Frontiers in parasitology最新文献

Intestinal helminths have evolved an abundance of immunomodulatory mechanisms to ensure long-lived infections in mammalian hosts. To manipulate mammalian immune responses helminths can directly produce immunomodulatory molecules, but helminth infection can also elicit functional changes in the intestinal microbiome which can impact immune functioning. Here we examined how bile acids (BA)s, a group of host-produced, microbiota-modified immunomodulatory metabolites, were altered in abundance and composition during a murine small intestinal helminth infection. We found that murine helminth infection resulted in consistently reduced concentrations of specific taurine-conjugated primary BAs (T-α-MCA and T-CDCA) in the small intestinal luminal contents of mice. BA transporters facilitate the uptake of BAs from the small intestinal lumen, allowing BAs to engage with nuclear BA receptors, and helminth infected mice showed reduced expression of genes encoding basal BA transporters in the small intestine. Finally, we report that there is reduced signaling through the nuclear BA receptor FXR in both the proximal small intestine and ileum of mice during small intestinal helminth infection. Together, our data reveal disruptions to BA homeostasis and signaling in the small intestine during helminth infection. As BAs are known to impact many aspects of mucosal physiology and immunity, examining the functional consequences of BA disruptions during helminth infection will be an important avenue for future research.

Parasitic worms (helminths) infect almost all taxa across the animal kingdom, and pose significant challenges to public health and economies, particularly in developing countries. To address this problem, researchers have developed various tools to measure the motility and viability of helminths. However, the conditions used in anthelmintic screening assays are often not optimized, and can vary considerably between research teams. These unoptimized conditions may impact novel drug screens, as little is known about the effects of different conditions on the health of the target parasites. To improve future research, this study determined the effects of key assay parameters including, media type, media concentration, in-well parasite density, and assay duration on the infective third-stage larva (L3) of two types of hookworms, namely Nippostrongylus brasiliensis in rodents, and Necator americanus in humans. Conditions were screened over several days using the xCELLigence worm real-time motility assay (xWORM); a real-time impedance-based helminth motility assay using the xCELLigence system with 96-well microplates. While results varied depending on the species and media used, the study found that 500-1,000 L3/200-µL and a media concentration of 3.13-25% generally produced good to excellent assay conditions. The findings of this study can guide the future selection of xWORM assay parameters for novel drug trials involving these parasite species and serve as a suggested model for optimizing trial conditions for alternative parasite targets and assays.

Introduction: Molecular mimicry is a strategy used by parasites to evade the host's immune system and facilitate transmission to a new host. To date, high-throughput examples of molecular mimicry have been limited to comparing protein sequences. However, recent advances in the prediction of tertiary structural models, led by Deepmind's AlphaFold, enable the comparison of thousands of proteins from parasites and their hosts at the structural level, allowing for the identification of more mimics. Here, we present the first proteome-level search for tertiary structure similarity between proteins from Plasmodium falciparum, a malaria-causing parasite, and humans.

Methods: We assembled a database of experimentally-characterized protein tertiary structures (from the Protein Data Bank) and AlphaFold-generated protein tertiary structures from P. falciparum, human, and 15 negative control species, i.e., species not infected by P. falciparum. We aligned human and control structures to the parasite structures using Foldseek.

Results: We identified molecular mimicry in three proteins that have been previously proposed as mediators of Plasmodium-human interactions. By extending this approach to all P. falciparum proteins, we identified an additional 41 potential mimics that are supported by additional experimental data.

Discussion: Our findings demonstrate a valuable application of AlphaFold-derived tertiary structural models, and we discuss key considerations for its effective use in other host-parasite systems.

Background: Gastrointestinal nematodes (GINs) are a serious problem in ruminant pastures worldwide. They generate production losses, from the point of view of both the food chain and animal mortality. This study provides preliminary results concerning the use of pasture plants in the Campania region (of southern Italy) to control GINs in sheep.

Methods: Sixteen species of wild and cultivated perennial plants present in seminatural pastures were sampled. All species were extracted with the conventional maceration technique, using three different solvents (i.e., H₂O, EtOH, and an EtOH:H₂O (8:2) mixture) in order to extract different bioactive compounds. The total phenolic content (TPC; assessed via the Folin-Ciocȃlteu assay) of all extract samples was preliminarily characterized. Each sample was aliquoted across six different concentrations and an in vitro egg hatching test (EHT) was conducted to evaluate the ovicidal effect on sheep GINs.

Results: The results indicated that Cichorium intybus L. and Foeniculum vulgare Mill. extracts greatly inhibited egg hatching within 48 hours of exposure, showing efficacy (≥ 62.6%) at the three higher concentrations when compared with the other plants.

Conclusion: The use of extracts of wild and cultivated perennial plant species in pastures can be a valid alternative to the use of synthetic anthelmintic drugs, which can generate problems, such as anthelmintic resistance, in the long term. Looking forward, further in vitro studies that evaluate the in vitro effect of these extracts on ruminant cell cultures, and field application through in vivo studies, would likely confirm the results obtained from preliminary in vitro EHTs. All these studies should be aimed at evaluating the therapeutic potential and future applicability of specific plant cultures in pastures to achieve sustainable pest control.

The most important soil-transmitted helminths (STHs) affecting humans are roundworms, whipworms, and hookworms, with a large proportion of the world's population infected with one or more of these intestinal parasites. On top of that, concurrent infections with several viruses, bacteria, protozoa, and other helminths such as trematodes are common in STH-endemic areas. STHs are potent immunomodulators, but knowledge about the effects of STH infection on the direction and extent of coinfections with other pathogens and vice versa is incomplete. By focusing on Kenya, a country where STH infections in humans are widespread, we provide an exemplary overview of the current prevalence of STH and co-occurring infections (e.g. with Human Immunodeficiency Virus, Plasmodium falciparum, Giardia duodenalis and Schistosoma mansoni). Using human data and complemented by experimental studies, we outline the immunomechanistic interactions of coinfections in both acutely STH transmigrated and chronically infected tissues, also highlighting their systemic nature. Depending on the coinfecting pathogen and immunological readout, STH infection may restrain, support, or even override the immune response to another pathogen. Furthermore, the timing of the particular infection and host susceptibility are decisive for the immunopathological consequences. Some examples demonstrated positive outcomes of STH coinfections, where the systemic effects of these helminths mitigate the damage caused by other pathogens. Nevertheless, the data available to date are rather unbalanced, as only a few studies have considered the effects of coinfection on the worm's life cycle and associated host immunity. These interactions are complex and depend largely on the context and biology of the coinfection, which can act in either direction, both to the benefit and detriment of the infected host.

Trypanosoma cruzi infection, currently endemic in 21 countries, is a public health problem not only in the Americas but also in countries with Latin American migrants. However, it is estimated that two-thirds of people with Chagas disease currently live in urban areas and that only 10% of them are aware of it. This review summarizes the most important aspects of the diagnosis of human T. cruzi infection by describing the following aspects of clinical laboratory diagnosis: the most widely used tests available in Latin America and those expected to improve access to diagnosis of the affected population with their implementation; the advantages, disadvantages, and sensitivity of the tests in the different phases of infection; and their usefulness in the acute or chronic phases of infection and in the context of immunosuppression. In this way, we hope to contribute to broadening the knowledge about this prevalent infection in the Americas.

The emergence of artemisinin partial resistance (ART-r) in Plasmodium falciparum malaria parasites has substantially compromised the efficacy of antimalarial treatments across southeast Asia (SE Asia). The spread of ART-r within the African continent could jeopardize past progress made in reducing worldwide malaria burden. A clinical index malaria case was identified in Kaolack, Senegal with persistent fever after complete artesunate-amodiaquine (ASAQ) treatment. Fifteen malaria-infected blood samples were collected by Institut Pasteur Dakar's Senegalese sentinel surveillance system, from different healthcare centers surrounding the index case. We have identified one Plasmodium falciparum clinical isolate carrying R515K mutation in the artemisinin resistance gene PfKelch13. CRISPR-Cas9 genome editing was carried out and transgenic Pf3D7Pfkelch13^R515K was tested for in vitro standard Ring-stage Survival Assay (RSA ^0-3hpi). Gene editing has confirmed that PfKelch13^R515K drove increased in vitro RSA^0-3hpi value. In this article, we report the functional significance of PfKelch13^R515K mutation in an African context.

Control of protein levels is vital to cellular homeostasis, for maintaining a steady state, to coordinate changes during differentiation and other roles. In African trypanosomes surface proteins contribute to immune evasion, drug sensitivity and environmental sensing. The trypanosome surface is dominated by the GPI-anchored variant surface glycoprotein, but additional GPI-anchored and trans-membrane domain proteins are present with known roles as nutrient receptors and signal transducers. The evolutionarily conserved deubiquitinase orthologs of Usp7 and Vdu1 in trypanosomes modulate abundance of many surface proteins, including the invariant surface glycoproteins, which have roles in immune evasion and drug sensitivity. Here we identify multiple trypanosome Skp1 paralogs and specifically a divergent paralog SkpZ. Affinity isolation and LCMSMS indicates that SkpZ forms a heterotrimeric complex with TbUsp7 and TbTpr86, a tetratricopeptide-repeat protein. Silencing SkpZ decreases TbUsp7 and TbTpr86 abundance, confirming a direct association. Further, SkpZ knockdown decreases the abundance of multiple trans-membrane domain (TMD) proteins but increases GPI-anchored surface protein levels. Hence, a heterotrimeric complex of TbTpr86, TbUsp7 and SkpZ (TUSK) regulates expression levels of a significant cohort of trypanosome surface proteins mediating coordination between TMD and GPI-anchored protein expression levels.

Background: The first discovery of Plasmodium vivax infections in Senegal used archived patients' sera in place of blood pellet, the preferred specimen for the molecular diagnosis of Plasmodium species. The present study assessed the reliability of detecting P. vivax DNA in plasma in comparison to blood pellet from the same patient's samples.

Methods: A total of 616 blood samples obtained from febrile patients living in Kolda (2015 and 2020), Tambacounda (2017 and 2020), and Kedougou (2020) regions in Senegal, were first screened for Plasmodium species composition by 18S ssrRNA-based nested PCR. Paired blood pellets and plasma samples were selected from a subset of 50 P. vivax-positive patients matched by age and sex with 50 P. vivax-negative patients, and subjected to a cytochrome b-based qPCR to compare the detection and quantification of P. vivax genomic DNA between the two specimen types.

Results and discussion: The study reports 1.8% and 14.77% of single and mixed P. vivax infections in the study population, and a high concordance (84%) between the qPCR detection of P. vivax genomic DNA from paired blood pellets and plasma samples. Importantly, all P. vivax negative samples from the blood pellets were also confirmed plasma-negative, and parasitaemia in blood pellets was higher compared to plasma samples. The results support investigations of P. vivax infections in archived sera or plasma collections with a high degree of confidence to generate additional data on the neglected P. vivax malaria, and ultimately guide strategies to control the disease.

Chagas is a zoonotic disease conditioned by the need to eliminate or control the vector in human settlements before targeting infected individuals. Simultaneously it is necessary to raise awareness of health problems generated by chronic Chagas disease (ChD), for people to participate actively in vector control programs that will then enable the implementation of screening, treatment and follow-up strategies. Therefore, it is essential to engage the participation of the community in holistically designed integral programs to address ChD in all its complexity. This Perspective presents the case of Chagas management programs in the Department of General Taboada, Province of Santiago del Estero, Argentina, to showcase a possible strategy in vector control, diagnosis and treatment programs that integrate ChD into the local public health system and engage community participation. Through this Perspective we argue for the importance of the contribution of social science methodologies and epistemologies in the process of integrating ChD into the public (and primary) health care system.