-B (long wavelength) sources, and UV-C (germicidal) sources. There has been very little research into the UV sensitivity of helminths; only 47 studies were included in this review and the majority were carried out before the standard protocol for UV disinfection experiments was published. Only 18 species were studied; however all species could be inactivated by UV light. Fluences required to achieve a 1-log inactivation ranged from 5 mJ/cm2 to over 800 mJ/cm2. Larval forms were generally more sensitive to UV light than species which remain as an egg in the environment. This review confirms that further research is required to produce detailed recommendations for household or community scale UV-C LED or solar disinfection (SODIS) of water for preventing helminthiases. Helminth infections are currently controlled by mass administration of anthelmintic drugs which are effective at treating the diseases but cannot prevent reinfection. As we work to eliminate these diseases, complimentary control methods such as improving access to water, sanitation, and hygiene will be crucial to reduce re-exposure and cut transmission. UV disinfection is a widely used form of water treatment but it is often seen as incompatible with low income regions. Recently developed UV-C LEDs and SODIS offer alternative sources of UV light that may be more suitable for this context, but there is little guidance about how we can use this technology to prevent helminth infections. We carried out a systematic review to establish which helminths are more sensitive to UV light and identify the areas which need further research. This will enable the production of design...
Higo Fernando Santos Souza, Sandra Carla Rocha, Flávia Silva Damasceno, Ludmila Nakamura Rapado, Elisabeth Mieko Furusho Pral, Claudio Romero Farias Marinho, Ariel Mariano Silber
PLOS Neglected Tropical Diseases, Volume 13; doi:10.1371/journal.pntd.0007226

Abstract:Chagas disease, caused by Trypanosoma cruzi, is a neglected tropical disease that affects 5–6 million people in endemic areas of the Americas. Presently, chemotherapy relies on two compounds that were proposed as trypanocidal drugs four decades ago: nifurtimox and benznidazole. Both drugs are able to eliminate parasitemia and to avoid seroconversion in infected people when used in the acute phase; however, their use in the chronic phase (the time when the majority of cases are diagnosed) is limited due to their serious side effects. Memantine is a glutamate receptor antagonist in the central nervous system of mammals that has been used for the treatment of Alzheimer’s disease. Our group previously reported memantine as a trypanocidal drug that is able to induce apoptosis-like death in T. cruzi. In the present work, we further investigated the effects of memantine on the infection of RAW 264.7 macrophages and in vivo (in BALB/c mice). Here, we showed that memantine is able to diminish NO and Ca2+ entry in both LPS-activated and non-activated cells. These results, together with the fact that memantine was also able to reduce the infection of macrophages, led us to propose that this drug is able to activate a pro-oxidant non-NO-dependent cell defense mechanism. Finally, infected mice that were treated with memantine had diminished parasitemia, cardiac parasitic load, and inflammatory infiltrates. In addition, the treated mice had an increased survival rate. Taken together, these results indicate memantine to be a candidate drug for the treatment of Chagas disease. Chagas disease affects approximately 5 million people and is caused by the protist parasite Trypanosoma cruzi. Until now, there are no vaccines to prevent the human infection, and the therapy relies on the use of two drugs discovered more than 50 years ago, nifurtimox and benznidazole. Both drugs are efficient during the acute phase of the disease, however their efficacy in the chronic phase, when most of patients are diagnosed is controversial. In addition, both drugs are toxic, causing severe side effects during the treatment. For these reasons, new drugs against T. cruzi are urgently needed. In this work, we report a series of experiments supporting the repositioning of memantine, a drug used for treating Alzheimer´s disease, to treat the T. cruzi infection in an experimental infection model. Our data show that infected mice treated with memantine have diminished their parasitemia, cardiac parasitic load and inflammatory infiltrates and more importantly, they have diminished their mortality. Taken together, these results prompt memantine as a promising drug for treating Chagas disease.
Sarah Anne J. Guagliardo, Yoosook Lee, Amanda A. Pierce, Jacklyn Wong, Yui Yin Chu, Amy C. Morrison, Helvio Astete, Berry Brosi, Gonzalo Vazquez-Prokopec, Thomas W. Scott, et al.
PLOS Neglected Tropical Diseases, Volume 13; doi:10.1371/journal.pntd.0007552

Abstract:In the Americas, as in much of the rest of the world, the dengue virus vector Aedes aegypti is found in close association with human habitations, often leading to high population densities of mosquitoes in urban settings. In the Peruvian Amazon, this vector has been expanding to rural communities over the last 10–15 years, but to date, the population genetic structure of Ae. aegypti in this region has not been characterized. To investigate the relationship between Ae. aegypti gene flow and human transportation networks, we characterized mosquito population structure using a panel of 8 microsatellite markers and linked results to various potential mechanisms for long-distance dispersal. Adult and immature Ae. aegypti (>20 individuals per site) were collected from Iquitos city and from six neighboring riverine communities, i.e., Nauta, Indiana, Mazan, Barrio Florida, Tamshiaco, and Aucayo. FST statistics indicate significant, but low to moderate differentiation for the majority of study site pairs. Population structure of Ae. aegypti is not correlated with the geographic distance between towns, suggesting that human transportation networks provide a reasonable explanation for the high levels of population mixing. Our results indicate that Ae. aegypti gene flow among sub-populations is greatest between locations with heavy boat traffic, such as Iquitos-Tamshiaco and Iquitos-Indiana-Mazan, and lowest between locations with little or no boat/road traffic between them such as Barrio Florida-Iquitos. Bayesian clustering analysis showed ancestral admixture among three genetic clusters; no single cluster was exclusive to any site. Our results are consistent with the hypothesis that human transportation networks, particularly riverways, are responsible for the geographic spread of Ae. aegypti in the Peruvian Amazon. Our findings are applicable to other regions of the world characterized by networks of urban islands connected by fluvial transport routes. Aedes aegypti, the primary mosquito vector of dengue, is a highly invasive species that is expanding from urban to peri-urban and rural areas throughout the Americas. Previous studies documented the role of human transportation networks in Ae. aegypti long-distance dispersal. We examined whether patterns of Ae. aegypti gene flow are consistent with this observation. Mosquitoes were collected from seven locations, including the large Amazonian city of Iquitos, Peru, and six neighboring rural communities, and their genetic relatedness was compared using 8 microsatellite markers. Our results showed ample gene flow among mosquito populations in this region, with greater gene flow observed among sites that are connected by fluvial routes. These findings are consistent with the hypothesis that human transportation networks, especially via boats, are a primary contributing factor to the spread of Ae. aegypti in the Peruvian Amazon.
Mariam Siala, Cécile Cassan, Salma Smaoui, Sana Kammoun, Chema Marouane, Sylvain Godreuil, Salma Hachicha, Emna Mhiri, Leila Slim, Dhikrayet Gamara, et al.
PLOS Neglected Tropical Diseases, Volume 13; doi:10.1371/journal.pntd.0007707

Abstract:In Tunisia, almost 77% of clinically and bacteriologically diagnosed cases of extrapulmonary tuberculosis (EPTB) are zoonotic TB, caused by M. bovis. Although several studies have analyzed bovine TB in cattle in Tunisia, no study has evaluated the risk of transmission to humans in such an endemic country. We aimed to study the genetic diversity of M. bovis human isolates, to ascertain the causes of human EPTB infection by M. bovis and to investigate the distribution and population structure of this species in Tunisia. A total of 110 M. bovis isolates taken from patients with confirmed EPTB were characterized by spoligotyping and MIRU-VNTR typing methods. Among the 15 spoligotypes detected in our study, 6 (SB0120, SB0121, SB2025, SB1200, SB1003 and SB0134) were the most prevalent (83.5%) of which SB0120, SB0121 and SB2025 were the most prevailing. MIRU-VNTR typing method showed a high genotypic and genetic diversity. The genetic differentiation based on MIRU-VNTR was significant between populations from South East (Tataouine, Medenine) and Central West (Gafsa, Sidi Bouzid, Kasserine) regions. Of note, 13/15 (86.7%) spoligotypes detected in our study were previously identified in cattle in Tunisia with different frequencies suggesting a peculiar ability of some genotypes to infect humans. Using combined spoligotyping and MIRU-VNTR method, a high clustering rate of 43.9% was obtained. Our results underlined that human EPTB due to M. bovis was more commonly found in female gender and in young patients. Most of our patients, 66.4% (73/110) were raw milk or derivatives consumers, whereas 30.9% (34/110) patients would have contracted EPTB through contact with livestock. The findings suggest that the transmission of Zoonotic TB caused by M. bovis to humans mainly occurred by oral route through raw milk or derivatives. Our study showed the urgent need of a better veterinary control with the implementation of effective and comprehensive strategies in order to reach a good protection of animals as well as human health. In South Tunisia, the prevalence of bovine TB is high with Mycobacterium bovis as causative agent and cattle as reservoir of the bacteria. However as previously mentioned in several studies, M. bovis is also responsible for human extrapulmonary tuberculosis (EPTB) cases in South Tunisia. Despite the veterinary and medical problems, M. bovis is still little studied. In this context, this work aimed to study the molecular epidemiology of M. bovis in EPTB patients in south Tunisia in order to determine the main risk factors of transmission. Our results underlined that SB0120, SB0121 and SB2025, previously described in cattle in Tunisia, represent the predominant genotypes. The findings highlighted that human EPTB caused by M. bovis mainly occurred through the consumption of raw milk or derivatives. These data demonstrate the urgent need to implement strategies for preventing and controlling zoonotic TB.
Juan Rivera-Correa, Isadora Cristina De Siqueira, Sabrina Mota, Mateus Santana Do Rosário, Pedro Antônio Pereira De Jesus, Luiz Carlos Junior Alcantara, Joel D. Ernst, Ana Rodriguez
PLOS Neglected Tropical Diseases, Volume 13; doi:10.1371/journal.pntd.0007695

Abstract:Zika virus infection is associated with the development of Guillain-Barré syndrome (GBS), a neurological autoimmune disorder caused by immune recognition of gangliosides and other components at nerve membranes. Using a high-throughput ELISA, we have analyzed the anti-glycolipid antibody profile, including gangliosides, of plasma samples from patients with Zika infections associated or not with GBS in Salvador, Brazil. We have observed that Zika patients that develop GBS present higher levels of anti-ganglioside antibodies when compared to Zika patients without GBS. We also observed that a broad repertoire of gangliosides was targeted by both IgM and IgG anti-self antibodies in these patients. Since Zika virus infects neurons, which contain membrane gangliosides, antigen presentation of these infected cells may trigger the observed autoimmune anti-ganglioside antibodies suggesting direct infection-induced autoantibodies as a cause leading to GBS development. Collectively, our results establish a link between anti-ganglioside antibodies and Zika-associated GBS in patients. Zika virus infection can trigger the development of Guillain Barré syndrome (GBS), a neurological autoimmune disorder mediated by antibodies recognizing gangliosides in nerve membranes. Mechanisms such as molecular mimicry have been identified as a cause for GBS development in certain infections, such as Campylobacter jejuni, but the broad self reactivity observed during GBS suggests a role for alternative mechanisms. Our finding that Zika patients with GBS present higher levels of anti-ganglioside antibodies compared to uncomplicated Zika patients in Brazil points to these auto-antibodies as a trigger for GBS in these patients. These findings further support infection-induced autoantibodies as a factor contributing to GBS development, adding novel mechanisms for GBS development beyond molecular mimicry.
Hugo Vicentin Alves, Amarilis Giaretta De Moraes, Afonso Carrasco Pepineli, Bruna Tiaki Tiyo, Quirino Alves De Lima Neto, Thais Da Silva Santos, Jorge Juarez Vieira Teixeira, Eliane P. Ambrosio-Albuquerque, Ana Maria Sell, Jeane Eliete Laguila Visentainer
PLOS Neglected Tropical Diseases, Volume 13; doi:10.1371/journal.pntd.0007696

Abstract:Killer-cell immunoglobulin-like receptors (KIRs) are a group of regulatory molecules able to activate or inhibit natural killer cells upon interaction with human leukocyte antigen (HLA) class I molecules. Combinations of KIR and HLA may contribute to the occurrence of different immunological and clinical responses to infectious diseases. Leprosy is a chronic neglected disease, both disabling and disfiguring, caused mainly by Mycobacterium leprae. In this case–control study, we examined the influence of KIRs and HLA ligands on the development of multibacillary leprosy. Genotyping of KIR and HLA genes was performed in 264 multibacillary leprosy patients and 518 healthy unrelated controls (238 healthy household contacts and 280 healthy subjects). These are unprecedented results in which KIR2DL2/KIR2DL2/C1/C2 and KIR2DL3/2DL3/C1/C1 indicated a risk for developing lepromatous and borderline leprosy, respectively. Concerning to 3DL2/A3/A11+, our study demonstrated that independent of control group (contacts or healthy subjects), this KIR receptor and its ligand act as a risk factor for the borderline clinical form. Our finding suggests that synergetic associations of activating and inhibitory KIR genes may alter the balance between these receptors and thus interfere in the progression of multibacillary leprosy. Leprosy is a neglected disease with the highest worldwide prevalence, and remains a public health problem in Brazil. The innate immune mechanisms are determinants in the management of leprosy and its different clinical manifestations. Accordingly, genetic association study provides information about the contribution of host genetic factors and the environment in which the individual lives on the development of leprosy. The individuals considered most affected and associated with a major risk for developing leprosy are household contacts with an intimate relation to patients living in crowded households. For this reason, we chose the contacts as one of our control groups, since they are more exposed to infection compared to the general population. We investigated the influence of KIR and HLA genes on the susceptibility to multibacillary leprosy. Our results reinforce the importance of host genetic background in the susceptibility to leprosy demonstrating that, independent from the control group (contacts or healthy subjects) the KIR and HLA act as risk factors in the development of lepromatous and borderline leprosy.
Xinghua Su, Yijia Guo, Jielin Deng, Jiabao Xu, Guofa Zhou, Tengfei Zhou, Yiji Li, Daibin Zhong, Ling Kong, XiaoMing Wang, et al.
PLOS Neglected Tropical Diseases, Volume 13; doi:10.1371/journal.pntd.0007665

Abstract:Dengue is one of the most serious mosquito-borne infectious diseases in the world. Aedes albopictus is the most invasive mosquito and one of the primary vectors of dengue. Vector control using insecticides is the only viable strategy to prevent dengue virus transmission. In Guangzhou, after the 2014 pandemic, massive insecticides have been implemented. Massive insecticide use may lead to the development of resistance, but few reports are available on the status of insecticide resistance in Guangzhou after 2014. In this study, Ae. albopictus were collected from four districts with varied dengue virus transmission intensity in Guangzhou from 2015 to 2017. Adult Ae. albopictus insecticide susceptibility to deltamethrin (0.03%), permethrin(0.25%), DDT(4%), malathion (0.8%) and bendiocarb (0.1%) was determined by the standard WHO tube test, and larval resistance bioassays were conducted using temephos, Bacillus thuringiensis israelensis (Bti), pyriproxyfen (PPF) and hexaflumuron. Mutations at the voltage-gated sodium channel (VGSC) gene and acetylcholinesterase (AChE) gene were analyzed. The effect of cytochrome P450s on the resistance of Ae. albopictus to deltamethrin was tested using the synergistic agent piperonyl butoxide (PBO). The results showed that Ae. albopictus populations have rapidly developed very high resistances to multiple commonly used insecticides at all study areas except malathion, Bti and hexaflumuron. We found 1534 codon mutations in the VGSC gene that were significantly correlated with the resistance to pyrethroids and DDT, and 11 synonymous mutations were also found in the gene. The resistance to deltamethrin can be significantly reduced by PBO but may generated cross-resistance to PPF. Fast emerging resistance in Ae. albopictus may affect mosquito management and threaten the prevention and control of dengue, similar to the resistance in Anopheles mosquitoes has prevented the elimination of malaria and call for timely and guided insecticide management. Guangzhou is the most epidemic area of dengue in China. Massive insecticides have been used to control the vector mosquito Ae. albopictus, as no specific vaccines are available for dengue. Regular monitoring of insecticide susceptibility is essential for insecticide resistance management. In this study, the insecticide resistances of Ae. albopictus in Guangzhou were comparatively analyzed from 2015 to 2017. The results displayed that Ae. albopictus had rapidly generated high resistance to the most commonly used adult insecticide pyrethroid (deltamethrin and permethrin) and larvicide organophosphate (temephos). The combination of malathion for adult mosquitoes and Bti or hexaflumuron for larvae might be a better choice for vector control. Resistance to deltamethrin can be significantly reduced by PBO but may generated cross-resistance to PPF. F1534S and F1534L mutations in the VGSC gene were significantly correlated with resistance to pyrethroids. This study indicated that...
Rajib Chowdhury, Vashkar Chowdhury, Shyla Faria, Sakila Akter, Aditya Prasad Dash, Sujit Kumar Bhattacharya, Narayan Prosad Maheswary, Caryn Bern, Shireen Akhter, Jorge Alvar, et al.
PLOS Neglected Tropical Diseases, Volume 13; doi:10.1371/journal.pntd.0007724

Abstract:Visceral leishmaniasis (VL) is a parasitic disease, transmitted by the sand fly species Phlebotomus argentipes in the Indian sub-continent. Effective vector control is highly desirable to reduce vector density and human and vector contact in the endemic communities with the aim to curtail disease transmission. We evaluated the effect of long lasting insecticide treated bed nets (LLIN) and bed nets impregnated with slow-release insecticide tablet K-O TAB 1-2-3 (jointly insecticide-treated nets or ITN) on VL incidence in a highly endemic sub-district (upazila) in Bangladesh. Several distributions of LLIN or K-O TAB 1-2-3 for self-impregnation of bed nets at home took place in Fulbaria upazila, Mymensigh district from 2004 to 2008 under three research projects, respectively funded by CDC, Atlanta, USA (2004) and WHO-TDR, Geneva, Switzerland (2006 & 2008). We included all households (n = 8142) in the 20 villages that had benefited in the past from one of these interventions (1295 donated LLIN and 11,918 local bed nets impregnated with K-O TAB 1-2-3) in the “exposed cohort”. We recruited a “non-exposed cohort” in villages with contemporaneously similar incidence rates who had not received such vector control interventions (7729 HHs from nine villages). In both cohorts, we visited all families house to house and ascertained any VL cases for the 3 year period before and after the intervention. We evaluated the incidence rate (IR) of VL in both cohorts as primary endpoint, applying the difference-in-differences method. The study identified 1011 VL cases (IR 140.47/10,000 per year [py]) before the intervention, of which 534 and 477 cases in the intervention and control areas respectively. The IR was 144.13/10,000 py (534/37050) and 136.59/10,000 py (477/34923) in the intervention and control areas respectively, with no significant difference (p = 0.3901) before the intervention. After the intervention, a total of 555 cases (IR 77.11/10,000 py) were identified of which 178 (IR 48.04/10,000 py) in the intervention and 377 (107.95/10,000 py) in the control area. The intervention area had a significant lower IR than the control area during follow up, rate difference = –59.91, p<0.0001. The IR during follow up was significantly reduced by 96.09/10,000 py in the intervention area (p<0.0001) and 28.63/10,000 py in control area (p<0.0001) compared to baseline. There was a strong and significant overall effect of the ITN intervention, δ = –67.45, p <0.0001. Sex (OR = 1.36, p<0.0001) and age (OR = 0.99, p<0.0001) also had a significant effect on VL incidence. Male had a higher risk of VL than female and one year increase in age decreased the likelihood of VL by about 0.92%. Two third of the VL incidence occurred in the age range 2 to 30 years (median age of VL patients was 17 years). VL incidence rate was significantly lower in the ITN intervention cohort compared to control in Bangladesh. Some bias due to more intense screen-and-treat activities...