RSS news feeds

Endomyocardial involvement in asymptomatic sub-Saharan immigrants with helminth-related eosinophilia

PLoS Neglected Tropical Diseases News - 24 February 2017 - 10:00pm

by Cristina Carranza-Rodríguez, Daniel San-Román-Sánchez, Héctor Marrero-Santiago, Michele Hernández-Cabrera, Carlos Gil-Guillén, Elena Pisos-Álamo, Nieves Jaén-Sánchez, José-Luis Pérez-Arellano

Background

Among immigrants of sub-Saharan origin, parasitic infection is the leading cause of eosinophilia, which is generally interpreted as a defense mechanism. A side effect of the inflammatory mediators released by eosinophils is damage to host organs, especially the heart. The main objectives of this study were to i) assess cardiac involvement in asymptomatic sub-Saharan immigrants with eosinophilia, ii) relate the presence of lesions with the degree of eosinophilia, and iii) study the relationship between cardiac involvement and the type of causative parasite.

Methodology/Principle findings

In total, the study included 50 black immigrants (37 patients and 13 controls) from sub-Saharan Africa. In all subjects, heart structure and function were evaluated in a blinded manner using Sonos 5500 echocardiographic equipment. The findings were classified and described according to established criteria. The diagnostic criteria for helminthosis were those reported in the literature. Serum eosinophil-derived neurotoxin levels were measured using enzyme-linked immunosorbent assay. A significant association was found between the presence of eosinophilia and structural alterations (mitral valve thickening). However, the lack of an association between the degree of eosinophilia and heart valve disease and the absence of valve involvement in some patients with eosinophilia suggest the role of other factors in the appearance of endocardial lesions. There was also no association between the type of helminth and valve involvement.

Conclusions

We, therefore, suggest that transthoracic echocardiography be performed in every sub-Saharan individual with eosinophilia in order to rule out early heart valve lesions.

Experimental infection and transmission of <i>Leishmania</i> by <i>Lutzomyia cruzi</i> (Diptera: Psychodidae): Aspects of the ecology of parasite-vector interactions

PLoS Neglected Tropical Diseases News - 24 February 2017 - 10:00pm

by Everton Falcão de Oliveira, Elisa Teruya Oshiro, Wagner Souza Fernandes, Paula Guerra Murat, Márcio José de Medeiros, Alda Izabel Souza, Alessandra Gutierrez de Oliveira, Eunice Aparecida Bianchi Galati

Several parameters should be addressed before incriminating a vector for Leishmania transmission. Those may include its ability to become infected by the same Leishmania species found in humans, the degree of attractiveness for reservoirs and humans and capacity to sustain parasite infection under laboratory conditions. This study evaluated the vectorial capacity of Lutzomyia cruzi for Leishmania infantum and gathered information on its ability to harbor L. amazonensis. Laboratory-reared Lu. cruzi were infected experimentally by feeding them on dogs infected naturally with L. infantum and hamsters infected with L. amazonensis. Sand fly attractiveness to dogs and humans was determined using wild caught insects. The expected daily survival of infected Lu. cruzi, the duration of the gonotrophic cycle, and the extrinsic incubation period were also investigated for both parasites. Vector competence was investigated for both Leishmania species. The mean proportion of female sand flies that fed on hosts was 0.40. For L. infantum and L. amazonensis, Lu. cruzi had experimental infection rates of 10.55% and 41.56%, respectively. The extrinsic incubation period was 3 days for both Leishmania species, regardless of the host. Survival expectancy of females infected with L. infantum and L. amazonensis after completing the gonotrophic cycle was 1.32 and 0.43, respectively. There was no association between L. infantum infection and sand fly longevity, but L. amazonensis–infected flies had significantly greater survival probabilities. Furthermore, egg-laying was significantly detrimental to survival. Lu. cruzi was found to be highly attracted to both dogs and humans. After a bloodmeal on experimentally infected hosts, both parasites were able to survive and develop late-stage infections in Lu. cruzi. However, transmission was demonstrated only for L. amazonensis–infected sand flies. In conclusion, Lu. cruzi fulfilled several of the requirements of vectorial capacity for L. infantum transmission. Moreover, it was also permissive to L. amazonensis.

Immunization with Tc52 or its amino terminal domain adjuvanted with c-di-AMP induces Th17+Th1 specific immune responses and confers protection against <i>Trypanosoma cruzi</i>

PLoS Neglected Tropical Diseases News - 24 February 2017 - 10:00pm

by Marina N. Matos, Silvia I. Cazorla, Kai Schulze, Thomas Ebensen, Carlos A. Guzmán, Emilio L. Malchiodi

The development of new adjuvants enables fine modulation of the elicited immune responses. Ideally, the use of one or more adjuvants should result in the induction of a protective immune response against the specific pathogen. We have evaluated the immune response and protection against Trypanosoma cruzi infection in mice vaccinated with recombinant Tc52 or its N- and C-terminal domains (NTc52 and CTc52) adjuvanted either with the STING (Stimulator of Interferon Genes) agonist cyclic di-AMP (c-di-AMP), a pegylated derivative of α-galactosylceramide (αGC-PEG), or oligodeoxynucleotides containing unmethylated CpG motifs (ODN-CpG). All groups immunized with the recombinant proteins plus adjuvant: Tc52+c-di-AMP, NTc52+c-di-AMP, CTc52+c-di-AMP, NTc52+c-di-AMP+αGC-PEG, NTc52+CpG, developed significantly higher anti-Tc52 IgG titers than controls. Groups immunized with c-di-AMP and Tc52, NTc52 or CTc52 showed the highest Tc52-specific IgA titers in nasal lavages. All groups immunized with the recombinant proteins plus adjuvant developed a strong specific cellular immune response in splenocytes and lymph node cells with significant differences for groups immunized with c-di-AMP and Tc52, NTc52 or CTc52. These groups also showed high levels of Tc52-specific IL-17 and IFN-γ producing cells, while NTc52+CpG group only showed significant difference with control in IFN-γ producing cells. Groups immunized with c-di-AMP and Tc52, NTc52 or CTc52 developed predominantly a Th17 and Th1immune response, whereas for NTc52+CpG it was a dominant Th1 response. It was previously described that αGC-PEG inhibits Th17 differentiation by activating NKT cells. Thus, in this work we have also included a group immunized with both adjuvants (NTc52+c-di-AMP+αGC-PEG) with the aim to modulate the Th17 response induced by c-di-AMP. This group showed a significant reduction in the number of Tc52-specific IL-17 producing splenocytes, as compared to the group NTc52+c-di-AMP, which has in turn correlated with a reduction in protection against infection. These results suggest that the Th17 immune response developed after immunizing with NTc52+c-di-AMP could have a protective role against T. cruzi infection. Groups NTc52+c-di-AMP, Tc52+c-di-AMP and NTc52PB, were the ones that showed better protection against infection with lower parasitemia and weight loss, and higher survival.

Favipiravir pharmacokinetics in Ebola-Infected patients of the JIKI trial reveals concentrations lower than targeted

PLoS Neglected Tropical Diseases News - 23 February 2017 - 10:00pm

by Thi Huyen Tram Nguyen, Jérémie Guedj, Xavier Anglaret, Cédric Laouénan, Vincent Madelain, Anne-Marie Taburet, Sylvain Baize, Daouda Sissoko, Boris Pastorino, Anne Rodallec, Géraldine Piorkowski, Sara Carazo, Mamoudou N. Conde, Jean-Luc Gala, Joseph Akoi Bore, Caroline Carbonnelle, Frédéric Jacquot, Hervé Raoul, Denis Malvy, Xavier de Lamballerie, France Mentré, JIKI study group

Background

In 2014–2015, we assessed favipiravir tolerance and efficacy in patients with Ebola virus (EBOV) disease (EVD) in Guinea (JIKI trial). Because the drug had never been used before for this indication and that high concentrations of the drugs were needed to achieve antiviral efficacy against EBOV, a pharmacokinetic model had been used to propose relevant dosing regimen. Here we report the favipiravir plasma concentrations that were achieved in participants in the JIKI trial and put them in perspective with the model-based targeted concentrations.

Methods and findings

Pre-dose drug concentrations were collected at Day-2 and Day-4 of treatment in 66 patients of the JIKI trial and compared to those predicted by the model taking into account patient’s individual characteristics. At Day-2, the observed concentrations were slightly lower than the model predictions adjusted for patient’s characteristics (median value of 46.1 versus 54.3 μg/mL for observed and predicted concentrations, respectively, p = 0.012). However, the concentrations dropped at Day-4, which was not anticipated by the model (median values of 25.9 and 64.4 μg/mL for observed and predicted concentrations, respectively, p<10−6). There was no significant relationship between favipiravir concentrations and EBOV viral kinetics or mortality.

Conclusions

Favipiravir plasma concentrations in the JIKI trial failed to achieve the target exposure defined before the trial. Furthermore, the drug concentration experienced an unanticipated drop between Day-2 and Day-4. The origin of this drop could be due to severe sepsis conditions and/or to intrinsic properties of favipiravir metabolism. Dose-ranging studies should be performed in healthy volunteers to assess the concentrations and the tolerance that could be achieved with high doses.

Trial registration

ClinicalTrials.gov NCT02329054

Unexpectedly high leprosy seroprevalence detected using a random surveillance strategy in midwestern Brazil: A comparison of ELISA and a rapid diagnostic test

PLoS Neglected Tropical Diseases News - 23 February 2017 - 10:00pm

by Marco Andrey C. Frade, Natália A. de Paula, Ciro M. Gomes, Sebastian Vernal, Fred Bernardes Filho, Helena B. Lugão, Marilda M. M. de Abreu, Patrícia Botini, Malcolm S. Duthie, John S. Spencer, Rosa Castália F. R. Soares, Norma T. Foss

Background

Leprosy diagnosis is mainly based on clinical evaluation, although this approach is difficult, especially for untrained physicians. We conducted a temporary campaign to detect previously unknown leprosy cases in midwestern Brazil and to compare the performance of different serological tests.

Methods

A mobile clinic was stationed at the main bus terminal in Brasília, Brazil. Volunteers were quizzed and given a clinical exam to allow categorization as either patients, known contacts of patients or non-contacts, and blood was collected to determine anti-PGL-I and anti-LID-1 antibody titers by ELISA and by the NDO-LID rapid test. New cases of leprosy and the impact of performing this broad random surveillance strategy were evaluated. Accuracy values and concordance between the test results were evaluated among all groups.

Results

Four hundred thirty-four individuals were evaluated, and 44 (10.1%) were diagnosed with leprosy. Borderline forms were the most frequent presentation. Both tests presented higher positivity in those individuals with multibacillary disease. All tests demonstrated a specificity of approximately 90% but only a sensitivity for clinical disease of less than 20%. A substantial agreement between NDO-LID and ELISA with concomitant positive results was found within leprosy patients (Kappa index = 0.79 CI95% 0.36–1.22).

Conclusions

The unexpectedly high leprosy prevalence in this population indicates ongoing community-based exposure to Mycobacterium leprae antigens and high rates of subclinical infection. All tests showed high specificity but low sensitivity and therefore cannot be considered for use as stand-alone diagnostics. Rather, considering their positivity among MB patients and non-patients, these tests can be considered effective tools for screening and identifying individuals at high risk who might benefit from regular monitoring.

Hydrocephalus and arthrogryposis in an immunocompetent mouse model of ZIKA teratogeny: A developmental study

PLoS Neglected Tropical Diseases News - 23 February 2017 - 10:00pm

by Jose Xavier-Neto, Murilo Carvalho, Bruno dos Santos Pascoalino, Alisson Campos Cardoso, Ângela Maria Sousa Costa, Ana Helena Macedo Pereira, Luana Nunes Santos, Ângela Saito, Rafael Elias Marques, Juliana Helena Costa Smetana, Silvio Roberto Consonni, Carla Bandeira, Vivian Vasconcelos Costa, Marcio Chaim Bajgelman, Paulo Sérgio Lopes de Oliveira, Marli Tenorio Cordeiro, Laura Helena Vega Gonzales Gil, Bianca Alves Pauletti, Daniela Campos Granato, Adriana Franco Paes Leme, Lucio Freitas-Junior, Carolina Borsoi Moraes Holanda de Freitas, Mauro Martins Teixeira, Estela Bevilacqua, Kleber Franchini

The teratogenic mechanisms triggered by ZIKV are still obscure due to the lack of a suitable animal model. Here we present a mouse model of developmental disruption induced by ZIKV hematogenic infection. The model utilizes immunocompetent animals from wild-type FVB/NJ and C57BL/6J strains, providing a better analogy to the human condition than approaches involving immunodeficient, genetically modified animals, or direct ZIKV injection into the brain. When injected via the jugular vein into the blood of pregnant females harboring conceptuses from early gastrulation to organogenesis stages, akin to the human second and fifth week of pregnancy, ZIKV infects maternal tissues, placentas and embryos/fetuses. Early exposure to ZIKV at developmental day 5 (second week in humans) produced complex manifestations of anterior and posterior dysraphia and hydrocephalus, as well as severe malformations and delayed development in 10.5 days post-coitum (dpc) embryos. Exposure to the virus at 7.5–9.5 dpc induces intra-amniotic hemorrhage, widespread edema, and vascular rarefaction, often prominent in the cephalic region. At these stages, most affected embryos/fetuses displayed gross malformations and/or intrauterine growth restriction (IUGR), rather than isolated microcephaly. Disrupted conceptuses failed to achieve normal developmental landmarks and died in utero. Importantly, this is the only model so far to display dysraphia and hydrocephalus, the harbinger of microcephaly in humans, as well as arthrogryposis, a set of abnormal joint postures observed in the human setting. Late exposure to ZIKV at 12.5 dpc failed to produce noticeable malformations. We have thus characterized a developmental window of opportunity for ZIKV-induced teratogenesis encompassing early gastrulation, neurulation and early organogenesis stages. This should not, however, be interpreted as evidence for any safe developmental windows for ZIKV exposure. Late developmental abnormalities correlated with damage to the placenta, particularly to the labyrinthine layer, suggesting that circulatory changes are integral to the altered phenotypes.

Predicting Ebola infection: A malaria-sensitive triage score for Ebola virus disease

PLoS Neglected Tropical Diseases News - 23 February 2017 - 10:00pm

by Mary-Anne Hartley, Alyssa Young, Anh-Minh Tran, Harry Henry Okoni-Williams, Mohamed Suma, Brooke Mancuso, Ahmed Al-Dikhari, Mohamed Faouzi

Background

The non-specific symptoms of Ebola Virus Disease (EVD) pose a major problem to triage and isolation efforts at Ebola Treatment Centres (ETCs). Under the current triage protocol, half the patients allocated to high-risk “probable” wards were EVD(-): a misclassification speculated to predispose nosocomial EVD infection. A better understanding of the statistical relevance of individual triage symptoms is essential in resource-poor settings where rapid, laboratory-confirmed diagnostics are often unavailable.

Methods/Principal findings

This retrospective cohort study analyses the clinical characteristics of 566 patients admitted to the GOAL-Mathaska ETC in Sierra Leone. The diagnostic potential of each characteristic was assessed by multivariate analysis and incorporated into a statistically weighted predictive score, designed to detect EVD as well as discriminate malaria. Of the 566 patients, 28% were EVD(+) and 35% were malaria(+). Malaria was 2-fold more common in EVD(-) patients (p<0.05), and thus an important differential diagnosis. Univariate analyses comparing EVD(+) vs. EVD(-) and EVD(+)/malaria(-) vs. EVD(-)/malaria(+) cohorts revealed 7 characteristics with the highest odds for EVD infection, namely: reported sick-contact, conjunctivitis, diarrhoea, referral-time of 4–9 days, pyrexia, dysphagia and haemorrhage. Oppositely, myalgia was more predictive of EVD(-) or EVD(-)/malaria(+). Including these 8 characteristics in a triage score, we obtained an 89% ability to discriminate EVD(+) from either EVD(-) or EVD(-)/malaria(+).

Conclusions/Significance

This study proposes a highly predictive and easy-to-use triage tool, which stratifies the risk of EVD infection with 89% discriminative power for both EVD(-) and EVD(-)/malaria(+) differential diagnoses. Improved triage could preserve resources by identifying those in need of more specific differential diagnostics as well as bolster infection prevention/control measures by better compartmentalizing the risk of nosocomial infection.

Intensive trapping of blood-fed <i>Anopheles darlingi</i> in Amazonian Peru reveals unexpectedly high proportions of avian blood-meals

PLoS Neglected Tropical Diseases News - 23 February 2017 - 10:00pm

by Marta Moreno, Marlon P. Saavedra, Sara A. Bickersmith, Catharine Prussing, Adrian Michalski, Carlos Tong Rios, Joseph M. Vinetz, Jan E. Conn

Anopheles darlingi, the main malaria vector in the Neotropics, has been considered to be highly anthropophilic. However, many behavioral aspects of this species remain unknown, such as the range of blood-meal sources. Barrier screens were used to collect resting Anopheles darlingi mosquitoes from 2013 to 2015 in three riverine localities (Lupuna, Cahuide and Santa Emilia) in Amazonian Peru. Overall, the Human Blood Index (HBI) ranged from 0.58–0.87, with no significant variation among years or sites. Blood-meal analysis revealed that humans are the most common blood source, followed by avian hosts (Galliformes-chickens and turkeys), and human/Galliforme mixed-meals. The Forage Ratio and Selection Index both show a strong preference for Galliformes over humans in blood-fed mosquitoes. Our data show that 30% of An. darlingi fed on more than one host, including combinations of dogs, pigs, goats and rats. There appears to be a pattern of host choice in An. darlingi, with varying proportions of mosquitoes feeding only on humans, only on Galliformes and some taking mixed-meals of blood (human plus Galliforme), which was detected in the three sites in different years, indicating that there could be a structure to these populations based on blood-feeding preferences. Mosquito age, estimated in two localities, Lupuna and Cahuide, ranged widely between sites and years. This variation may reflect the range of local environmental factors that influence longevity or possibly potential changes in the ability of the mosquito to transmit the parasite. Of 6,204 resting An. darlingi tested for Plasmodium infection, 0.42% were infected with P. vivax. This study provides evidence for the first time of the usefulness of barrier screens for the collection of blood-fed resting mosquitoes to calculate the Human Blood Index (HBI) and other blood-meal sources in a neotropical malaria endemic setting.

Product development programs for neglected tropical diseases: A crucial role for expert meetings

PLoS Neglected Tropical Diseases News - 23 February 2017 - 10:00pm

by Leonie Hussaarts, Kim van der Weijde, Pierre Dome, Elly Kourany-Lefoll, Jutta Reinhard-Rupp, Remco de Vrueh, on behalf of the Pediatric Praziquantel Consortium

Galectin-3, histone deacetylases, and Hedgehog signaling: Possible convergent targets in schistosomiasis-induced liver fibrosis

PLoS Neglected Tropical Diseases News - 23 February 2017 - 10:00pm

by Felipe Leite de Oliveira, Katia Carneiro, José Marques Brito, Mariana Cabanel, Jonathas Xavier Pereira, Ligia de Almeida Paiva, Wingkin Syn, Neil C. Henderson, Marcia Cury El-Cheikh

Schistosomiasis affects approximately 240 million people in the world. Schistosoma mansoni eggs in the liver induce periportal fibrosis and hepatic failure driven by monocyte recruitment and macrophage activation, resulting in robust Th2 response. Here, we suggested a possible involvement of Galectin-3 (Gal-3), histone deacetylases (HDACs), and Hedgehog (Hh) signaling with macrophage activation during Th1/Th2 immune responses, fibrogranuloma reaction, and tissue repair during schistosomiasis. Gal-3 is highly expressed by liver macrophages (Kupffer cells) around Schistosoma eggs. HDACs and Hh regulate macrophage polarization and hepatic stellate cell activation during schistosomiasis-associated fibrogenesis. Previously, we demonstrated an abnormal extracellular matrix distribution in the liver that correlated with atypical monocyte–macrophage differentiation in S. mansoni-infected, Gal-3-deficient (Lgals3-/-) mice. New findings explored in this review focus on the chronic phase, when wild-type (Lgals3+/+) and Lgals3-/- mice were analyzed 90 days after cercariae infection. In Lgals3-/- infected mice, there was significant inflammatory infiltration with myeloid cells associated with egg destruction (hematoxylin and eosin staining), phagocytes (specifically Kupffer cells), numerically reduced and diffuse matrix extracellular deposition in fibrotic areas (Gomori trichrome staining), and severe disorganization of collagen fibers surrounding the S. mansoni eggs (reticulin staining). Granuloma-derived stromal cells (GR cells) of Lgals3-/- infected mice expressed lower levels of alpha smooth muscle actin (α-SMA) and eotaxin and higher levels of IL-4 than Lgals3+/+ mice (real-time PCR). The relevant participation of macrophages in these events led us to suggest distinct mechanisms of activation that culminate in defective fibrosis in the liver of Lgals3-/- infected mice. These aspects were discussed in this review, as well as the possible interference between Gal-3, HDACs, and Hh signaling during progressive liver fibrosis in S. mansoni-infected mice. Further studies focused on macrophage roles could elucidate these questions and clear the potential utility of these molecules as antifibrotic targets.

Cynomolgus macaques naturally infected with <i>Trypanosoma cruzi</i>-I exhibit an overall mixed pro-inflammatory/modulated cytokine signature characteristic of human Chagas disease

PLoS Neglected Tropical Diseases News - 22 February 2017 - 10:00pm

by Danielle Marquete Vitelli-Avelar, Renato Sathler-Avelar, Armanda Moreira Mattoso-Barbosa, Nicolas Gouin, Marcelo Perdigão-de-Oliveira, Leydiane Valério-dos-Reis, Ronaldo Peres Costa, Silvana Maria Elói-Santos, Matheus de Souza Gomes, Laurence Rodrigues do Amaral, Andréa Teixeira-Carvalho, Olindo Assis Martins-Filho, Edward J. Dick Jr., Gene B. Hubbard, Jane F. VandeBerg, John L. VandeBerg

Background

Non-human primates have been shown to be useful models for Chagas disease. We previously reported that natural T. cruzi infection of cynomolgus macaques triggers clinical features and immunophenotypic changes of peripheral blood leukocytes resembling those observed in human Chagas disease. In the present study, we further characterize the cytokine-mediated microenvironment to provide supportive evidence of the utility of cynomolgus macaques as a model for drug development for human Chagas disease.

Methods and findings

In this cross-sectional study design, flow cytometry and systems biology approaches were used to characterize the ex vivo and in vitro T. cruzi-specific functional cytokine signature of circulating leukocytes from TcI-T. cruzi naturally infected cynomolgus macaques (CH). Results showed that CH presented an overall CD4+-derived IFN-γ pattern regulated by IL-10-derived from CD4+ T-cells and B-cells, contrasting with the baseline profile observed in non-infected hosts (NI). Homologous TcI-T. cruzi-antigen recall in vitro induced a broad pro-inflammatory cytokine response in CH, mediated by TNF from innate/adaptive cells, counterbalanced by monocyte/B-cell-derived IL-10. TcIV-antigen triggered a more selective cytokine signature mediated by NK and T-cell-derived IFN-γ with modest regulation by IL-10 from T-cells. While NI presented a cytokine network comprised of small number of neighborhood connections, CH displayed a complex cross-talk amongst network elements. Noteworthy, was the ability of TcI-antigen to drive a complex global pro-inflammatory network mediated by TNF and IFN-γ from NK-cells, CD4+ and CD8+ T-cells, regulated by IL-10+CD8+ T-cells, in contrast to the TcIV-antigens that trigger a modest network, with moderate connecting edges.

Conclusions

Altogether, our findings demonstrated that CH present a pro-inflammatory/regulatory cytokine signature similar to that observed in human Chagas disease. These data bring additional insights that further validate these non-human primates as experimental models for Chagas disease.

Cytotoxic effector functions of T cells are not required for protective immunity against fatal <i>Rickettsia typhi</i> infection in a murine model of infection: Role of T<sub>H</sub>1 and T<sub>H</sub>17 cytokines in protection and pathology

PLoS Neglected Tropical Diseases News - 21 February 2017 - 10:00pm

by Kristin Moderzynski, Liza Heine, Jessica Rauch, Stefanie Papp, Svenja Kuehl, Ulricke Richardt, Bernhard Fleischer, Anke Osterloh

Endemic typhus caused by Rickettsia (R.) typhi is an emerging febrile disease that can be fatal due to multiple organ pathology. Here we analyzed the requirements for protection against R. typhi by T cells in the CB17 SCID model of infection. BALB/c wild-type mice generate CD4+ TH1 and cytotoxic CD8+ T cells both of which are sporadically reactivated in persistent infection. Either adoptively transferred CD8+ or CD4+ T cells protected R. typhi-infected CB17 SCID mice from death and provided long-term control. CD8+ T cells lacking either IFNγ or Perforin were still protective, demonstrating that the cytotoxic function of CD8+ T cells is not essential for protection. Immune wild-type CD4+ T cells produced high amounts of IFNγ, induced the release of nitric oxide in R. typhi-infected macrophages and inhibited bacterial growth in vitro via IFNγ and TNFα. However, adoptive transfer of CD4+IFNγ-/- T cells still protected 30–90% of R. typhi-infected CB17 SCID mice. These cells acquired a TH17 phenotype, producing high amounts of IL-17A and IL-22 in addition to TNFα, and inhibited bacterial growth in vitro. Surprisingly, the neutralization of either TNFα or IL-17A in CD4+IFNγ-/- T cell recipient mice did not alter bacterial elimination by these cells in vivo, led to faster recovery and enhanced survival compared to isotype-treated animals. Thus, collectively these data show that although CD4+ TH1 cells are clearly efficient in protection against R. typhi, CD4+ TH17 cells are similarly protective if the harmful effects of combined production of TNFα and IL-17A can be inhibited.

Ultrasonographic evaluation of urinary tract morbidity in school-aged and preschool-aged children infected with <i>Schistosoma haematobium</i> and its evolution after praziquantel treatment: A randomized controlled trial

PLoS Neglected Tropical Diseases News - 21 February 2017 - 10:00pm

by Beatrice Barda, Jean T. Coulibaly, Christoph Hatz, Jennifer Keiser

Background

Schistosoma haematobium infections are responsible for significant urinary tract (UT) complications. Schistosomiasis control programs aim to reduce morbidity, yet the extent of morbidity in preschool-aged children and the impact of treatment on morbidity reduction are not well studied.

Methodology

Our study was embedded in a randomized, placebo-controlled, single-blind trial in Côte d’Ivoire, which evaluated the efficacy and safety of three doses (20, 40 and 60 mg/kg) of praziquantel in school-aged (SAC) and preschool-aged (PSAC) children infected with S. haematobium. Enrolled children were invited to participate in an ultrasound examination prior and six months after treatment. At these time points 3 urine samples were collected for parasitological and clinical examinations.

Principal findings

162 PSAC and 141 SAC participated in the ultrasound examination at baseline, of which 128 PSAC and 122 SAC were present at follow-up. At baseline 43% (70/162) of PSAC had UT morbidity, mostly at bladder level and 7% had hydronephrosis. 67% (94/141) of SAC revealed mainly moderate UT pathology, 4% presented pseudopolyps on the bladder wall, and 6% had pyelectasis. At follow up, 45% of PSAC and 58% of SAC were S. haematobium positive, mostly harboring light infection intensities (41% and 51%, respectively). Microhematuria was present in 33% of PSAC and 42% of SAC and leukocyturia in 53% and 40% of PSAC and SAC, respectively. 50% (64/128) of PSAC and 58% (71/122) of SAC presented urinary tract morbidity, which was mainly mild. A significant correlation (p<0.05) was observed between praziquantel treatment and reversal of S. haematobium induced morbidity. Progression of UT pathology decreased with increasing praziquantel dosages. A worsening of morbidity was observed among children in the placebo group.

Conclusion/Significance

Bladder morbidity is widespread among PSAC. Praziquantel treatment is significantly associated with the reversal of S. haematobium induced morbidity, which underscores the importance of preventive chemotherapy programs. These programs should be expanded to PSAC to prevent or decrease the prevalence of morbidity in young children. This trial is registered as an International Standard Randomized Controlled Trial, number ISRCTN15280205.

Leprosy reactions: The predictive value of <i>Mycobacterium leprae</i>-specific serology evaluated in a Brazilian cohort of leprosy patients (U-MDT/CT-BR)

PLoS Neglected Tropical Diseases News - 21 February 2017 - 10:00pm

by Emerith Mayra Hungria, Samira Bührer-Sékula, Regiane Morillas de Oliveira, Lúcio Cartaxo Aderaldo, Araci de Andrade Pontes, Rossilene Cruz, Heitor de Sá Gonçalves, Maria Lúcia Fernandes Penna, Gerson Oliveira Penna, Mariane Martins de Araújo Stefani

Background

Leprosy reactions, reversal reactions/RR and erythema nodosum leprosum/ENL, can cause irreversible nerve damage, handicaps and deformities. The study of Mycobacterium leprae-specific serologic responses at diagnosis in the cohort of patients enrolled at the Clinical Trial for Uniform Multidrug Therapy Regimen for Leprosy Patients in Brazil/U-MDT/CT-BR is suitable to evaluate its prognostic value for the development of reactions.

Methodology

IgM and IgG antibody responses to PGL-I, LID-1, ND-O-LID were evaluated by ELISA in 452 reaction-free leprosy patients at diagnosis, enrolled and monitored for the development of leprosy reactions during a total person-time of 780,930 person-days, i.e. 2139.5 person-years, with a maximum of 6.66 years follow-up time.

Principal findings

Among these patients, 36% (160/452) developed reactions during follow-up: 26% (119/452) RR and 10% (41/452) had ENL. At baseline higher anti-PGL-I, anti-LID-1 and anti-ND-O-LID seropositivity rates were seen in patients who developed ENL and RR compared to reaction-free patients (p<0.0001). Seroreactivity in reactional and reaction-free patients was stratified by bacilloscopic index/BI categories. Among BI negative patients, higher anti-PGL-I levels were seen in RR compared to reaction-free patients (p = 0.014). In patients with 0 Conclusions

Overall, detection of anti-PGL-I, anti-LID-1 and anti-ND-O-LID antibodies at diagnosis, showed low sensitivity and specificity for RR prediction, indicating low applicability of serological tests for RR prognosis. On the other hand, anti-LID-1 serology at diagnosis has shown prognostic value for ENL development in BI positive patients.

Trial Registration

ClinicalTrials.gov NCT00669643

Dengue virus antibody database: Systematically linking serotype-specificity with epitope mapping in dengue virus

PLoS Neglected Tropical Diseases News - 21 February 2017 - 10:00pm

by Sidhartha Chaudhury, Gregory D. Gromowski, Daniel R. Ripoll, Ilja V. Khavrutskii, Valmik Desai, Anders Wallqvist

Background

A majority infections caused by dengue virus (DENV) are asymptomatic, but a higher incidence of severe illness, such as dengue hemorrhagic fever, is associated with secondary infections, suggesting that pre-existing immunity plays a central role in dengue pathogenesis. Primary infections are typically associated with a largely serotype-specific antibody response, while secondary infections show a shift to a broadly cross-reactive antibody response.

Methods/Principal findings

We hypothesized that the basis for the shift in serotype-specificity between primary and secondary infections can be found in a change in the antibody fine-specificity. To investigate the link between epitope- and serotype-specificity, we assembled the Dengue Virus Antibody Database, an online repository containing over 400 DENV-specific mAbs, each annotated with information on 1) its origin, including the immunogen, host immune history, and selection methods, 2) binding/neutralization data against all four DENV serotypes, and 3) epitope mapping at the domain or residue level to the DENV E protein. We combined epitope mapping and activity information to determine a residue-level index of epitope propensity and cross-reactivity and generated detailed composite epitope maps of primary and secondary antibody responses. We found differing patterns of epitope-specificity between primary and secondary infections, where secondary responses target a distinct subset of epitopes found in the primary response. We found that secondary infections were marked with an enhanced response to cross-reactive epitopes, such as the fusion-loop and E-dimer region, as well as increased cross-reactivity in what are typically more serotype-specific epitope regions, such as the domain I-II interface and domain III.

Conclusions/Significance

Our results support the theory that pre-existing cross-reactive memory B cells form the basis for the secondary antibody response, resulting in a broadening of the response in terms of cross-reactivity, and a focusing of the response to a subset of epitopes, including some, such as the fusion-loop region, that are implicated in poor neutralization and antibody-dependent enhancement of infection.

Anti-trypanosomal activity of non-peptidic nitrile-based cysteine protease inhibitors

PLoS Neglected Tropical Diseases News - 21 February 2017 - 10:00pm

by Antonio C. B. Burtoloso, Sérgio de Albuquerque, Mark Furber, Juliana C. Gomes, Cristiana Gonçalez, Peter W. Kenny, Andrei Leitão, Carlos A. Montanari, José Carlos Quilles Júnior, Jean F. R. Ribeiro, Josmar R. Rocha

The cysteine protease cruzipain is considered to be a validated target for therapeutic intervention in the treatment of Chagas disease. Anti-trypanosomal activity against the CL Brener strain of T. cruzi was observed in the 0.1 μM to 1 μM range for three nitrile-based cysteine protease inhibitors based on two scaffolds known to be associated with cathepsin K inhibition. The two compounds showing the greatest potency against the trypanosome were characterized by EC50 values (0.12 μM and 0.25 μM) that were an order of magnitude lower than the corresponding Ki values measured against cruzain, a recombinant form of cruzipain, in an enzyme inhibition assay. This implies that the anti-trypanosomal activity of these two compounds may not be explained only by the inhibition of the cruzain enzyme, thereby triggering a putative polypharmacological profile towards cysteine proteases.

Unusual pattern of chikungunya virus epidemic in the Americas, the Panamanian experience

PLoS Neglected Tropical Diseases News - 21 February 2017 - 10:00pm

by Jean-Paul Carrera, Yamilka Díaz, Bernardino Denis, Itza Barahona de Mosca, Dennys Rodriguez, Israel Cedeño, Dimelza Arauz, Publio González, Lizbeth Cerezo, Lourdes Moreno, Lourdes García, Lisseth E. Sáenz, María Aneth Atencio, Eddy Rojas-Fermin, Fernando Vizcaino, Nicolas Perez, Brechla Moreno, Sandra López-Vergès, Anayansi Valderrama, Blas Armién

Background

Chikungunya virus (CHIKV) typically causes explosive epidemics of fever, rash and polyarthralgia after its introduction into naïve populations. Since its introduction in Panama in May of 2014, few autochthonous cases have been reported; most of them were found within limited outbreaks in Panama City in 2014 and Puerto Obaldia town, near the Caribbean border with Colombia in 2015. In order to confirm that Panama had few CHIKV cases compared with neighboring countries, we perform an epidemiological analysis of chikungunya cases reported from May 2014 to July 2015. Moreover, to understand this paucity of confirmed CHIKV cases, a vectorial analysis in the counties where these cases were reported was performed.

Methods

Chikungunya cases were identified at medical centers and notified to health authorities. Sera samples were analyzed at Gorgas Memorial Institute for viral RNA and CHIKV-specific antibody detection.

Results

A total of 413 suspected cases of CHIKV infections were reported, with incidence rates of 0.5 and 0.7 per 100,000 inhabitants in 2014 and 2015, respectively. During this period, 38.6% of CHIKV cases were autochthonous with rash and polyarthralgia as predominant symptoms. CHIKV and DENV incidence ratios were 1:306 and 1:34, respectively. A phylogenetic analysis of E1/E2 genomic segment indicates that the outbreak strains belong to the Asian genotype and cluster together with CHIKV isolates from other American countries during the same period. Statistical analysis of the National Vector Control program at the district level shows low and medium vector infestation level for most of the counties with CHIKV cases. This index was lower than for neighboring countries.

Conclusions

Previous training of clinical, laboratory and vector workers allowed a good caption and detection of the chikungunya cases and fast intervention. It is possible that low/medium vector infestation level could explain in part the paucity of chikungunya infections in Panama.

Decline in infection-related morbidities following drug-mediated reductions in the intensity of <i>Schistosoma</i> infection: A systematic review and meta-analysis

PLoS Neglected Tropical Diseases News - 17 February 2017 - 10:00pm

by Gisele Andrade, David J. Bertsch, Andrea Gazzinelli, Charles H. King

Background

Since 1984, WHO has endorsed drug treatment to reduce Schistosoma infection and its consequent morbidity. Cross-sectional studies suggest pre-treatment correlation between infection intensity and risk for Schistosoma-related pathology. However, evidence also suggests that post-treatment reduction in intensity may not reverse morbidity because some morbidities occur at all levels of infection, and some reflect permanent tissue damage. The aim of this project was to systematically review evidence on drug-based control of schistosomiasis and to develop a quantitative estimate of the impact of post-treatment reductions in infection intensity on prevalence of infection-associated morbidity.

Methodology/Principal findings

This review was registered at inception with PROSPERO (CRD42015026080). Studies that evaluated morbidity before and after treatment were identified by online searches and searches of private archives. Post-treatment odds ratios or standardized mean differences were calculated for each outcome, and these were correlated to treatment-related egg count reduction ratios (ERRs) by meta-regression. A greater ERR correlated with greater reduction in odds of most morbidities. Random effects meta-analysis was used to derive summary estimates: after treatment of S. mansoni and S. japonicum, left-sided hepatomegaly was reduced by 54%, right-sided hepatomegaly by 47%, splenomegaly by 37%, periportal fibrosis by 52%, diarrhea by 53%, and blood in stools by 75%. For S. haematobium, hematuria was reduced by 92%, proteinuria by 90%, bladder lesions by 86%, and upper urinary tract lesions by 72%. There were no consistent changes in portal dilation or hemoglobin levels. In sub-group analysis, age, infection status, region, parasite species, and interval to follow-up were associated with meaningful differences in outcome.

Conclusion/Significance

While there are challenges to implementing therapy for schistosomiasis, and praziquantel therapy is not fully curative, reductions in egg output are significantly correlated with decreased morbidity and can be used to project diminution in disease burden when contemplating more aggressive strategies to minimize infection intensity.

Modelling the risk of <i>Taenia solium</i> exposure from pork produced in western Kenya

PLoS Neglected Tropical Diseases News - 17 February 2017 - 10:00pm

by Lian F. Thomas, William A. de Glanville, Elizabeth A. J. Cook, Barend M. De C. Bronsvoort, Ian Handel, Claire N. Wamae, Samuel Kariuki, Eric M. Fèvre

The tapeworm Taenia solium is the parasite responsible for neurocysticercosis, a neglected tropical disease of public health importance, thought to cause approximately 1/3 of epilepsy cases across endemic regions. The consumption of undercooked infected pork perpetuates the parasite’s life-cycle through the establishment of adult tapeworm infections in the community. Reducing the risk associated with pork consumption in the developing world is therefore a public health priority. The aim of this study was to estimate the risk of any one pork meal in western Kenya containing a potentially infective T. solium cysticercus at the point of consumption, an aspect of the parasite transmission that has not been estimated before. To estimate this, we used a quantitative food chain risk assessment model built in the @RISK add-on to Microsoft Excel. This model indicates that any one pork meal consumed in western Kenya has a 0.006 (99% Uncertainty Interval (U.I). 0.0002–0.0164) probability of containing at least one viable T. solium cysticercus at the point of consumption and therefore being potentially infectious to humans. This equates to 22,282 (99% U.I. 622–64,134) potentially infective pork meals consumed in the course of one year within Busia District alone. This model indicates a high risk of T. solium infection associated with pork consumption in western Kenya and the work presented here can be built upon to investigate the efficacy of various mitigation strategies for this locality.

Pages