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LAMP-2 absence interfere with plasma membrane repair and decreases <i>T</i>. <i>cruzi</i> host cell invasion

PLoS Neglected Tropical Diseases News - 6 June 2017 - 9:00pm

by Natália Fernando 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

Trypanosoma cruzi enters host cells by subverting the mechanism of cell membrane repair. In this process, the parasite induces small injuries in the host cell membrane leading to calcium entry and lysosomal exocytosis, which are followed by compensatory endocytosis events that drive parasites into host cells. We have previously shown that absence of both LAMP-1 and 2, major components of lysosomal membranes, decreases invasion of T. cruzi into host cells, but the mechanism by which they interfere with parasite invasion has not been described. Here we investigated the role of these proteins in parasitophorous vacuole morphology, host cell lysosomal exocytosis, and membrane repair ability. First, we showed that cells lacking only LAMP-2 present the same invasion phenotype as LAMP1/2-/- cells, indicating that LAMP-2 is an important player during T. cruzi invasion process. Second, neither vacuole morphology nor lysosomal exocytosis was altered in LAMP-2 lacking cells (LAMP2-/- and LAMP1/2-/- cells). We then investigated the ability of LAMP-2 deficient cells to perform compensatory endocytosis upon lysosomal secretion, the mechanism by which cells repair their membrane and T. cruzi ultimately enters cells. We observed that these cells perform less endocytosis upon injury when compared to WT cells. This was a consequence of impaired cholesterol traffic in cells lacking LAMP-2 and its influence in the distribution of caveolin-1 at the cell plasma membrane, which is crucial for plasma membrane repair. The results presented here show the major role of LAMP-2 in caveolin traffic and membrane repair and consequently in T. cruzi invasion.

Transmission dynamics and control of <i>Rickettsia rickettsii</i> in populations of <i>Hydrochoerus hydrochaeris</i> and <i>Amblyomma sculptum</i>

PLoS Neglected Tropical Diseases News - 5 June 2017 - 9:00pm

by Gina Polo, Carlos Mera Acosta, Marcelo B. Labruna, Fernando Ferreira

Background

Brazilian Spotted Fever (BSF), caused by the bacterium Rickettsia rickettsii, is the tick-borne disease that generates the largest number of human deaths in the world. In Brazil, the current increase of BSF human cases has been associated with the presence and expansion of capybaras Hydrochoerus hydrochaeris, which act as primary hosts for the tick Amblyomma sculptum, vector of the R. rickettsii in this area.

Methods

We proposed a semi-discrete-time stochastic model to evaluate the role of capybaras in the transmission dynamics of R. rickettsii. Through a sensitivity analysis, we identified the parameters with significant influence on the R. rickettsii establishment. Afterward, we implemented the Gillespie’s algorithm to simulate the impact of potential public health interventions to prevent BSF human cases.

Results

The introduction of a single infected capybara with at least one infected attached tick is enough to trigger the disease in a non-endemic area. We found that to avoid the formation of new BSF-endemic areas, it is crucial to impede the emigration of capybaras from endemic areas by reducing their birth rate by more than 58%. Model results were corroborated by ex-situ data generated from field studies, and this supports our proposal to prevent BSF human cases by implementing control strategies focused on capybaras.

Conclusion

The proposed stochastic model illustrates how strategies for the control and prevention of vector-borne infectious diseases can be focused on amplifier hosts management practices. This work provides a basis for future prevention strategies for other neglected vector-borne diseases.

Accuracy of parasitological and immunological tests for the screening of human schistosomiasis in immigrants and refugees from African countries: An approach with Latent Class Analysis

PLoS Neglected Tropical Diseases News - 5 June 2017 - 9:00pm

by Anna Beltrame, Massimo Guerriero, Andrea Angheben, Federico Gobbi, Ana Requena-Mendez, Lorenzo Zammarchi, Fabio Formenti, Francesca Perandin, Dora Buonfrate, Zeno Bisoffi

Background

Schistosomiasis is a neglected infection affecting millions of people, mostly living in sub-Saharan Africa. Morbidity and mortality due to chronic infection are relevant, although schistosomiasis is often clinically silent. Different diagnostic tests have been implemented in order to improve screening and diagnosis, that traditionally rely on parasitological tests with low sensitivity. Aim of this study was to evaluate the accuracy of different tests for the screening of schistosomiasis in African migrants, in a non endemic setting.

Methodology/Principal findings

A retrospective study was conducted on 373 patients screened at the Centre for Tropical Diseases (CTD) in Negrar, Verona, Italy. Biological samples were tested with: stool/urine microscopy, Circulating Cathodic Antigen (CCA) dipstick test, ELISA, Western blot, immune-chromatographic test (ICT). Test accuracy and predictive values of the immunological tests were assessed primarily on the basis of the results of microscopy (primary reference standard): ICT and WB resulted the test with highest sensitivity (94% and 92%, respectively), with a high NPV (98%). CCA showed the highest specificity (93%), but low sensitivity (48%). The analysis was conducted also using a composite reference standard, CRS (patients classified as infected in case of positive microscopy and/or at least 2 concordant positive immunological tests) and Latent Class Analysis (LCA). The latter two models demonstrated excellent agreement (Cohen’s kappa: 0.92) for the classification of the results. In fact, they both confirmed ICT as the test with the highest sensitivity (96%) and NPV (97%), moreover PPV was reasonably good (78% and 72% according to CRS and LCA, respectively). ELISA resulted the most specific immunological test (over 99%). The ICT appears to be a suitable screening test, even when used alone.

Conclusions

The rapid test ICT was the most sensitive test, with the potential of being used as a single screening test for African migrants.

Increased miltefosine tolerance in clinical isolates of <i>Leishmania donovani</i> is associated with reduced drug accumulation, increased infectivity and resistance to oxidative stress

PLoS Neglected Tropical Diseases News - 2 June 2017 - 9:00pm

by Deepak Kumar Deep, Ruchi Singh, Vasundhra Bhandari, Aditya Verma, Vanila Sharma, Saima Wajid, Shyam Sundar, V. Ramesh, Jean Claude Dujardin, Poonam Salotra

Background

Miltefosine (MIL) is an oral antileishmanial drug used for treatment of visceral leishmaniasis (VL) in the Indian subcontinent. Recent reports indicate a significant decline in its efficacy with a high rate of relapse in VL as well as post kala-azar dermal leishmaniasis (PKDL). We investigated the parasitic factors apparently involved in miltefosine unresponsiveness in clinical isolates of Leishmania donovani.

Methodology

L. donovani isolated from patients of VL and PKDL at pretreatment stage (LdPreTx, n = 9), patients that relapsed after MIL treatment (LdRelapse, n = 7) and parasites made experimentally resistant to MIL (LdM30) were included in this study. MIL uptake was estimated using liquid chromatography coupled mass spectrometry. Reactive oxygen species and intracellular thiol content were measured fluorometrically. Q-PCR was used to assess the differential expression of genes associated with MIL resistance.

Results

LdRelapse parasites exhibited higher IC50 both at promastigote level (7.92 ± 1.30 μM) and at intracellular amastigote level (11.35 ± 6.48 μM) when compared with LdPreTx parasites (3.27 ± 1.52 μM) and (3.85 ± 3.11 μM), respectively. The percent infectivity (72 hrs post infection) of LdRelapse parasites was significantly higher (80.71 ± 5.67%, P<0.001) in comparison to LdPreTx (60.44 ± 2.80%). MIL accumulation was significantly lower in LdRelapse parasites (1.7 fold, P<0.001) and in LdM30 parasites (2.4 fold, P<0.001) when compared with LdPreTx parasites. MIL induced ROS levels were significantly lower (p<0.05) in macrophages infected with LdRelapse while intracellular thiol content were significantly higher in LdRelapse compared to LdPreTx, indicating a better tolerance for oxidative stress in LdRelapse isolates. Genes associated with oxidative stress, metabolic processes and transporters showed modulated expression in LdRelapse and LdM30 parasites in comparison with LdPreTx parasites.

Conclusion

The present study highlights the parasitic factors and pathways responsible for miltefosine unresponsiveness in VL and PKDL.

Radiological evolution of porcine neurocysticercosis after combined antiparasitic treatment with praziquantel and albendazole

PLoS Neglected Tropical Diseases News - 2 June 2017 - 9:00pm

by Carla Cangalaya, Javier A. Bustos, Juan Calcina, Ana Vargas-Calla, Javier Mamani, Diego Suarez, Gianfranco Arroyo, Armando E. Gonzalez, Juan Chacaltana, Cristina Guerra-Giraldez, Siddhartha Mahanty, Theodore E. Nash, Héctor H. García, for the Cysticercosis Working Group in Peru

Background

The onset of anthelmintic treatment of neurocysticercosis (NCC) provokes an acute immune response of the host, which in human cases is associated with exacerbation of neurological symptoms. This inflammation can occur at the first days of therapy. So, changes in the brain cysts appearance may be detected by medical imaging. We evaluated radiological changes in the appearance of brain cysts (enhancement and size) on days two and five after the onset of antiparasitic treatment using naturally infected pigs as a model for human NCC.

Methods and results

Contrast T1-weighted magnetic resonance imaging with gadolinium was performed before and after antiparasitic treatment. Eight NCC-infected pigs were treated with praziquantel plus albendazole and euthanized two (n = 4) and five (n = 4) days after treatment; another group of four infected pigs served as untreated controls. For each lesion, gadolinium enhancement intensity (GEI) and cyst volume were measured at baseline and after antiparasitic treatment. Volume and GEI quantification ratios (post/pre-treatment measures) were used to appraise the effect of treatment. Cysts from untreated pigs showed little variations between their basal and post treatment measures. At days 2 and 5 there were significant increases in GEI ratio compared with the untreated group (1.32 and 1.47 vs 1.01, p = 0.021 and p = 0.021). Cyst volume ratios were significantly lower at days 2 and 5 compared with the untreated group (0.60 and 0.22 vs 0.95, p = 0.04 and p = 0.02). Cysts with lower cyst volume ratios showed more marked post-treatment inflammation, loss of vesicular fluid and cyst wall wrinkling.

Conclusion/Significance

A significant and drastic reduction of cyst size and increased pericystic enhancement occur in the initial days after antiparasitic treatment as an effect of acute perilesional immune response. These significant changes showed that early anthelmintic efficacy (day two) can be detected using magnetic resonance imaging.

Ebola virus disease contact tracing activities, lessons learned and best practices during the Duport Road outbreak in Monrovia, Liberia, November 2015

PLoS Neglected Tropical Diseases News - 2 June 2017 - 9:00pm

by Caitlin M. Wolfe, Esther L. Hamblion, Jacqueline Schulte, Parker Williams, Augustine Koryon, Jonathan Enders, Varlee Sanor, Yatta Wapoe, Dash Kwayon, David Blackey, Anthony S. Laney, Emily J. Weston, Emily K. Dokubo, Gloria Davies-Wayne, Annika Wendland, Valerie T. S. Daw, Mehboob Badini, Peter Clement, Nuha Mahmoud, Desmond Williams, Alex Gasasira, Tolbert G. Nyenswah, Mosoka Fallah

Background

Contact tracing is one of the key response activities necessary for halting Ebola Virus Disease (EVD) transmission. Key elements of contact tracing include identification of persons who have been in contact with confirmed EVD cases and careful monitoring for EVD symptoms, but the details of implementation likely influence their effectiveness. In November 2015, several months after a major Ebola outbreak was controlled in Liberia, three members of a family were confirmed positive for EVD in the Duport Road area of Monrovia. The cluster provided an opportunity to implement and evaluate modified approaches to contact tracing.

Methods

The approaches employed for improved contact tracing included classification and risk-based management of identified contacts (including facility based isolation of some high risk contacts, provision of support to persons being monitored, and school-based surveillance for some persons with potential exposure but not listed as contacts), use of phone records to help locate missing contacts, and modifications to data management tools. We recorded details about the implementation of these approaches, report the overall outcomes of the contact tracing efforts and the challenges encountered, and provide recommendations for management of future outbreaks.

Results

165 contacts were identified (with over 150 identified within 48 hours of confirmation of the EVD cases) and all initially missing contacts were located. Contacts were closely monitored and promptly tested if symptomatic; no contacts developed disease. Encountered challenges related to knowledge gaps among contact tracing staff, data management, and coordination of contact tracing activities with efforts to offer Ebola vaccine.

Conclusions

The Duport Road EVD cluster was promptly controlled. Missing contacts were effectively identified, and identified contacts were effectively monitored and rapidly tested. There is a persistent risk of EVD reemergence in Liberia; the experience controlling each cluster can help inform future Ebola control efforts in Liberia and elsewhere.

Mosquito co-infection with Zika and chikungunya virus allows simultaneous transmission without affecting vector competence of <i>Aedes aegypti</i>

PLoS Neglected Tropical Diseases News - 1 June 2017 - 9:00pm

by Giel P. Göertz, Chantal B. F. Vogels, Corinne Geertsema, Constantianus J. M. Koenraadt, Gorben P. Pijlman

Background

Zika virus (ZIKV) and chikungunya virus (CHIKV) are highly pathogenic arthropod-borne viruses that are currently a serious health burden in the Americas, and elsewhere in the world. ZIKV and CHIKV co-circulate in the same geographical regions and are mainly transmitted by Aedes aegypti mosquitoes. There is a growing number of case reports of ZIKV and CHIKV co-infections in humans, but it is uncertain whether co-infection occurs via single or multiple mosquito bites. Here we investigate the potential of Ae. aegypti mosquitoes to transmit both ZIKV and CHIKV in one bite, and we assess the consequences of co-infection on vector competence.

Methodology/Principal findings

First, growth curves indicated that co-infection with CHIKV negatively affects ZIKV production in mammalian, but not in mosquito cells. Next, Ae. aegypti mosquitoes were infected with ZIKV, CHIKV, or co-infected via an infectious blood meal or intrathoracic injections. Infection and transmission rates, as well as viral titers of positive mosquitoes, were determined at 14 days after blood meal or 7 days after injection. Saliva and bodies of (co-)infected mosquitoes were scored concurrently for the presence of ZIKV and/or CHIKV using a dual-colour immunofluorescence assay. The results show that orally exposed Ae. aegypti mosquitoes are highly competent, with transmission rates of up to 73% for ZIKV, 21% for CHIKV, and 12% of mosquitoes transmitting both viruses in one bite. However, simultaneous oral exposure to both viruses did not change infection and transmission rates compared to exposure to a single virus. Intrathoracic injections indicate that the selected strain of Ae. aegypti has a strong salivary gland barrier for CHIKV, but a less profound barrier for ZIKV.

Conclusions/Significance

This study shows that Ae. aegypti can transmit both ZIKV and CHIKV via a single bite. Furthermore, co-infection of ZIKV and CHIKV does not influence the vector competence of Ae. aegypti.

Rabies surveillance in dogs in Lao PDR from 2010-2016

PLoS Neglected Tropical Diseases News - 1 June 2017 - 9:00pm

by Bounlom Douangngeun, Watthana Theppangna, Phouvong Phommachanh, Keo Chomdara, Sithong Phiphakhavong, Syseng Khounsy, Mavuto Mukaka, David A. B. Dance, Stuart D. Blacksell

Background

Rabies is a fatal viral disease that continues to threaten both human and animal health in endemic countries. The Lao People’s Democratic Republic (Lao PDR) is a rabies-endemic country in which dogs are the main reservoir and continue to present health risks for both human and animals throughout the country.

Methods

Passive, laboratory–based rabies surveillance was performed for suspected cases of dog rabies in Vientiane Capital during 2010–2016 and eight additional provinces between 2015–2016 using the Direct Fluorescent Antibody Test (DFAT).

Results

There were 284 rabies positive cases from 415 dog samples submitted for diagnosis. 257 cases were from Vientiane Capital (2010–2016) and the remaining 27 cases were submitted during 2015–2016 from Champassak (16 cases), Vientiane Province (4 cases) Xieng Kuang (3 cases) Luang Prabang (2 cases), Saravan (1 case), Saisomboun (1 case) and Bokeo (1 case). There was a significant increase in rabies cases during the dry season (p = 0.004) (November to April; i.e., <100mm of rainfall per month). No significant differences were noted between age, sex, locality of rabies cases.

Conclusion

The use of laboratory-based rabies surveillance is a useful method of monitoring rabies in Lao PDR and should be expanded to other provincial centers, particularly where there are active rabies control programs.

Prevalence of depression and associated clinical and socio-demographic factors in people living with lymphatic filariasis in Plateau State, Nigeria

PLoS Neglected Tropical Diseases News - 1 June 2017 - 9:00pm

by James Obindo, Jibril Abdulmalik, Emeka Nwefoh, Michael Agbir, Charles Nwoga, Aishatu Armiya’u, Francis Davou, Kurkat Maigida, Emmanuel Otache, Ajuma Ebiloma, Samuel Dakwak, John Umaru, Elisha Samuel, Christopher Ogoshi, Julian Eaton

Background

Lymphatic filariasis is a chronic, disabling and often disfiguring condition that principally impacts the world’s poorest people. In addition to the well-recognised physical disability associated with lymphedema and hydrocele, affected people often experience rejection, stigma and discrimination. The resulting emotional consequences are known to impact on the quality of life and the functioning of the affected individuals. However, the management of this condition has focused on prevention and treatment through mass drug administration, with scant attention paid to the emotional impact of the condition on affected individuals. This study aimed to determine the prevalence and severity of depression among individuals with physical disfigurement from lymphatic filariasis in Plateau State, Nigeria.

Methodology

A cross-sectional 2-stage convenience study was conducted at 5 designated treatment centers across Plateau State, Nigeria. All available and consenting clients with clearly visible physical disfigurement were recruited. A semi-structured socio-demographic questionnaire, Rosenberg Self-esteem and a 9-item Patient Health Questionnaire (PHQ-9) were administered at the first stage. Those who screened positive (with a PHQ-9 score of five and above) were further interviewed using the Depression module of the Composite International Diagnostic Interview (CIDI).

Results

Ninety-eight individuals met the criteria and provided consent. Twenty percent of the respondents met criteria for depression, with the following proportions based on severity: Mild (42.1%), Moderate (31.6%) and Severe (26.3%). History of mental illness (OR 40.83, p = 0.008); Median duration of the illness was 17 years (IQR 7.0–30 years) and being unemployed (OR 12.71, p = 0.003) were predictive of depression. High self-esteem was negatively correlated (OR 0.09, p<0.004).

Conclusion

Prevalence of depression is high among individuals with lymphatic filariasis and depression in sufferers is associated with low self-esteem and low levels of life satisfaction.

qPCR-High resolution melt analysis for drug susceptibility testing of <i>Mycobacterium leprae</i> directly from clinical specimens of leprosy patients

PLoS Neglected Tropical Diseases News - 1 June 2017 - 9:00pm

by Sergio Araujo, Luiz Ricardo Goulart, Richard W. Truman, Isabela Maria B. Goulart, Varalakshmi Vissa, Wei Li, Masanori Matsuoka, Philip Suffys, Amanda B. Fontes, Patricia S. Rosa, David M. Scollard, Diana L. Williams

Background

Real-Time PCR-High Resolution Melting (qPCR-HRM) analysis has been recently described for rapid drug susceptibility testing (DST) of Mycobacterium leprae. The purpose of the current study was to further evaluate the validity, reliability, and accuracy of this assay for M. leprae DST in clinical specimens.

Methodology/Principal findings

The specificity and sensitivity for determining the presence and susceptibility of M. leprae to dapsone based on the folP1 drug resistance determining region (DRDR), rifampin (rpoB DRDR) and ofloxacin (gyrA DRDR) was evaluated using 211 clinical specimens from leprosy patients, including 156 multibacillary (MB) and 55 paucibacillary (PB) cases. When comparing the results of qPCR-HRM DST and PCR/direct DNA sequencing, 100% concordance was obtained. The effects of in-house phenol/chloroform extraction versus column-based DNA purification protocols, and that of storage and fixation protocols of specimens for qPCR-HRM DST, were also evaluated. qPCR-HRM results for all DRDR gene assays (folP1, rpoB, and gyrA) were obtained from both MB (154/156; 98.7%) and PB (35/55; 63.3%) patients. All PCR negative specimens were from patients with low numbers of bacilli enumerated by an M. leprae-specific qPCR. We observed that frozen and formalin-fixed paraffin embedded (FFPE) tissues or archival Fite’s stained slides were suitable for HRM analysis. Among 20 mycobacterial and other skin bacterial species tested, only M. lepromatosis, highly related to M. leprae, generated amplicons in the qPCR-HRM DST assay for folP1 and rpoB DRDR targets. Both DNA purification protocols tested were efficient in recovering DNA suitable for HRM analysis. However, 3% of clinical specimens purified using the phenol/chloroform DNA purification protocol gave false drug resistant data. DNA obtained from freshly frozen (n = 172), formalin-fixed paraffin embedded (FFPE) tissues (n = 36) or archival Fite’s stained slides (n = 3) were suitable for qPCR-HRM DST analysis. The HRM-based assay was also able to identify mixed infections of susceptible and resistant M. leprae. However, to avoid false positives we recommend that clinical specimens be tested for the presence of the M. leprae using the qPCR-RLEP assay prior to being tested in the qPCR-HRM DST and that all specimens demonstrating drug resistant profiles in this assay be subjected to DNA sequencing.

Conclusion/Significance

Taken together these results further demonstrate the utility of qPCR-HRM DST as an inexpensive screening tool for large-scale drug resistance surveillance in leprosy.

Introducing the TrypanoGEN biobank: A valuable resource for the elimination of human African trypanosomiasis

PLoS Neglected Tropical Diseases News - 1 June 2017 - 9:00pm

by Hamidou Ilboudo, Harry Noyes, Julius Mulindwa, Magambo Phillip Kimuda, Mathurin Koffi, Justin Windingoudi Kaboré, Bernadin Ahouty, Dieudonné Mumba Ngoyi, Olivier Fataki, Gustave Simo, Elvis Ofon, John Enyaru, John Chisi, Kelita Kamoto, Martin Simuunza, Vincent P. Alibu, Veerle Lejon, Vincent Jamonneau, Annette Macleod, Mamadou Camara, Bruno Bucheton, Christiane Hertz-Fowler, Issa Sidibe, Enock Matovu, for the TrypanoGEN Research Group as members of The H3Africa Consortium

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