Exploring the Potential of Natural Products as Antiparasitic Agents for Neglected Tropical Diseases.

Recent developments in the use of natural product-based molecules as antiparasitic agents for Malaria, leishmaniasis (LE), Chagas disease (CD), and Human African trypanosomiasis (HAT) are reviewed. The role of diverse plants in developing bioactive species is discussed in addition to analyzing the structural diversity of natural products as active agents and the diverse biological applications in CD, HAT, LE, and Malaria. This review focuses on medicinal chemistry, emphasizing the structural characteristics of natural molecules as bioactive agents against parasitic infections caused by Leishmania, Trypanosoma, and Plasmodium parasites.

Neglected tropical diseases risk correlates with poverty and early ecosystem destruction.

BACKGROUND: Neglected tropical diseases affect the most vulnerable populations and cause chronic and debilitating disorders. Socioeconomic vulnerability is a well-known and important determinant of neglected tropical diseases. For example, poverty and sanitation could influence parasite transmission. Nevertheless, the quantitative impact of socioeconomic conditions on disease transmission risk remains poorly explored. METHODS: This study investigated the role of socioeconomic variables in the predictive capacity of risk models of neglected tropical zoonoses using a decade of epidemiological data (2007-2018) from Brazil. Vector-borne diseases investigated in this study included dengue, malaria, Chagas disease, leishmaniasis, and Brazilian spotted fever, while directly-transmitted zoonotic diseases included schistosomiasis, leptospirosis, and hantaviruses. Environmental and socioeconomic predictors were combined with infectious disease data to build environmental and socioenvironmental sets of ecological niche models and their performances were compared. RESULTS: Socioeconomic variables were found to be as important as environmental variables in influencing the estimated likelihood of disease transmission across large spatial scales. The combination of socioeconomic and environmental variables improved overall model accuracy (or predictive power) by 10% on average (P < 0.01), reaching a maximum of 18% in the case of dengue fever. Gross domestic product was the most important socioeconomic variable (37% relative variable importance, all individual models exhibited P < 0.00), showing a decreasing relationship with disease indicating poverty as a major factor for disease transmission. Loss of natural vegetation cover between 2008 and 2018 was the most important environmental variable (42% relative variable importance, P < 0.05) among environmental models, exhibiting a decreasing relationship with disease probability, showing that these diseases are especially prevalent in areas where natural ecosystem destruction is on its initial stages and lower when ecosystem destruction is on more advanced stages. CONCLUSIONS: Destruction of natural ecosystems coupled with low income explain macro-scale neglected tropical and zoonotic disease probability in Brazil. Addition of socioeconomic variables improves transmission risk forecasts on tandem with environmental variables. Our results highlight that to efficiently address neglected tropical diseases, public health strategies must target both reduction of poverty and cessation of destruction of natural forests and savannas.

Diagnosis of visceral and cutaneous leishmaniasis using loop-mediated isothermal amplification (LAMP) protocols: a systematic review and meta-analysis.

Sensitive, reliable and fast diagnostic tools that are applicable in low-resource settings, at the point of care (PoC), are seen as crucial in the fight against visceral leishmaniasis (VL) and cutaneous leishmaniasis (CL). Addressing the need for a PoC test, several diagnostic tests, including serological and molecular methods, have been developed and evaluated in the past. One promising molecular method, already implemented for diagnosis of a range of diseases, is the loop-mediated isothermal amplification (LAMP) protocol. In this systematic review and meta-analysis, using a comprehensive search strategy, we focus on studies evaluating the performance of LAMP for the diagnosis of leishmaniasis in humans and other mammals such as dogs, compared with microscopy and/or any other molecular diagnostic method. A meta-analysis, pooling sensitivity and specificity rates and calculating areas under the curve (AUCs) in summary receiver operating characteristic (SROC) plots, was conducted on datasets extracted from studies, grouped by clinical condition and sample type. We found high sensitivity and specificity for LAMP when compared with microscopy and PCR using blood samples, with pooled estimate values of > 90% for all subgroups, corresponding to calculated AUC values > 0.96, except for LAMP compared to microscopy for diagnosis of CL. However, only a limited number of studies were truly comparable. Most of the observed heterogeneity is likely based on true differences between the studies rather than sampling error only. Due to simple readout methods and low laboratory equipment requirements for sample preparation compared to other molecular methods, LAMP is a promising candidate for a molecular (near-)PoC diagnostic method for VL and CL.

Multiple-bead assay for the differential serodiagnosis of neglected human cestodiases: Neurocysticercosis and cystic echinococcosis.

BACKGROUND: Neurocysticercosis (NCC), and cystic echinococcosis (CE) are two neglected diseases caused by cestodes, co-endemic in many areas of the world. Imaging studies and serological tests are used in the diagnosis of both parasitic diseases, but cross-reactions may confound the results of the latter. The novel multiplex bead-based assay with recombinant antigens has been reported to increases the diagnostic accuracy of serological techniques. METHODOLOGY: We set-up an immunoassay based on the multiplex bead-based platform (MBA), using the rT24H (against Cysticercus cellulosae, causing cysticercosis) and r2B2t (against Echinococcus granulosus sensu lato, causing CE) recombinant antigens, for simultaneous and differential diagnosis of these infections. The antigens were tested on 356 sera from 151 patients with CE, 126 patients with NCC, and 79 individuals negative for both diseases. Specificity was calculated including sera from healthy donors, other neurological diseases and the respective NCC or CE sera counterpart. The diagnostic accuracy of this assay was compared with two commercial ELISA tests, Novalisa and Ridascreen, widely used in the routine diagnosis of cysticercosis and CE, respectively. MAIN FINDINGS: For the diagnosis of NCC, sensitivity ranged from 57.94-63.49% for the rT24H-MBA, and 40.48-46.03% for Novalisa ELISA depending on exclusion or inclusion of sera having equivocal results on ELISA from the analysis; specificities ranged from 90.87-91.30% and 70.43-76.96%, respectively. AUC values of the ROC curve were 0.783 (rT24H) and 0.619 (Novalisa) (p-value < 0.001). For the diagnosis of CE, the sensitivity of the r2B2t-MBA ranged from 68.87-69.77% and of Ridascreen ELISA from 50.00-57.62%; specificities from 92.47-92.68% and from 74.15-80.98%, respectively. AUC values were 0.717 and 0.760, respectively. CONCLUSIONS/SIGNIFICANCE: Overall, the recombinant antigens tested with the bead-based technology showed better diagnostic accuracy than the commercial assays, particularly for the diagnosis of NCC. The possibility of testing the same serum sample simultaneously for the presence of antibodies against both antigens is an added value particularly in seroprevalence studies for cysticercosis linked to control programs in endemic areas where these two parasites coexist.

Antiprotozoal agents: How have they changed over a decade?

Neglected tropical diseases are a diverse group of communicable diseases that are endemic in low- or low-to-middle-income countries located in tropical and subtropical zones. The number and availability of drugs for treating these diseases are low, the administration route is inconvenient in some cases, and most of them have safety, efficacy, or adverse/toxic reaction issues. The need for developing new drugs to deal with these issues is clear, but one of the most drastic consequences of this negligence is the lack of interest in the research and development of new therapeutic options among major pharmaceutical companies. Positive changes have been achieved over the last few years, although the overall situation remains alarming. After more than one decade since the original work reviewing antiprotozoal agents came to light, now it is time to question ourselves: How has the scenario for the treatment of protozoal diseases such as malaria, leishmaniasis, human African trypanosomiasis, and American trypanosomiasis changed? This review covers the last decade in terms of the drugs currently available for the treatment of these diseases as well as the clinical candidates being currently investigated.

Eosinophils participate in modulation of liver immune response and tissue damage induced by Schistosoma mansoni infection in mice.

The severity of chronic schistosomiasis has been mainly associated with the intensity and extension of the inflammatory response induced by egg-secreted antigens in the host tissue, especially in the liver and intestine. During acute schistosomiasis, eosinophils account for approximately 50% of the cells that compose the liver granulomas; however, the role of this cell-type in the pathology of schistosomiasis remains controversial. In the current study, we compared the parasite burden and liver immunopathological changes during experimental schistosomiasis in wild-type (WT) BALB/c mice and BALB/c mice selectively deficient for the differentiation of eosinophils (ΔdblGATA). Our data demonstrated that the absence of eosinophil differentiation did not alter the S. mansoni load or the liver retention of parasite eggs; however, there were significant changes in the liver immune response profile and tissue damage. S. mansoni infection in ΔdblGATA mice resulted in significantly lower liver concentrations of IL-5, IL-13, IL-33, IL-17, IL-10, and TGF-ß and higher concentrations of IFN-γ and TNF-α, as compared to WT mice. The changes in liver immune response observed in infected ΔdblGATA mice were accompanied by lower collagen deposition, but higher liver damage and larger granulomas. Moreover, the absence of eosinophils resulted in a higher mortality rate in mice infected with a high parasite load. Therefore, the data indicated that eosinophils participate in the establishment and/or amplification of liver Th-2 and regulatory response induced by S. mansoni, which is necessary for the balance between liver damage and fibrosis, which in turn is essential for modulating disease severity.

Neglected malaria parasites in hard-to-reach areas of Odisha, India: implications in elimination programme.

BACKGROUND: Information on the foci of Plasmodium species infections is essential for any country heading towards elimination. Odisha, one of the malaria-endemic states of India is targeting elimination of malaria by 2030. To support decision-making regarding targeted intervention, the distribution of Plasmodium species infections was investigated in hard-to-reach areas where a special malaria elimination drive, namely Durgama Anchalare Malaria Nirakaran (DAMaN) began in 2017. METHODS: A cross-sectional survey was conducted in 2228 households during July to November 2019 in six districts, to evaluate the occurrence of Plasmodium species. The species were identified by polymerase chain reaction (PCR) followed by sequencing, in case of Plasmodium ovale. RESULTS: Of the 3557 blood specimens tested, malaria infection was detected in 282 (7.8%) specimens by PCR. Of the total positive samples, 14.1% were P. ovale spp. and 10.3% were Plasmodium malariae infections. The majority of P. ovale spp. (75.8%) infections were mixed with either Plasmodium falciparum and/or Plasmodium vivax and found to be distributed in three geophysical regions (Northern-plateau, Central Tableland and Eastern Ghat) of the State, while P. malariae has been found in Northern-plateau and Eastern Ghat regions. Speciation revealed occurrence of both Plasmodium ovale curtisi (classic type) and Plasmodium ovale wallikeri (variant type). CONCLUSIONS: In the present study a considerable number of P. ovale spp. and P. malariae were detected in a wide geographical areas of Odisha State, which contributes around 40% of the country's total malaria burden. For successful elimination of malaria within the framework of national programme, P. ovale spp. along with P. malariae needs to be incorporated in surveillance system, especially when P. falciparum and P. vivax spp. are in rapid decline.

Sodium butyrate ameliorates Schistosoma japonicum-induced liver fibrosis by inhibiting HMGB1 expression.

Schistosomiasis is a prevalent zoonotic parasitic disease caused by schistosomes. Its main threat to human health is hepatic granuloma and fibrosis due to worm eggs. Praziquantel remains the first choice for the treatment of schistosomiasis but has limited benefit in treating liver fibrosis. Therefore, the need to develop effective drugs for treating schistosomiasis-induced hepatic fibrosis is urgent. High-mobility group box 1 protein (HMGB1) is a potential immune mediator that is highly associated with the development of some fibrotic diseases and may be involved in the liver pathology of schistosomiasis. We speculated that HMGB1 inhibitors could have an anti-fibrotic effect. Sodium butyrate (SB), a potent inhibitor of HMGB1, has shown anti-inflammatory activity in some animal disease models. In this study, we evaluated the effects of SB on a murine schistosomiasis model. Mice were percutaneously infected with 20 ± 2 cercariae of Schistosoma japonicum. SB (500 mg/kg/day) was administered every 3 days for the entire experiment period. The activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), liver histopathology, HMGB1 expression, and the levels of interferon gamma (IFN-γ), transforming growth factor-ß1 (TGF-ß1), and interleukin-6 (IL-6) in serum were analyzed. SB reduced hepatic granuloma and fibrosis of schistosomiasis, reflected by the decreased levels of ALT and AST in serum and the reduced expression of pro-inflammatory and fibrogenic cytokines (IFN-γ, TGF-ß1, and IL-6). The protective effect could be attributable to the inhibition of the expression of HMGB1 and release by SB.

Spillover, hybridization, and persistence in schistosome transmission dynamics at the human-animal interface.

Zoonotic spillover and hybridization of parasites are major emerging public and veterinary health concerns at the interface of infectious disease biology, evolution, and control. Schistosomiasis is a neglected tropical disease of global importance caused by parasites of the Schistosoma genus, and the Schistosoma spp. system within Africa represents a key example of a system where spillover of animal parasites into human populations has enabled formation of hybrids. Combining model-based approaches and analyses of parasitological, molecular, and epidemiological data from northern Senegal, a region with a high prevalence of schistosome hybrids, we aimed to unravel the transmission dynamics of this complex multihost, multiparasite system. Using Bayesian methods and by estimating the basic reproduction number (R0 ), we evaluate the frequency of zoonotic spillover of Schistosoma bovis from livestock and the potential for onward transmission of hybrid S. bovis × S. haematobium offspring within human populations. We estimate R0 of hybrid schistosomes to be greater than the critical threshold of one (1.76; 95% CI 1.59 to 1.99), demonstrating the potential for hybridization to facilitate spread and establishment of schistosomiasis beyond its original geographical boundaries. We estimate R0 for S. bovis to be greater than one in cattle (1.43; 95% CI 1.24 to 1.85) but not in other ruminants, confirming cattle as the primary zoonotic reservoir. Through longitudinal simulations, we also show that where S. bovis and S. haematobium are coendemic (in livestock and humans respectively), the relative importance of zoonotic transmission is predicted to increase as the disease in humans nears elimination.

A review of the leishmanin skin test: A neglected test for a neglected disease.

The leishmanin skin test (LST) has been used for decades to detect exposure and immunity to the parasite Leishmania, the causative agent of the neglected tropical disease leishmaniasis. In the LST, Leishmania antigen (leishmanin) is intradermally injected into the forearm. In an individual who has been previously infected, a delayed-type hypersensitivity (DTH) reaction results in a measurable induration at the site of the injection, indicating that previous exposure to Leishmania has resulted in the development of cell-mediated immunity. LST positivity is associated with long-lasting protective immunity against reinfection, most notably as reported for visceral leishmaniasis (VL). Despite efforts over the past few decades, leishmanin antigen is no longer produced under good manufacturing practice (GMP) conditions anywhere in the world. Consequently, the use of the LST in epidemiological studies has declined in favor of serological and molecular tests. In this review, we provide a historical overview of the LST and justification for the reintroduction of leishmanin. A GMP-grade leishmanin can be used to detect immunity in vivo by the LST and can be investigated for use in an interferon-γ release assay (IGRA), which may serve as an in vitro version of the LST. The LST will be a valuable tool for surveillance and epidemiological studies in support of the VL elimination programs and as a surrogate marker of immunity in vaccine clinical trials. METHODS: A review of the literature was conducted using PubMed as the primary database, with MeSH terms "leishmanin skin test" OR "Montenegro test" OR "Montenegro skin test." Articles written in English that describe the history or standardization of leishmanin, the use of leishmanin in an IGRA, or the use of the LST in epidemiological studies or vaccine trials were prioritized in our appraisal of the literature.

A hidden deadly venomous insect: First eco-epidemiological assessment and risk mapping of lonomism in Argentina.

BACKGROUND: Envenomation by the South American Lonomia saturniid caterpillars, named lonomism, constitutes an emerging and somewhat neglected public health issue in Argentina and neighboring countries. Considering that there is an intricate relationship between environment and human health in such cases, this study aimed to analyze the eco-epidemiological profile of 40 accidents and 33 occurrences of Lonomia spp. in Misiones (Argentina) between January 2014 and May 2020. METHODOLOGY/PRINCIPAL FINDINGS: We described the eco-epidemiological variables and characterized the abiotic scenario of such cases. Additionally, we obtained a density map that shows the punctual intensity of Lonomia records throughout Misiones. Most of the accidents occurred in the Department of Guaraní and involved male victims younger than 20 years old. The accidental/occasional occurrence of Lonomia spp. (considering both adult and caterpillar stages together) was significantly higher in the rural area, whereas only adult specimens were found in urban areas. We determined that the presence of this insect in Misiones is positively related to higher temperatures and solar radiation, and larger precipitation and evapotranspiration throughout the year. CONCLUSION/SIGNIFICANCE: This study represents an initial step towards the global understanding of lonomism as a public health problem in Argentina. It provides a map of the risk level for this envenomation in Misiones, which could help authorities address public health policy efforts to implement sustainable strategies for prevention and response to this threat in Northeastern Argentina and neighboring regions.

Furan derivatives impair proliferation and affect ultrastructural organization of Trypanosoma cruzi and Leishmania amazonensis.

Chagas disease and leishmaniasis are neglected diseases caused by parasites of the Trypanosomatidae family and together they affect millions of people in the five continents. The treatment of Chagas disease is based on benznidazole, whereas for leishmaniasis few drugs are available, such as amphotericin B and miltefosine. In both cases, the current treatment is not entirely efficient due to toxicity or side effects. Encouraged by the need to discover valid targets and new treatment options, we evaluated 8 furan compounds against Trypanosoma cruzi and Leishmania amazonensis, considering their effects against proliferation, infection, and ultrastructure. Many of them were able to impair T. cruzi and L. amazonensis proliferation, as well as cause ultrastructural alterations, such as Golgi apparatus disorganization, autophagosome formation, and mitochondrial swelling. Taken together, the results obtained so far make these compounds eligible for further steps of chemotherapy study.

Cerebral Coenurosis of a Long-Tailed Goral, Naemorhedus caudatus, in Korea.

We intended to describe a case of cerebral coenurosis in a long-tailed goral, Naemorhedus caudatus, from Hwacheon-gun, Gangwon-do (Province), in the Korea. The goral, a 10-year-old male, was suffering from neurological symptoms, such as turning the circle to one side without lifting the head straight, and died at 30 days after admission to the wildlife medical rescue center in Chuncheon-si, Gangwon-do. A fluid-filled cyst was detected in the left cerebral hemisphere by computed tomography and magnetic resonance imaging. The cyst removed from the deceased goral was transparent, about 3×3 cm in size, contained a clear fluid and approximately 320 protoscolices invaginating from the internal germinal layer. The protoscolex had 4 suckers and a rostellum with 28 hooklets arranged in 2 rows. By the present study, a case of cerebral coenurosis was first confirmed in a long-tailed goral, N. caudatus, from Gangwon-do, in Korea. The residents frequently exposed in the sylvatic environment should be careful the accidental infections of zoonotic metacestode of Taenia multiceps, Coenurus cerebralis, in Korea.

Comparison of Plasmodium ovale curtisi and Plasmodium ovale wallikeri infections by a meta-analysis approach.

Malaria caused by Plasmodium ovale species is considered a neglected tropical disease with limited information about its characteristics. It also remains unclear whether the two distinct species P. ovale curtisi and P. ovale wallikeri exhibit differences in their prevalence, geographic distribution, clinical characteristics, or laboratory parameters. Therefore, this study was conducted to clarify these differences to support global malaria control and eradication programs. Studies reporting the occurrence of P. ovale curtisi and P. ovale wallikeri were explored in databases. Differences in proportion, clinical data, and laboratory parameters between the two species were estimated using a random-effects model and expressed as pooled odds ratios (ORs), mean difference (MD), or standardized MD depending on the types of extracted data. The difference in geographical distribution was visualized by mapping the origin of the two species. A total of 1453 P. ovale cases extracted from 35 studies were included in the meta-analysis. The p-value in the meta-analyses provided evidence favoring a real difference between P. ovale curtisi malaria cases (809/1453, 55.7%) and P. ovale wallikeri malaria cases (644/1453, 44.3%) (p: 0.01, OR 1.61, 95% CI 0.71-3.63, I2: 77%). Subgroup analyses established evidence favoring a real difference between P. ovale curtisi and P. ovale wallikeri malaria cases among the imported cases (p: 0.02, 1135 cases). The p value in the meta-analyses provided evidence favoring a real difference in the mean latency period between P. ovale curtisi (289 cases) and P. ovale wallikeri malaria (266 cases) (p: 0.03, MD: 27.59, 95% CI 1.99-53.2, I2: 94%), total leukocyte count (p < 0.0001, MD: 840, 95% CI 610-1070, I2: 0%, two studies) and platelet count (p < 0.0001, MD: 44,750, 95% CI 2900-60,500, I2: 32%, three studies). Four continents were found to have reports of P. ovale spp., among which Africa had the highest number of reports for both P. ovale spp. in its 37 countries, with a global proportion of 94.46%, and an almost equal distribution of both P. ovale spp., where P. ovale curtisi and P. ovale wallikeri reflected 53.09% and 46.90% of the continent's proportion, respectively. This is the first systematic review and meta-analysis to demonstrate the differences in the characteristics of the two distinct P. ovale species. Malaria caused by P. ovale curtisi was found in higher proportions among imported cases and had longer latency periods, higher platelet counts, and higher total leukocyte counts than malaria caused by P. ovale wallikeri. Further studies with a larger sample size are required to confirm the differences or similarities between these two species to promote malaria control and effective eradication programs.

Plasmodium malariae, current knowledge and future research opportunities on a neglected malaria parasite species.

Plasmodium malariae is often reported as a benign malaria parasite. There are limited data on its biology and disease burden in sub-Saharan Africa (sSA) possibly due to the unavailability of specific and affordable tools for routine diagnosis and large epidemiology studies. In addition, P. malariae occurs at low parasite densities and in co-infections with other species, predominately P. falciparum. The paucity of data on P. malariae infections limits the capacity to accurately determine its contribution to malaria and the effect of control interventions against P. falciparum on its prevalence. Here, we summarise the current knowledge on P. malariae epidemiology in sSA - overall prevalence ranging from 0-32%, as detected by different diagnostic methods; seroprevalence ranging from 0-56% in three countries (Mozambique, Benin and Zimbabwe), and explore the future application of next-generation sequencing technologies as a tool for enriching P. malariae genomic epidemiology. This will provide insights into important adaptive mechanisms of this neglected non-falciparum species, including antimalarial drug resistance, local and regional parasite transmission patterns and genomic signatures of selection. Improved diagnosis and genomic surveillance of non-falciparum malaria parasites in Africa would be helpful in evaluating progress towards elimination of all human Plasmodium species.

Potentials of marine natural products against malaria, leishmaniasis, and trypanosomiasis parasites: a review of recent articles.

BACKGROUND: Malaria and neglected communicable protozoa parasitic diseases, such as leishmaniasis, and trypanosomiasis, are among the otherwise called diseases for neglected communities, which are habitual in underprivileged populations in developing tropical and subtropical regions of Africa, Asia, and the Americas. Some of the currently available therapeutic drugs have some limitations such as toxicity and questionable efficacy and long treatment period, which have encouraged resistance. These have prompted many researchers to focus on finding new drugs that are safe, effective, and affordable from marine environments. The aim of this review was to show the diversity, structural scaffolds, in-vitro or in-vivo efficacy, and recent progress made in the discovery/isolation of marine natural products (MNPs) with potent bioactivity against malaria, leishmaniasis, and trypanosomiasis. MAIN TEXT: We searched PubMed and Google scholar using Boolean Operators (AND, OR, and NOT) and the combination of related terms for articles on marine natural products (MNPs) discovery published only in English language from January 2016 to June 2020. Twenty nine articles reported the isolation, identification and antiparasitic activity of the isolated compounds from marine environment. A total of 125 compounds were reported to have been isolated, out of which 45 were newly isolated compounds. These compounds were all isolated from bacteria, a fungus, sponges, algae, a bryozoan, cnidarians and soft corals. In recent years, great progress is being made on anti-malarial drug discovery from marine organisms with the isolation of these potent compounds. Comparably, some of these promising antikinetoplastid MNPs have potency better or similar to conventional drugs and could be developed as both antileishmanial and antitrypanosomal drugs. However, very few of these MNPs have a pharmaceutical destiny due to lack of the following: sustainable production of the bioactive compounds, standard efficient screening methods, knowledge of the mechanism of action, partnerships between researchers and pharmaceutical industries. CONCLUSIONS: It is crystal clear that marine organisms are a rich source of antiparasitic compounds, such as alkaloids, terpenoids, peptides, polyketides, terpene, coumarins, steroids, fatty acid derivatives, and lactones. The current and future technological innovation in natural products drug discovery will bolster the drug armamentarium for malaria and neglected tropical diseases.

ASCVac-1, a Multi-Peptide Chimeric Vaccine, Protects Mice Against Ascaris suum Infection.

Control of human ascariasis, the most prevalent neglected tropical disease globally affecting 450 million people, mostly relies on mass drug administration of anthelmintics. However, chemotherapy alone is not efficient due to the high re-infection rate for people who live in the endemic area. The development of a vaccine that reduces the intensity of infection and maintains lower morbidity should be the primary target for infection control. Previously, our group demonstrated that immunization with crude Ascaris antigens in mice induced an IgG-mediated protective response with significant worm reduction. Here, we aimed to develop a multipeptide chimera vaccine based on conserved B-cell epitopes predicted from 17 common helminth proteomes using a bioinformatics algorithm. More than 480 B-cell epitopes were identified that are conserved in all 17 helminths. The Ascaris-specific epitopes were selected based on their reactivity to the pooled sera of mice immunized with Ascaris crude antigens or infected three times with A. suum infective eggs. The top 35 peptides with the strongest reactivity to Ascaris immune serum were selected to construct a chimeric antigen connected in sequence based on conformation. This chimera, called ASCVac-1, was produced as a soluble recombinant protein in an Escherichia coli expression system and, formulated with MPLA, was used to immunize mice. Mice immunized with ASCVac-1/MPLA showed around 50% reduced larvae production in the lungs after being challenged with A. suum infective eggs, along with significantly reduced inflammation and lung tissue/function damage. The reduced parasite count and pathology in infected lungs were associated with strong Th2 immune responses characterized by the high titers of antigen-specific IgG and its subclasses (IgG1, IgG2a, and IgG3) in the sera and significantly increased IL-4, IL-5, IL-13 levels in lung tissues. The reduced IL-33 titers and stimulated eosinophils were also observed in lung tissues and may also contribute to the ASCVac-1-induced protection. Taken together, the preclinical trial with ASCVac-1 chimera in a mouse model demonstrated its significant vaccine efficacy associated with strong IgG-based Th2 responses, without IgE induction, thus reducing the risk of an allergic response. All results suggest that the multiepitope-based ASCVac-1 chimera is a promising vaccine candidate against Ascaris sp. infections.

Polymorphism in the catalytic subunit of the PI3Kγ gene is associated with Trypanosoma cruzi-induced chronic chagasic cardiomyopathy.

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi. During the chronic phase of disease, while most infected people do not present symptoms, characterizing the asymptomatic form, some patients develop the cardiac form or chronic chagasic cardiomyopathy, which is considered the most severe manifestation of this disease. Considering that the activation of the PI3Kγ signaling pathway is essential for an efficient immune response against T. cruzi infection, we evaluated the PIK3CG C > T (rs1129293) polymorphism in exon 3 of this gene, which encodes the catalytic subunit of PI3Kγ. The PIK3CG CT and TT genotypes were found to be associated with an increased risk of developing the cardiac form of the disease rather than the asymptomatic or digestive forms. In conclusion, the presence of the T allele at single or double doses may differentiate the cardiac from other clinical manifestations of Chagas disease. This finding should help in further studies to evaluate the mechanisms underlying the differential association of PIK3CG in Chagas disease.