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Community-based sero-prevalence of chikungunya and yellow fever in the South Omo Valley of Southern Ethiopia

PLoS Neglected Tropical Diseases News - 3 September 2020 - 9:00pm

by Adugna Endale, Daniela Michlmayr, Woldaregay Erku Abegaz, Getahun Asebe, James W. Larrick, Girmay Medhin, Mengistu Legesse

Background

Chikungunya (CHIK) and yellow fever (YF) are becoming major public health threats in East African countries including Ethiopia. In Ethiopia, there is no reliable information about the epidemiology of CHIK. This study aimed to assess a community-based sero-prevalence of CHIK and YF in the South Omo Valley, an endemic area for YF.

Methods

Between February and June 2018, blood samples were collected from study participants and screened for IgG antibody against CHIK virus (CHIKV) and YF virus (YFV) infections using ELISA. Data were computerized using Epi Data Software v.3.1 and analyzed using SPSS.

Results

A total of 360 participants (51.7% males, age range from 6 to 80, mean age ± SD = 31.95 ± 14.05 years) participated in this study. The overall sero-prevalence of IgG antibody was 43.6% (157/360) against CHIKV, while it was 49.5% (155/313) against YFV. Out of 155 samples which were positive for IgG antibody to YFV, 93 (60.0%) were positive for IgG antibody to CHIKV. Out of 158 samples which were negative for IgG antibody to YFV, 64(40.5%) were positive for IgG antibody to CHIKV. There was a significant positive correlation between IgG antibodies to CHIKV and YFV (sr = 0.82; P<0.01). Residency in the Debub Ari district (AOR = 8.47; 95% CI: 1.50, 47.74) and travel history to sylvatic areas (AOR = 2.21; 95% CI: 1.02, 4.81) were significantly and positively associated with high sero-prevalence of IgG antibody to CHIKV and YFV, respectively.

Conclusion

High sero-prevalence of IgG antibody to CHIKV shows the circulation of the virus in the present study area. A low sero-prevalence of IgG antibody to YFV in YF vaccine received individuals is highly concerning from a public health point of view as waning of immune response to YFV infection could result in a periodic outbreaks of YF in endemic areas.Nevertheless, the present study has not investigated for possible cross-reactivity of antibody to CHIKV with other alphaviruses like O’nyong-nyong virus and antibody to YFV with other flaviviruses like Dengue fever virus and this warrants further studies in the present study area.

A cost-analysis of conducting population-based prevalence surveys for the validation of the elimination of trachoma as a public health problem in Amhara, Ethiopia

PLoS Neglected Tropical Diseases News - 3 September 2020 - 9:00pm

by Randall P. Slaven, Aisha E. P. Stewart, Mulat Zerihun, Eshetu Sata, Tigist Astale, Berhanu Melak, Melsew Chanyalew, Demelash Gessese, Paul M. Emerson, Zerihun Tadesse, E. Kelly Callahan, Scott D. Nash, Deborah A. McFarland

Background

Trachoma prevalence surveys, including impact surveys (TIS) and surveillance surveys (TSS), provide information to program managers on the impact of the SAFE (surgery, antibiotics, facial cleanliness, and environmental improvement) strategy and current burden of disease, and they provide a crucial component of the evidence base necessary for the validation of the elimination of trachoma as a public health problem. The prevalence surveys included in this analysis are multi-level cluster random surveys that provide population-based estimates for program planning. This study conducted an analysis of the cost of 8 rounds of TIS/TSS executed in Amhara, Ethiopia, 2012–2016, comprising 232,357 people examined over 1,828 clusters in 187 districts.

Methodology and findings

Cost data were collected retrospectively from accounting and procurement records from the implementing partner, The Carter Center, and coded by survey activity (i.e. training and field work) and input category (i.e. personnel, transportation, supplies, venue rental, and other). Estimates of staff time were obtained from The Carter Center Ethiopia. Data were analyzed by activity and input category. The mean total cost per cluster surveyed was $752 (standard deviation $101). Primary cost drivers were personnel (39.6%) and transportation (49.2%), with costs increasing in the last 3 rounds of TIS/TSS.

Conclusion

Despite the considerable cost of conducting TIS and TSS, these surveys provide necessary information for program managers. Limited options are available to reduce the costs of TIS/TSS and gain economies of scale, as the surveys must be designed to achieve their designated sample size. However, surveys must also be designed in a way that is possible to be executed given the financial resources, personnel, and time required. Program managers can use these findings to improve estimates of the total cost of a survey and its components to ensure that sufficient resources are budgeted accordingly.

A new Korean Research Investment for Global Health Technology (RIGHT) Fund to advance innovative neglected-disease technologies

PLoS Neglected Tropical Diseases News - 3 September 2020 - 9:00pm

by Peter J. Hotez, Kim Bush, Andrin Oswald, Glenn Rockman, In-taek Lim, Youngmee Jee, Chang Jin Moon, Jerome H. Kim, Younbeen Kim

In 2018, the government of the Republic of Korea (ROK), South Korean life science companies, and a group of international funders led by the Bill & Melinda Gates Foundation launched a new and innovative funding agency to support neglected-disease research and development (R&D). The new venture is known as the Research Investment for Global Health Technology (RIGHT) Fund.

Meta-analyses of <i>Schistosoma japonicum</i> infections in wild rodents across China over time indicates a potential challenge to the 2030 elimination targets

PLoS Neglected Tropical Diseases News - 2 September 2020 - 9:00pm

by Hui-Ying Zou, Qiu-Fu Yu, Chen Qiu, Joanne P. Webster, Da-Bing Lu

China once suffered greatly from schistosomiasis japonica, a major zoonotic disease. Nearly 70 years of multidisciplinary efforts have achieved great progress in disease control, with infections in both humans and bovines significantly reduced to very low levels. However, reaching for the target of complete interruption of transmission at the country level by 2030 still faces great challenges, with areas of ongoing endemicity and/or re-emergence within previously ‘eliminated’ regions. The objectives of this study were, by using meta-analytical methods, to estimate the overall prevalence of Schistosoma japonicum infections in abundant commensal rodent species in mainland China after the introduction of praziquantel for schistosomiasis treatment in humans and bovines in 1980s. In doing so we thereby aimed to further assess the role of wild rodents as potential reservoirs in ongoing schistosome transmission. Published studies on infection prevalence of S. japonicum in wild rodents in mainland China since 1980 were searched across five electronic bibliographic databases and lists of article references. Eligible studies were selected based on inclusion and exclusion criteria. Risks of within and across study biases, and the variations in prevalence estimates attributable to heterogeneities were assessed. The pooled infection prevalence and its 95% confidence intervals (CIs) were calculated with the Freeman-Tukey double arcsine transformation. We identified a total of 37 relevant articles involving 61 field studies which contained eligible data on 8,795 wild rodents across mainland China. The overall pooled infection prevalence was 3.86% (95% CI: 2.16–5.93%). No significant change in the overall pooled prevalence was observed between 1980–2003 (n = 23 studies) and 2004-current (n = 38 studies). However, whilst the estimated prevalence decreased over time in the marshland and lake regions, there was an apparent increase in prevalence within hilly and mountainous regions. Among seven provinces, a significant prevalence reduction was only seen in Jiangsu where most endemic settings are classified as the marshland and lakes. These estimates changed over season, ranging from 0.58% in spring to 22.39% in winter, in association with increases in rodent density. This study systematically analyzed S. japonicum infections in wild rodents from the published literature over the last forty years after the introduction of praziquantel for schistosomiasis treatment in humans and bovines in 1980s. Although numbers of schistosomiasis cases in humans and bovines have been greatly reduced, no such comparable overall change of infection prevalence in rodents was detected. Furthermore, there appeared to be an increase in S. japonicum prevalence in rodents over time within hilly and mountainous regions. Rodents have been projected to become the dominant wildlife in human-driven environments and the main reservoir of zoonotic diseases in general within tropical zones. Our findings thus suggest that it is now necessary to include monitoring and evaluation of potential schistosome infection within rodents, particularly in hilly and mountainous regions, if we are ever to reach the new 2030 elimination goals and to maximize the impact of future public, and indeed One Health, interventions across, regional, national and international scales.

Seroprevalence of antibodies against <i>Chlamydia trachomatis</i> and enteropathogens and distance to the nearest water source among young children in the Amhara Region of Ethiopia

PLoS Neglected Tropical Diseases News - 2 September 2020 - 9:00pm

by Kristen Aiemjoy, Solomon Aragie, Dionna M. Wittberg, Zerihun Tadesse, E. Kelly Callahan, Sarah Gwyn, Diana Martin, Jeremy D. Keenan, Benjamin F. Arnold

The transmission of trachoma, caused by repeat infections with Chlamydia trachomatis, and many enteropathogens are linked to water quantity. We hypothesized that children living further from a water source would have higher exposure to C. trachomatis and enteric pathogens as determined by antibody responses. We used a multiplex bead assay to measure IgG antibody responses to C. trachomatis, Giardia intestinalis, Cryptosporidium parvum, Entamoeba histolytica, Salmonella enterica, Campylobacter jejuni, enterotoxigenic Escherichia coli (ETEC) and Vibrio cholerae in eluted dried blood spots collected from 2267 children ages 0–9 years in 40 communities in rural Ethiopia in 2016. Linear distance from the child’s house to the nearest water source was calculated. We derived seroprevalence cutoffs using external negative control populations, if available, or by fitting finite mixture models. We used targeted maximum likelihood estimation to estimate differences in seroprevalence according to distance to the nearest water source. Seroprevalence among 1–9-year-olds was 43% for C. trachomatis, 28% for S. enterica, 70% for E. histolytica, 54% for G. intestinalis, 96% for C. jejuni, 76% for ETEC and 94% for C. parvum. Seroprevalence increased with age for all pathogens. Median distance to the nearest water source was 473 meters (IQR 268, 719). Children living furthest from a water source had a 12% (95% CI: 2.6, 21.6) higher seroprevalence of S. enterica and a 12.7% (95% CI: 2.9, 22.6) higher seroprevalence of G. intestinalis compared to children living nearest. Seroprevalence for C. trachomatis and enteropathogens was high, with marked increases for most enteropathogens in the first two years of life. Children living further from a water source had higher seroprevalence of S. enterica and G. intestinalis indicating that improving access to water in the Ethiopia’s Amhara region may reduce exposure to these enteropathogens in young children.

Correction: Female genital schistosomiasis and HIV/AIDS: Reversing the neglect of girls and women

PLoS Neglected Tropical Diseases News - 1 September 2020 - 9:00pm

by Peter J. Hotez, Wendy Harrison, Alan Fenwick, Amaya L. Bustinduy, Camilla Ducker, Pamela Sabina Mbabazi, Dirk Engels, Eyrun Floerecke Kjetland

Correction: LAMP-2 absence interferes with plasma membrane repair and decreases T. cruzi host cell invasion

PLoS Neglected Tropical Diseases News - 1 September 2020 - 9:00pm

by Natália Fernanda do Couto, Dina Pedersane, Luisa Rezende, Patrícia P. Dias, Tayanne L. Corbani, Lívia C. Bentini, Anny C. S. Oliveira, Ludmila F. Kelles, Thiago Castro-Gomes, Luciana O. Andrade

Correction: Geographic and socioeconomic factors associated with leprosy treatment default: An analysis from the 100 Million Brazilian Cohort

PLoS Neglected Tropical Diseases News - 1 September 2020 - 9:00pm

by Kaio Vinicius Freitas de Andrade, Joilda Silva Nery, Julia Moreira Pescarini, Anna Ramond, Carlos Antônio de Souza Teles Santos, Maria Yury Ichihara, Maria Lucia Fernandes Penna, Elizabeth B. Brickley, Laura C. Rodrigues, Liam Smeeth, Mauricio L. Barreto, Susan Martins Pereira, Gerson Oliveira Penna

Correction: Increased Von Willebrand factor, decreased ADAMTS13 and thrombocytopenia in melioidosis

PLoS Neglected Tropical Diseases News - 1 September 2020 - 9:00pm

by Emma Birnie, Gavin C. K. W. Koh, Ester C. Löwenberg, Joost C. M. Meijers, Rapeephan R. Maude, Nicholas P. J. Day, Sharon J. Peacock, Tom van der Poll, W. Joost Wiersinga

Correction: Schistosoma species detection by environmental DNA assays in African freshwaters

PLoS Neglected Tropical Diseases News - 1 September 2020 - 9:00pm

by Hind Alzaylaee, Rupert A. Collins, Gabriel Rinaldi, Asilatu Shechonge, Benjamin Ngatunga, Eric R. Morgan, Martin J. Genner

Correction: Preclinical antivenom-efficacy testing reveals potentially disturbing deficiencies of snakebite treatment capability in East Africa

PLoS Neglected Tropical Diseases News - 31 August 2020 - 9:00pm

by Robert A. Harrison, George O. Oluoch, Stuart Ainsworth, Jaffer Alsolaiss, Fiona Bolton, Ana-Silvia Arias, José-María Gutiérrez, Paul Rowley, Stephen Kalya, Hastings Ozwara, Nicholas R. Casewell

Molecular action of pyriproxyfen: Role of the Methoprene-tolerant protein in the pyriproxyfen-induced sterilization of adult female mosquitoes

PLoS Neglected Tropical Diseases News - 31 August 2020 - 9:00pm

by Tahmina Hossain Ahmed, T. Randolph Saunders, Donald Mullins, Mohammad Zillur Rahman, Jinsong Zhu

Exposure of adult mosquitoes to pyriproxyfen (PPF), an analog of insect juvenile hormone (JH), has shown promise to effectively sterilize female mosquitoes. However, the underlying mechanisms of the PPF-induced decrease in mosquito fecundity are largely unknown. We performed a comprehensive study to dissect the mode of PPF action in Aedes aegypti mosquitoes. Exposure to PPF prompted the overgrowth of primary follicles in sugar-fed Ae. aegypti females but blocked the development of primary follicles at Christopher’s Stage III after blood feeding. Secondary follicles were precociously activated in PPF-treated mosquitoes. Moreover, PPF substantially altered the expression of many genes that are essential for mosquito physiology and oocyte development in the fat body and ovary. In particular, many metabolic genes were differentially expressed in response to PPF treatment, thereby affecting the mobilization and utilization of energy reserves. Furthermore, PPF treatment on the previtellogenic female adults considerably modified mosquito responses to JH and 20-hydroxyecdysone (20E), two major hormones that govern mosquito reproduction. Krüppel homolog 1, a JH-inducible transcriptional regulator, showed consistently elevated expression after PPF exposure. Conversely, PPF upregulated the expression of several key players of the 20E regulatory cascades, including HR3 and E75A, in the previtellogenic stage. After blood-feeding, the expression of these 20E response genes was significantly weaker in PPF-treated mosquitoes than the solvent-treated control groups. RNAi-mediated knockdown of the Methoprene-tolerant (Met) protein, the JH receptor, partially rescued the impaired follicular development after PPF exposure and substantially increased the hatching of the eggs produced by PPF-treated female mosquitoes. Thus, the results suggested that PPF relied on Met to exert its sterilizing effects on female mosquitoes. In summary, this study finds that PPF exposure disturbs normal hormonal responses and metabolism in Ae. aegypti, shedding light on the molecular targets and the downstream signaling pathways activated by PPF.

Household spraying in cholera outbreaks: Insights from three exploratory, mixed-methods field effectiveness evaluations

PLoS Neglected Tropical Diseases News - 31 August 2020 - 9:00pm

by Karin Gallandat, Annie Huang, Justine Rayner, Gabrielle String, Daniele S. Lantagne

Household spraying is a commonly implemented, yet an under-researched, cholera response intervention where a response team sprays surfaces in cholera patients’ houses with chlorine. We conducted mixed-methods evaluations of three household spraying programs in the Democratic Republic of Congo and Haiti, including 18 key informant interviews, 14 household surveys and observations, and 418 surface samples collected before spraying, 30 minutes and 24 hours after spraying. The surfaces consistently most contaminated with Vibrio cholerae were food preparation areas, near the patient’s bed and the latrine. Effectiveness varied between programs, with statistically significant reductions in V. cholerae concentrations 30 minutes after spraying in two programs. Surface contamination after 24 hours was variable between households and programs. Program challenges included difficulty locating households, transportation and funding limitations, and reaching households quickly after case presentation (disinfection occurred 2–6 days after reported cholera onset). Program advantages included the concurrent deployment of hygiene promotion activities. Further research is indicated on perception, recontamination, cost-effectiveness, viable but nonculturable V. cholerae, and epidemiological coverage. We recommend that, if spraying is implemented, spraying agents should: disinfect surfaces systematically until wet using 0.2/2.0% chlorine solution, including kitchen spaces, patients’ beds, and latrines; arrive at households quickly; and, concurrently deploy hygiene promotion activities.

The Ras/ERK signaling pathway couples antimicrobial peptides to mediate resistance to dengue virus in <i>Aedes</i> mosquitoes

PLoS Neglected Tropical Diseases News - 31 August 2020 - 9:00pm

by Wen-Quan Liu, Si-Qi Chen, Hao-Qiang Bai, Qi-Mei Wei, Sheng-Nan Zhang, Chen Chen, Yi-Han Zhu, Tang-Wei Yi, Xiao-Pu Guo, Si-Yuan Chen, Meng-Jie Yin, Chen-Feng Sun, Shao-Hui Liang

Aedes mosquitoes can transmit dengue and several other severe vector-borne viral diseases, thereby influencing millions of people worldwide. Insects primarily control and clear the viral infections via their innate immune systems. Mitogen-Activated Protein Kinases (MAPKs) and antimicrobial peptides (AMPs) are both evolutionarily conserved components of the innate immune systems. In this study, we investigated the role of MAPKs in Aedes mosquitoes following DENV infection by using genetic and pharmacological approaches. We demonstrated that knockdown of ERK, but not of JNK or p38, significantly enhances the viral replication in Aedes mosquito cells. The Ras/ERK signaling is activated in both the cells and midguts of Aedes mosquitoes following DENV infection, and thus plays a role in restricting the viral infection, as both genetic and pharmacological activation of the Ras/ERK pathway significantly decreases the viral titers. In contrast, inhibition of the Ras/ERK pathway enhances DENV infection. In addition, we identified a signaling crosstalk between the Ras/ERK pathway and DENV-induced AMPs in which defensin C participates in restricting DENV infection in Aedes mosquitoes. Our results reveal that the Ras/ERK signaling pathway couples AMPs to mediate the resistance of Aedes mosquitoes to DENV infection, which provides a new insight into understanding the crosstalk between MAPKs and AMPs in the innate immunity of mosquito vectors during the viral infection.

Incidence, clinical course and risk factor for recurrent PCR positivity in discharged COVID-19 patients in Guangzhou, China: A prospective cohort study

PLoS Neglected Tropical Diseases News - 31 August 2020 - 9:00pm

by Jiazhen Zheng, Rui Zhou, Fengjuan Chen, Guofang Tang, Keyi Wu, Furong Li, Huamin Liu, Jianyun Lu, Jiyuan Zhou, Ziying Yang, Yuxin Yuan, Chunliang Lei, Xianbo Wu

The phenomenon of COVID-19 patients tested positive for SARS-CoV-2 after discharge (redetectable as positive, RP) emerged globally. The data of incidence rate and risk factors for RP event and the clinical features of RP patients may provide recommendations for virus containment and cases management for COVID-19. We prospectively collected and analyzed the epidemiological, clinical and virological data from 285 adult patients with COVID-19 and acquired their definite clinical outcome (getting PCR positive or not during post-discharge surveillance). By March 10, 27 (9.5%) discharged patients had tested positive for SARS-CoV-2 in their nasopharyngeal swab after a median duration of 7·0 days (IQR 5·0–8·0). Compared to first admission, RP patients generally had milder clinical symptoms, lower viral load, shorter length of stay and improved pulmonary conditions at readmission (p<0.05). Elder RP patients (≥ 60 years old) were more likely to be symptomatic compared to younger patients (7/8, 87.5% vs. 3/19, 18.8%, p = 0.001) at readmission. Age, sex, epidemiological history, clinical symptoms and underlying diseases were similar between RP and non-RP patients (p>0.05). A prolonged duration of viral shedding (>10 days) during the first hospitalization [adjusted odds ratio [aOR]: 5.82, 95% confidence interval [CI]: 2.50–13.57 for N gene; aOR: 9.64, 95% CI: 3.91–23.73 for ORF gene] and higher Ct value (ORF) in the third week of the first hospitalization (aOR: 0.69; 95% CI: 0.50–0.95) were associated with RP events. In conclusion, RP events occurred in nearly 10% of COVID-19 patients shortly after the negative tests, were not associated with worsening symptoms and unlikely reflect reinfection. Patients’ lack of efficiency in virus clearance was a risk factor for RP result. It is noteworthy that elder RP patients (≥ 60 years old) were more susceptible to clinical symptoms at readmission.

CRISPR-mediated Transfection of <i>Brugia malayi</i>

PLoS Neglected Tropical Diseases News - 31 August 2020 - 9:00pm

by Canhui Liu, Alexandra Grote, Elodie Ghedin, Thomas R. Unnasch

The application of reverse genetics in the human filarial parasites has lagged due to the difficult biology of these organisms. Recently, we developed a co-culture system that permitted the infective larval stage of Brugia malayi to be transfected and efficiently develop to fecund adults. This was exploited to develop a piggyBac transposon-based toolkit that can be used to produce parasites with transgene sequences stably integrated into the parasite genome. However, the piggyBac system has generally been supplanted by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) based technology, which allows precise editing of a genome. Here we report adapting the piggyBac mediated transfection system of B. malayi for CRISPR mediated knock-in insertion into the parasite genome. Suitable CRISPR insertion sites were identified in intergenic regions of the B. malayi genome. A dual reporter piggybac vector was modified, replacing the piggyBac inverted terminal repeat regions with sequences flanking the insertion site. B. malayi molting L3 were transfected with a synthetic guide RNA, the modified plasmid and the CAS9 nuclease. The transfected parasites were implanted into gerbils and allowed to develop into adults. Progeny microfilariae were recovered and screened for expression of a secreted luciferase reporter encoded in the plasmid. Approximately 3% of the microfilariae were found to secrete luciferase; all contained the transgenic sequences inserted at the expected location in the parasite genome. Using an adaptor mediated PCR assay, transgenic microfilariae were examined for the presence of off target insertions; no off-target insertions were found. These data demonstrate that CRISPR can be used to modify the genome of B. malayi, opening the way to precisely edit the genome of this important human filarial parasite.

The COVID-19 pandemic should not derail global vector control efforts

PLoS Neglected Tropical Diseases News - 31 August 2020 - 9:00pm

by Frederik Seelig, Haroldo Bezerra, Mary Cameron, Jeffrey Hii, Alexandra Hiscox, Seth Irish, Robert T. Jones, Trudie Lang, Steven W. Lindsay, Rachel Lowe, Tanaka Manikidza Nyoni, Grace M. Power, Juliana Quintero, Anna M. Stewart-Ibarra, Lucy S. Tusting, Scott Tytheridge, James G. Logan

<i>In vivo</i> experiments demonstrate the potent antileishmanial efficacy of repurposed suramin in visceral leishmaniasis

PLoS Neglected Tropical Diseases News - 31 August 2020 - 9:00pm

by Supriya Khanra, Subir Kumar Juin, Junaid Jibran Jawed, Sweta Ghosh, Shreyasi Dutta, Shaik Abdul Nabi, Jyotirmayee Dash, Dipak Dasgupta, Subrata Majumdar, Rahul Banerjee

Background

Treatment failure and resistance to the commonly used drugsremains a major obstacle for successful chemotherapy against visceral leishmaniasis (VL). Since the development of novel therapeutics involves exorbitant costs, the effectiveness of the currently available antitrypanosomatid drug suramin has been investigated as an antileishmanial, specifically for VL,in vitro and in animal model experiments.

Methodology/Principal

Leishmaniadonovanipromastigotes were treated with suramin and studieswere performed to determine the extent and mode of cell mortality, cell cycle arrest and other invitroparameters. In addition, L. donovani infected BALB/c mice were administered suramin and a host of immunological parameters determined to estimate the antileishmanial potency of the drug. Finally, isothermal titration calorimetry (ITC)and enzymatic assays were used to probe the interaction of the drug with one of its putative targets namely parasitic phosphoglycerate kinase (LmPGK).

Findings

The in vitro studiesrevealed the potential efficacy of suramin against theLeishmaniaparasite. This observation was further substantiated in the in vivomurine model, which demonstrated thatupon suramin administration, the Leishmania infected BALB/c mice were able to reduce the parasitic burden and alsogenerate the host protective immunological responses. ITC and enzyme assays confirmed the binding and consequent inhibition of LmPGK due to the drug.

Conclusions/Significance

Allexperiments affirmed the efficacy ofsuramin againstL. donovani infection, which could possibly lead to its inclusion in the repertoire of drugs against VL.

Telacebec (Q203)-containing intermittent oral regimens sterilized mice infected with <i>Mycobacterium ulcerans</i> after only 16 doses

PLoS Neglected Tropical Diseases News - 31 August 2020 - 9:00pm

by Aurélie Chauffour, Jérôme Robert, Nicolas Veziris, Alexandra Aubry, Kevin Pethe, Vincent Jarlier

Buruli ulcer (BU), caused by Mycobacterium ulcerans, is currently treated with a daily combination of rifampin and either injectable streptomycin or oral clarithromycin. An intermittent oral regimen would facilitate treatment supervision. We first evaluated the bactericidal activity of newer antimicrobials against M. ulcerans using a BU animal model. The imidazopyridine amine telacebec (Q203) exhibited high bactericidal activity whereas tedizolid (an oxazolidinone closely related to linezolid), selamectin and ivermectin (two avermectine compounds) and the benzothiazinone PBTZ169 were not active. Consequently, telacebec was evaluated for its bactericidal and sterilizing activities in combined intermittent regimens. Telacebec given twice a week in combination with a long-half-life compound, either rifapentine or bedaquiline, sterilized mouse footpads in 8 weeks, i.e. after a total of only 16 doses, and prevented relapse during a period of 20 weeks after the end of treatment. These results are very promising for future intermittent oral regimens which would greatly simplify BU treatment in the field.

An <i>in vitro</i> α-neurotoxin—nAChR binding assay correlates with lethality and <i>in vivo</i> neutralization of a large number of elapid neurotoxic snake venoms from four continents

PLoS Neglected Tropical Diseases News - 28 August 2020 - 9:00pm

by Kritsada Pruksaphon, Kae Yi Tan, Choo Hock Tan, Pavinee Simsiriwong, José María Gutiérrez, Kavi Ratanabanangkoon

The aim of this study was to develop an in vitro assay for use in place of in vivo assays of snake venom lethality and antivenom neutralizing potency. A novel in vitro assay has been developed based on the binding of post-synaptically acting α-neurotoxins to nicotinic acetylcholine receptor (nAChR), and the ability of antivenoms to prevent this binding. The assay gave high correlation in previous studies with the in vivo murine lethality tests (Median Lethal Dose, LD50), and the neutralization of lethality assays (Median Effective Dose, ED50) by antisera against Naja kaouthia, Naja naja and Bungarus candidus venoms. Here we show that, for the neurotoxic venoms of 20 elapid snake species from eight genera and four continents, the in vitro median inhibitory concentrations (IC50s) for α-neurotoxin binding to purified nAChR correlated well with the in vivo LD50s of the venoms (R2 = 0.8526, p < 0.001). Furthermore, using this assay, the in vitro ED50s of a horse pan-specific antiserum against these venoms correlated significantly with the corresponding in vivo murine ED50s, with R2 = 0.6896 (p < 0.01). In the case of four elapid venoms devoid or having a very low concentration of α-neurotoxins, no inhibition of nAChR binding was observed. Within the philosophy of 3Rs (Replacement, Reduction and Refinement) in animal testing, the in vitro α-neurotoxin-nAChR binding assay can effectively substitute the mouse lethality test for toxicity and antivenom potency evaluation for neurotoxic venoms in which α-neurotoxins predominate. This will greatly reduce the number of mice used in toxicological research and antivenom production laboratories. The simpler, faster, cheaper and less variable in vitro assay should also expedite the development of pan-specific antivenoms against various medically important snakes in many parts of the world.

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