Inhibition of malaria and babesiosis parasites by putative red blood cell targeting small molecules.

Background: Chemotherapies for malaria and babesiosis frequently succumb to the emergence of pathogen-related drug-resistance. Host-targeted therapies are thought to be less susceptible to resistance but are seldom considered for treatment of these diseases. Methods: Our overall objective was to systematically assess small molecules for host cell-targeting activity to restrict proliferation of intracellular parasites. We carried out a literature survey to identify small molecules annotated for host factors implicated in Plasmodium falciparum infection. Alongside P. falciparum, we implemented in vitro parasite susceptibility assays also in the zoonotic parasite Plasmodium knowlesi and the veterinary parasite Babesia divergens. We additionally carried out assays to test directly for action on RBCs apart from the parasites. To distinguish specific host-targeting antiparasitic activity from erythrotoxicity, we measured phosphatidylserine exposure and hemolysis stimulated by small molecules in uninfected RBCs. Results: We identified diverse RBC target-annotated inhibitors with Plasmodium-specific, Babesia-specific, and broad-spectrum antiparasitic activity. The anticancer MEK-targeting drug trametinib is shown here to act with submicromolar activity to block proliferation of Plasmodium spp. in RBCs. Some inhibitors exhibit antimalarial activity with transient exposure to RBCs prior to infection with parasites, providing evidence for host-targeting activity distinct from direct inhibition of the parasite. Conclusions: We report here characterization of small molecules for antiproliferative and host cell-targeting activity for malaria and babesiosis parasites. This resource is relevant for assessment of physiological RBC-parasite interactions and may inform drug development and repurposing efforts.

In vivo assessment of the antiparasitic effects of Allium sativum L. and Artemisia absinthium L. against gastrointestinal parasites in swine from low-input farms.

BACKGROUND: Ethno-veterinary practices could be used as a sustainable developmental tool by integrating traditional phytotherapy and husbandry. Phytotherapeutics are available and used worldwide. However, evidence of their antiparasitic efficacy is currently very limited. Parasitic diseases have a considerable effect on pig production, causing economic losses due to high morbidity and mortality. In this respect, especially smallholders and organic producers face severe challenges. Parasites, as disease causing agents, often outcompete other pathogens in such extensive production systems. A total of 720 faecal samples were collected in two farms from three age categories, i.e. weaners, fatteners, and sows. Flotation (Willis and McMaster method), modified Ziehl-Neelsen stained faecal smear, centrifugal sedimentation, modified Blagg technique, and faecal cultures were used to identify parasites and quantify the parasitic load. RESULTS: The examination confirmed the presence of infections with Eimeria spp., Cryptosporidium spp., Balantioides coli (syn. Balantidium coli), Ascaris suum, Oesophagostomum spp., Strongyloides ransomi, and Trichuris suis, distributed based on age category. A dose of 180 mg/kg bw/day of Allium sativum L. and 90 mg/kg bw/day of Artemisia absinthium L. powders, administered for 10 consecutive days, revealed a strong, taxonomy-based antiprotozoal and anthelmintic activity. CONCLUSIONS: The results highlighted the therapeutic potential of both A. sativum and A. absinthium against gastrointestinal parasites in pigs. Their therapeutic effectiveness may be attributed to the content in polyphenols, tocopherols, flavonoids, sterols, sesquiterpene lactones, and sulfoxide. Further research is required to establish the minimal effective dose of both plants against digestive parasites in pigs.

Cellular Immunity of Drosophila willistoni Reveals Novel Complexity in Insect Anti-Parasitoid Defense.

Coevolution of hosts and their parasites has shaped heterogeneity of effector hemocyte types, providing immune defense reactions with variable effectiveness. In this work, we characterize hemocytes of Drosophila willistoni, a species that has evolved a cellular immune system with extensive variation and a high degree of plasticity. Monoclonal antibodies were raised and used in indirect immunofluorescence experiments to characterize hemocyte subpopulations, follow their functional features and differentiation. Pagocytosis and parasitization assays were used to determine the functional characteristics of hemocyte types. Samples were visualized using confocal and epifluorescence microscopy. We identified a new multinucleated giant hemocyte (MGH) type, which differentiates in the course of the cellular immune response to parasitoids. These cells differentiate in the circulation through nuclear division and cell fusion, and can also be derived from the central hematopoietic organ, the lymph gland. They have a binary function as they take up bacteria by phagocytosis and are involved in the encapsulation and elimination of the parasitoid. Here, we show that, in response to large foreign particles, such as parasitoids, MGHs differentiate, have a binary function and contribute to a highly effective cellular immune response, similar to the foreign body giant cells of vertebrates.

Convergence between helminths and breast cancer: intratumoral injection of the excretory/secretory antigens of the human parasite Toxocara canis (EST) increase lung macro and micro metastasis.

Introduction: Worldwide, breast cancer is the most important cancer in incidence and prevalence in women. Different risk factors interact to increase the probability of developing it. Biological agents such as helminth parasites, particularly their excretory/secretory antigens, may play a significant role in tumor development. Helminths and their antigens have been recognized as inducers or promoters of cancer due to their ability to regulate the host's immune response. Previously in our laboratory, we demonstrated that chronic infection by Toxocara canis increases the size of mammary tumors, affecting the systemic response to the parasite. However, the parasite does not invade the tumor, and we decided to study if the excretion/secretion of antigens from Toxocara canis (EST) can affect the progression of mammary tumors or the pathophysiology of cancer which is metastasis. Thus, this study aimed to determine whether excretion/secretion T. canis antigens, injected directly into the tumor, affect tumor growth and metastasis. Methods: We evaluated these parameters through the monitoring of the intra-tumoral immune response. Results: Mice injected intratumorally with EST did not show changes in the size and weight of the tumors; although the tumors showed an increased microvasculature, they did develop increased micro and macro-metastasis in the lung. The analysis of the immune tumor microenvironment revealed that EST antigens did not modulate the proportion of immune cells in the tumor, spleen, or peripheral lymph nodes. Macroscopic and microscopic analyses of the lungs showed increased metastasis in the EST-treated animals compared to controls, accompanied by an increase in VEGF systemic levels. Discussion: Thus, these findings showed that intra-tumoral injection of T. canis EST antigens promote lung metastasis through modulation of the tumor immune microenvironment.

Infectious Diseases of the Brain and Spine: Parasitic and Other Atypical Transmissible Diseases.

Atypical infections of the brain and spine caused by parasites occur in immunocompetent and immunosuppressed hosts, related to exposure and more prevalently in endemic regions. In the United States, the most common parasitic infections that lead to central nervous system manifestations include cysticercosis, echinococcosis, and toxoplasmosis, with toxoplasmosis being the most common opportunistic infection affecting patients with advanced HIV/AIDS. Another rare but devastating transmittable disease is prion disease, which causes rapidly progressive spongiform encephalopathies. Familiarity and understanding of various infectious agents are a crucial aspect of diagnostic neuroradiology, and recognition of unique features can aid timely diagnosis and treatment.

Outcome of parasitological examinations in dogs in Germany: a retrospective survey.

Dog faecal samples examined from January 2019 to December 2019 were retrospectively analysed for frequency of endoparasites. The examinations were performed with several different methods: 29,219 samples were examined by flotation method and sodium acetate-acetic acid-formalin concentration (SAFC) technique, 1,330 samples by Baermann-Wetzel migration technique, 12,221 samples using a Giardia coproantigen enzyme-linked-immunosorbent assay (ELISA), 1,180 samples using a Cryptosporidium coproantigen ELISA, 1,671 samples by polymerase chain reaction (PCR) testing for Giardia duodenalis and 447 samples by PCR testing for Cryptosporidium spp.. A total of 7.1% of the samples were positive for parasites in the microscopical examination using the flotation method and SAFC technique. The parasites found included Cystoisospora spp. (2.8%), Giardia duodenalis (2.3%), Ancylostomatidae (1.8%), Toxocara canis (1.6%), Trichuris vulpis (0.7%), Toxascaris leonina (0.5%), Capillaria spp. (0.2%), Angiostrongylus vasorum (0.2%), Crenosoma vulpis (0.1%), Taeniidae (0.1%), Sarcocystis spp. (0.03%), Dipylidium caninum (0.01%), Diphyllobothrium latum (< 0.01%), Spirurida (< 0.01%) and Opisthorchiidae (< 0.01%). Using the Baermann-Wetzel migration technique, Angiostrongylus vasorum was found in 0.75% and Crenosoma vulpis in 0.3% of the samples. ELISAs for Giardia duodenalis and Cryptosporidium spp. revealed 13.9% and 1.0% positive faecal samples, and Giardia duodenalis and Cryptosporidium spp. PCRs 19.4% and 2.0%, respectively. Dogs in the first year of life were more frequently infected with parasites than older animals. In the microscopic examination using flotation method and SAFC technique, the significantly highest detection rates were found in dogs up to six months of age (p < 0.001).

Enteric parasites in free-living Mediterranean pond turtle (Mauremys leprosa leprosa) in contrasted areas (natural vs polluted) from central-western of Morocco.

The objective of this study is to assess the occurrence of intestinal parasites in Mediterranean pond turtle Mauremys leprosa leprosa collected from three contrasting environments in Morocco. Stool samples from 92 turtles were examined for parasite detection and enumeration. The identified intestinal parasites belong to helminths (oxyurids and ascarid) and protozoa (Entamoebidae). A total of 25 turtles (27.17%) were found to be infected by helminths and/or protozoan parasites. No adult form of these parasites was detected. Eggs of oxyurid and ascarid were detected in individuals of populations studied from Oued Ksob (23.07% and 30.76% of n = 13 turtles) and Oued Zat (34.14% and 24.39% of n = 41 turtles), respectively. For protozoa, Entamoeba cysts were present in turtles in Oued Ksob (15.38% of n = 13 turtles), Oued Zat (12.19% of n = 41 turtles), and Oued Tensift (5.26% of n = 38 turtles) localities. Oxyurid eggs showed the highest intensity at Oued Zat reaching 29.30 ± 59.59 eggs per gram (EPG), versus 12 ± 0.38 EPG for ascaris eggs in Oued Ksob. Entamoeba cysts were detected in lower levels with a maximum of 1.66 ± 1.50 cysts per gram (CPG), in Oued Zat. The prevalence of turtles eliminating eggs was statistically significant between localities for different parasite groups. This study reports for the first time a parasitological characterization of gastrointestinal parasites in wild populations of M. leprosa leprosa from contrasting environments, suggesting a relationship between turtles' infestation and the quality of their habitat.

A replication competent Plasmodium falciparum parasite completely attenuated by dual gene deletion.

Vaccination with infectious Plasmodium falciparum (Pf) sporozoites (SPZ) administered with antimalarial drugs (PfSPZ-CVac), confers superior sterilizing protection against infection when compared to vaccination with replication-deficient, radiation-attenuated PfSPZ. However, the requirement for drug administration constitutes a major limitation for PfSPZ-CVac. To obviate this limitation, we generated late liver stage-arresting replication competent (LARC) parasites by deletion of the Mei2 and LINUP genes (mei2-/linup- or LARC2). We show that Plasmodium yoelii (Py) LARC2 sporozoites did not cause breakthrough blood stage infections and engendered durable sterilizing immunity against various infectious sporozoite challenges in diverse strains of mice. We next genetically engineered a PfLARC2 parasite strain that was devoid of extraneous DNA and produced cryopreserved PfSPZ-LARC2. PfSPZ-LARC2 liver stages replicated robustly in liver-humanized mice but displayed severe defects in late liver stage differentiation and did not form liver stage merozoites. This resulted in complete abrogation of parasite transition to viable blood stage infection. Therefore, PfSPZ-LARC2 is the next-generation vaccine strain expected to unite the safety profile of radiation-attenuated PfSPZ with the superior protective efficacy of PfSPZ-CVac.

Iron depletion has different consequences on the growth and survival of Toxoplasma gondii strains.

Toxoplasma gondii is an obligate intracellular parasite responsible for a pathology called toxoplasmosis, which primarily affects immunocompromised individuals and developing foetuses. The parasite can scavenge essential nutrients from its host to support its growth and survival. Among them, iron is one of the most important elements needed to sustain basic cellular functions as it is involved in a number of key metabolic processes, including oxygen transport, redox balance, and electron transport. We evaluated the effects of an iron chelator on the development of several parasite strains and found that they differed in their ability to tolerate iron depletion. The growth of parasites usually associated with a model of acute toxoplasmosis was strongly affected by iron depletion, whereas cystogenic strains were less sensitive as they were able to convert into persisting developmental forms that are associated with the chronic form of the disease. Ultrastructural and biochemical characterization of the impact of iron depletion on parasites also highlighted striking changes in both their metabolism and that of the host, with a marked accumulation of lipid droplets and perturbation of lipid homoeostasis. Overall, our study demonstrates that although acute iron depletion has an important effect on the growth of T. gondii, it has a more profound impact on actively dividing parasites, whereas less metabolically active parasite forms may be able to avoid some of the most detrimental consequences.

Insights from structure-activity relationships and the binding mode of peptidic α-ketoamide inhibitors of the malaria drug target subtilisin-like SUB1.

Plasmodium multi-resistance, including against artemisinin, seriously threatens malaria treatment and control. Hence, new drugs are urgently needed, ideally targeting different parasitic stages, which are not yet targeted by current drugs. The SUB1 protease is involved in both hepatic and blood stages due to its essential role in the egress of parasites from host cells, and, as potential new target, it would meet the above criteria. We report here the synthesis as well as the biological and structural evaluation of substrate-based α-ketoamide SUB1 pseudopeptidic inhibitors encompassing positions P4-P2'. By individually substituting each position of the reference compound 1 (MAM-117, Ac-Ile-Thr-Ala-AlaCO-Asp-Glu (Oall)-NH2), we better characterized the structural determinants for SUB1 binding. We first identified compound 8 with IC50 values of 50 and 570 nM against Pv- and PfSUB1, respectively (about 3.5-fold higher potency compared to 1). Compound 8 inhibited P. falciparum merozoite egress in culture by 37% at 100 µM. By increasing the overall hydrophobicity of the compounds, we could improve the PfSUB1 inhibition level and antiparasitic activity, as shown with compound 40 (IC50 values of 12 and 10 nM against Pv- and PfSUB1, respectively, IC50 value of 23 µM on P. falciparum merozoite egress). We also found that 8 was highly selective towards SUB1 over three mammalian serine peptidases, supporting the promising value of this compound. Finally, several crystal 3D-structures of SUB1-inhibitor complexes, including with 8, were solved at high resolution to decipher the binding mode of these compounds.

The cytosolic hyperoxidation-sensitive and -robust Leishmania peroxiredoxins cPRX1 and cPRX2 are both dispensable for parasite infectivity.

Typical two-cysteine peroxiredoxins (2-Cys-PRXs) are H2O2-metabolizing enzymes whose activity relies on two cysteine residues. Protists of the family Trypanosomatidae invariably express one cytosolic 2-Cys-PRX (cPRX1). However, the Leishmaniinae sub-family features an additional isoform (cPRX2), almost identical to cPRX1, except for the lack of an elongated C-terminus with a Tyr-Phe (YF) motif. Previously, cytosolic PRXs were considered vital components of the trypanosomatid antioxidant machinery. Here, we shed new light on the properties, functions and relevance of cPRXs from the human pathogen Leishmania infantum. We show first that LicPRX1 is sensitive to inactivation by hyperoxidation, mirroring other YF-containing PRXs participating in redox signaling. Using genetic fusion constructs with roGFP2, we establish that LicPRX1 and LicPRX2 can act as sensors for H2O2 and oxidize protein thiols with implications for signal transduction. Third, we show that while disrupting the LicPRX-encoding genes increases susceptibility of L. infantum promastigotes to external H2O2in vitro, both enzymes are dispensable for the parasites to endure the macrophage respiratory burst, differentiate into amastigotes and initiate in vivo infections. This study introduces a novel perspective on the functions of trypanosomatid cPRXs, exposing their dual roles as both peroxidases and redox sensors. Furthermore, the discovery that Leishmania can adapt to the absence of both enzymes has significant implications for our understanding of Leishmania infections and their treatment. Importantly, it questions the conventional notion that the oxidative response of macrophages during phagocytosis is a major barrier to infection and the suitability of cPRXs as drug targets for leishmaniasis.

Toxoplasma sortilin interacts with secretory proteins and it is critical for parasite proliferation.

BACKGROUND: The human sortilin protein is an important drug target and detection marker for cancer research. The sortilin from Toxoplasma gondii transports proteins associated with the apical organelles of the parasite. In this study, we aimed to determine the intracellular localization and structural domains of T. gondii sortilin, which may mediate protein transportation. Approaches to the functional inhibition of sortilin to establish novel treatments for T. gondii infections were explored. METHODS: A gene encoding the sortilin protein was identified in the T. gondii genome. Immunoprecipitation and mass spectrometry were performed to identify the protein species transported by T. gondii sortilin. The interaction of each structural domain of sortilin with the transported proteins was investigated using bio-layer interferometry. The binding regions of the transported proteins in sortilin were identified. The effect of the sortilin inhibitor AF38469 on the infectivity of T. gondii was investigated. The binding site of AF38469 on sortilin was determined. RESULTS: The subdomains Vps10, sortilin-C, and sortilin-M of the sortilin were identified as the binding regions for intracellular transportation of the target proteins. The sortilin inhibitor AF38469 bound to the Vps10 structural domain of T. gondii sortilin, which inhibited parasite invasion, replication, and intracellular growth in vitro and was therapeutic in mice infected with T. gondii. CONCLUSION: The Vps10, sortilin-C, and sortilin-M subdomains of T. gondii sortilin were identified as functional regions for intracellular protein transport. The binding region for the sortilin inhibitor AF38469 was also identified as the Vps10 subdomain. This study establishes sortilin as a promising drug target against T. gondii and provides a valuable reference for the development of anti-T. gondii drug-target studies.

To live free or being a parasite: The optimal foraging behavior may favor the evolution of entomopathogenic nematodes.

Facultative parasites can alternate between a free-living and a parasitic existence to complete their life cycle. Yet, it remains uncertain which lifestyle they prefer. The optimal foraging theory suggests that food preferences align with fitness benefits. To test this hypothesis, we investigated the facultative parasite nematode Rhabditis regina, assessing its host preference and the associated benefits. Two experiments were conducted using wild nematode populations collected from Phyllophaga polyphylla, their natural host. In the first experiment, we used a behavioral arena to assess host preference between the natural host and two experimental hosts: Spodoptera frugiperda which is an alternative host and dead Tenebrio molitor, which simulates a saprophytic environment. In the second experiment, we subjected wild nematodes to "experimental evolution" lasting 50 generations in S. frugiperda and 53 generations in T. molitor carcass. We then compared life history traits (the size, survival, number of larvae, and glycogen and triglycerides as energy reserves) of dauer larvae with those nematodes from P. polyphylla (control group). We found a significant preference for P. polyphylla, which correlated with higher values in the nematode's life history traits. In contrast, the preference for S. frugiperda and the saprophytic environment was lower, resulting in less efficient life history traits. These findings align with the optimal foraging theory, as the nematode's parasitic preferences are in line with maximizing fitness. This also indicates that R. regina exhibits specificity to P. polyphylla and is better adapted to a parasitic lifestyle than a free-living one, suggesting an evolutionary pathway towards parasitism.

Theileria parasites sequester host eIF5A to escape elimination by host-mediated autophagy.

Intracellular pathogens develop elaborate mechanisms to survive within the hostile environments of host cells. Theileria parasites infect bovine leukocytes and cause devastating diseases in cattle in developing countries. Theileria spp. have evolved sophisticated strategies to hijack host leukocytes, inducing proliferative and invasive phenotypes characteristic of cell transformation. Intracellular Theileria parasites secrete proteins into the host cell and recruit host proteins to induce oncogenic signaling for parasite survival. It is unknown how Theileria parasites evade host cell defense mechanisms, such as autophagy, to survive within host cells. Here, we show that Theileria annulata parasites sequester the host eIF5A protein to their surface to escape elimination by autophagic processes. We identified a small-molecule compound that reduces parasite load by inducing autophagic flux in host leukocytes, thereby uncoupling Theileria parasite survival from host cell survival. We took a chemical genetics approach to show that this compound induced host autophagy mechanisms and the formation of autophagic structures via AMPK activation and the release of the host protein eIF5A which is sequestered at the parasite surface. The sequestration of host eIF5A to the parasite surface offers a strategy to escape elimination by autophagic mechanisms. These results show how intracellular pathogens can avoid host defense mechanisms and identify a new anti-Theileria drug that induces autophagy to target parasite removal.

Iron Stress Affects the Growth and Differentiation of Toxoplasma gondii.

Iron is an indispensable nutrient for the survival of Toxoplasma gondii; however, excessive amounts can lead to toxicity. The parasite must overcome the host's "nutritional immunity" barrier and compete with the host for iron. Since T. gondii can infect most nucleated cells, it encounters increased iron stress during parasitism. This study assessed the impact of iron stress, encompassing both iron depletion and iron accumulation, on the growth of T. gondii. Iron accumulation disrupted the redox balance of T. gondii while enhancing the parasite's ability to adhere in high-iron environments. Conversely, iron depletion promoted the differentiation of tachyzoites into bradyzoites. Proteomic analysis further revealed proteins affected by iron depletion and identified the involvement of phosphotyrosyl phosphatase activator proteins in bradyzoite formation.

Inhibition of AMPK activation in Echinococcus granulosus sensu stricto limits the parasite's glucose metabolism and survival.

Cystic echinococcosis (CE) is a zoonotic parasitic disease caused by larvae of the Echinococcus granulosus sensu lato (s.l.) cluster. There is an urgent need to develop new drug targets and drug molecules to treat CE. Adenosine monophosphate (AMP)-activated protein kinase (AMPK), a serine/threonine protein kinase consisting of α, ß, and γ subunits, plays a key role in the regulation of energy metabolism. However, the role of AMPK in regulating glucose metabolism in E. granulosus s.l. and its effects on parasite viability is unknown. In this study, we found that targeted knockdown of EgAMPKα or a small-molecule AMPK inhibitor inhibited the viability of E. granulosus sensu stricto (s.s.) and disrupted the ultrastructure. The results of in vivo experiments showed that the AMPK inhibitor had a significant therapeutic effect on E. granulosus s.s.-infected mice and resulted in the loss of cellular structures of the germinal layer. In addition, the inhibition of the EgAMPK/EgGLUT1 pathway limited glucose uptake and glucose metabolism functions in E. granulosus s.s.. Overall, our results suggest that EgAMPK can be a potential drug target for CE and that inhibition of EgAMPK activation is an effective strategy for the treatment of disease.

Surveillance for Selected Pathogens and Parasites of Northern Bobwhite (Colinus virginianus) from Western Oklahoma, USA, 2018-20.

The Northern Bobwhite (Colinus virginianus) has been undergoing a range-wide population decline. Potential causes for declines across its historic range have been investigated for decades and include habitat loss and fragmentation and a variety of parasitic and infectious diseases. Although there have been studies on bobwhite ecology in Oklahoma, USA, relatively little is known about parasites and pathogens in the region. We evaluated the health of free-ranging bobwhites from nine sites in western Oklahoma. From 2018 to 2020, 206 bobwhites were evaluated for gross and microscopic lesions and tested for selected pathogens. In general, bobwhites were in good nutritional condition with ample muscle mass and fat stores. No significant gross lesions were observed in any bobwhite and no significant histologic lesions were detected in a subset. There was no evidence of infection with or exposure to reticuloendotheliosis virus, West Nile virus, respiratory Mycoplasmataceae species, Pasteurella multocida, intestinal Eimeria spp., or oral Trichomonas spp. Several pathogens of potential concern were detected, including avian adenovirus (8.6%), Toxoplasma gondii (2.3%), and haemosporidians (a Haemoproteus sp. (1.5%), Leucocytozoon schoutedeni (1.5%), and Plasmodium homopolare haplotype 2 [lineage LAIRI01; 3.6%]). Physaloptera sp. (12%) and Sarcocystis sp. (1%) were detected in the breast muscle. Low intraspecific genetic diversity was noted for Physaloptera sp., and sequences were most similar to Physaloptera sequences from bobwhites and grasshoppers (Orthoptera) in Texas. Low intensities of chewing lice, chiggers, and ticks were observed. A subset of bobwhites had evidence of exposure to selected toxicants and heavy metals; a small number had low levels of iron, manganese, zinc, molybdenum, and copper, which were not considered diagnostically relevant. In general, bobwhites from western Oklahoma appeared to be in good health with a low diversity of pathogens detected, but future work is needed to understand potentially changing disease risks for this population.

Parasite-induced IFN-γ regulates host defense via CD115 and mTOR-dependent mechanism of tissue-resident macrophage death.

Host resistance to a common protozoan parasite Toxoplasma gondii relies on a coordinated immune response involving multiple cell types, including macrophages. Embryonically seeded tissue-resident macrophages (TRMs) play a critical role in maintaining tissue homeostasis, but their role in parasite clearance is poorly understood. In this study, we uncovered a crucial aspect of host defense against T. gondii mediated by TRMs. Through the use of neutralizing antibodies and conditional IFN-γ receptor-deficient mice, we demonstrated that IFN-γ directly mediated the elimination of TRMs. Mechanistically, IFN-γ stimulation in vivo rendered macrophages unresponsive to macrophage colony-stimulating factor (M-CSF) and inactivated mTOR signaling by causing the shedding of CD115 (CSFR1), the receptor for M-CSF. Further experiments revealed the essential role of macrophage IFN-γ responsiveness in host resistance to T. gondii. The elimination of peritoneal TRMs emerged as an additional host defense mechanism aimed at limiting the parasite's reservoir. The identified mechanism, involving IFN-γ-induced suppression of CD115-dependent mTOR signaling in macrophages, provides insights into the adaptation of macrophage subsets during infection and highlights a crucial aspect of host defense against intracellular pathogens.

Epigenetic regulation as a therapeutic target in the malaria parasite Plasmodium falciparum.

Over the past thirty years, epigenetic regulation of gene expression has gained increasing interest as it was shown to be implicated in illnesses ranging from cancers to parasitic diseases. In the malaria parasite, epigenetics was shown to be involved in several key steps of the complex life cycle of Plasmodium, among which asexual development and sexual commitment, but also in major biological processes like immune evasion, response to environmental changes or DNA repair. Because epigenetics plays such paramount roles in the Plasmodium parasite, enzymes involved in these regulating pathways represent a reservoir of potential therapeutic targets. This review focuses on epigenetic regulatory processes and their effectors in the malaria parasite, as well as the inhibitors of epigenetic pathways and their potential as new anti-malarial drugs. Such types of drugs could be formidable tools that may contribute to malaria eradication in a context of widespread resistance to conventional anti-malarials.