sirolimus and Malaria

The mechanistic (or mammalian) target of rapamycin (mTOR) is considered as a critical regulatory enzyme involved in essential signaling pathways affecting cell growth, cell proliferation, protein translation, regulation of cellular metabolism, and cytoskeletal structure. Also, mTOR signaling has crucial roles in cell homeostasis via processes such as autophagy. Autophagy prevents many pathogen infections and is involved on immunosurveillance and pathogenesis. Immune responses and autophagy are therefore key host responses and both are linked by complex mTOR regulatory mechanisms. In recent years, the mTOR pathway has been highlighted in different diseases such as diabetes, cancer, and infectious and parasitic diseases including leishmaniasis, toxoplasmosis, and malaria. The current review underlines the implications of mTOR signals and intricate networks on pathogen infections and the modulation of this master regulator by parasites. Parasitic infections are able to induce dynamic metabolic reprogramming leading to mTOR alterations in spite of many other ways impacting this regulatory network. Accordingly, the identification of parasite effects and interactions over such a complex modulation might reveal novel information regarding the biology of the abovementioned parasites and might allow the development of therapeutic strategies against parasitic diseases. In this sense, the effects of inhibiting the mTOR pathways are also considered in this context in the light of their potential for the prevention and treatment of parasitic diseases.

Topics: Animals; Autophagy; Cell Cycle; Cell Proliferation; Humans; Immunity; Leishmaniasis; Malaria; Parasites; Parasitic Diseases; Phosphorylation; Protein Biosynthesis; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Toxoplasmosis

Mosquito-borne diseases threaten human health, but mosquito control faces various challenges, such as resistance to chemical insecticides. Thus, there is an urgent need for more effective and environment-friendly control agents. Capsaicin can downregulate the mTOR signaling pathway of tumor cells. The TOR signaling pathway can mediate the expression of vitellogenin (Vg) to regulate the fecundity of insects. Whether capsaicin has the potential to inhibit fecundity of mosquitoes by regulating TOR pathway and Vg expression is currently unclear.. Anopheles stephensi were fed with blood of mice administered capsaicin by gavage or sugar containing capsaicin followed by a blood feeding with normal mice. Then, the engorged female mosquitoes were tubed individually and underwent oviposition. The eggs and individuals in the subsequent development stages, including larvae, pupae, and emerging adults, were counted and compared between the capsaicin treatment and control groups. Additionally, total RNA and protein were extracted from the engorged mosquitoes at 24 h post blood feeding. Real-time PCR and western blot were performed to detect the transcriptional level and protein expression of the key fecundity-related molecules of mosquitoes. Finally, TOR signaling pathway was inhibited via rapamycin treatment, and changes in fecundity and the key molecule transcription and protein expression levels were examined to verify the role of TOR signaling pathway in the effect of capsaicin on mosquito fecundity.. The laid and total eggs (laid eggs plus retained eggs) of An. stephensi were significantly reduced by feeding on the blood of capsaicin-treated mice (P < 0.01) or capsaicin-containing sugar (P < 0.01) compared with those in the control group. Moreover, the transcription and protein expression or phosphorylation levels of fecundity-related molecules, such as Akt, TOR, S6K, and Vg, were significantly decreased by capsaicin treatment. However, the effects disappeared between control group and CAP group after the TOR signaling pathway was inhibited by rapamycin.. Capsaicin can decrease the fecundity of An. stephensi by inhibiting the TOR signaling pathway. These data can help us to not only understand the effect of capsaicin on the reproductive ability of An. stephensi and its underlying mechanism, but also develop new efficient, safe, and pollution-free mosquito vector control agents.

Topics: Animals; Anopheles; Capsaicin; Female; Humans; Malaria; Mice; Mosquito Vectors; Signal Transduction; Sirolimus; Sugars; Vitellogenins

Repeated blood meals provide essential nutrients for mosquito egg development and routes for pathogen transmission. The target of rapamycin, the TOR pathway, is essential for vitellogenesis. However, its influence on pathogen transmission remains to be elucidated. Here, we show that rapamycin, an inhibitor of the TOR pathway, effectively suppresses Plasmodium berghei infection in Anopheles stephensi. An. stephensi injected with rapamycin or feeding on rapamycin-treated mice showed increased resistance to P. berghei infection. Exposing An. stephensi to a rapamycin-coated surface not only decreased the numbers of both oocysts and sporozoites but also impaired mosquito survival and fecundity. Transcriptome analysis revealed that the inhibitory effect of rapamycin on parasite infection was through the enhanced activation of immune responses, especially the NF-κB transcription factor REL2, a regulator of the immune pathway and complement system. Knockdown of REL2 in rapamycin-treated mosquitoes abrogated the induction of the complement-like proteins TEP1 and SPCLIP1 and abolished rapamycin-mediated refractoriness to Plasmodium infection. Together, these findings demonstrate a key role of the TOR pathway in regulating mosquito immune responses, thereby influencing vector competence.

Topics: Animals; Anopheles; Female; Gene Expression Profiling; Immunity, Innate; Immunosuppressive Agents; Malaria; Mice; Mice, Inbred BALB C; Mosquito Vectors; Oocysts; Plasmodium berghei; Sirolimus; Sporozoites

It has been reported that non-selective autophagy of infected hepatocytes could facilitate the development of malaria in the liver stage, but the fate of parasites following selective autophagy of infected hepatocytes is still not very clear. Here, we confirmed that sporozoite infection can induce a selective autophagy-like process targeting EEFs (exo-erythrocytic forms) in Hepa1-6. Rapamycin treatment greatly enhanced this process in EEFs and non-selective autophagy of infected Hepa1-6 cells and enhanced the development of the malaria liver stage in vivo. Although rapamycin promoted the fusion of autophagosomes containing the malaria parasite with lysosomes, some parasites inside the autophagosome survived and replicated normally. Further study showed that the maturation of affected autolysosomes was greatly inhibited. Therefore, in addition to the previously described positive role of rapamycin-induced nonselective autophagy of hepatocytes, we provide evidence that the survival of EEFs in the autophagosome of the infected hepatocytes also contributes to rapamycin-enhanced development of the malaria liver stage, possibly due to the suppression of autolysosome maturation by EEFs. These data suggest that the inhibition of autolysosome maturation might be a novel escape strategy used by the malaria liver stage.

Topics: Animals; Antibiotics, Antineoplastic; Autophagosomes; Autophagy; Carcinoma, Hepatocellular; Cell Line, Tumor; Hepatocytes; Host-Parasite Interactions; Liver; Liver Neoplasms; Malaria; Mice; Plasmodium yoelii; Sirolimus; Sporozoites

As global efforts to eliminate malaria intensify, accurate information on vector populations and transmission dynamics is critical for directing control efforts, developing new control tools, and predicting the effects of these interventions under various conditions. Currently available sampling tools for mosquito population monitoring suffer from well-recognized limitations. As reported in this workshop summary, a recent gathering of medical entomologists, modelers, and malaria experts reviewed these issues and agreed that efforts are needed to improve methods to monitor key transmission parameters. Identified needs include standardized methods for sampling of both mosquito adults and larvae, improved tools for mosquito species identification and age-grading, and a better means for determining the entomological inoculation rate.

Topics: Animals; Culicidae; Global Health; Humans; Insect Vectors; Larva; Malaria; Sirolimus

There is an urgent need for the design and development of new and selective drugs for the treatment of malaria and bacterial infections as these pathogens are developing resistance to presently available therapies. Malaria is a life threatening disease in many countries and responsible for almost one million deaths annually. In particular, drug-resistant malarial parasites are hindering effective control of malaria and prompting to find novel druggable targets and develop compounds with mechanism of action different from the conventional drugs. In this quest, efforts were made to determine three-dimensional structures of Plasmodium falciparum and Plasmodium vivax FK506 binding proteins which bind the macrolides (FK506 and rapamycin) and also demonstrate peptidylprolyl cis-trans isomerase activity in a similar manner as human FKBP12. Previous studies revealed that the immunosuppressive drug FK506 exhibits potential anti-malarial activity by binding FK506 binding domains (FKBD). This review focuses on three different types of FK506 binding proteins/domains in pathogens, their structural characteristics and biological roles. Binding ability of these proteins with the macrolides has opened new possibilities to develop selective inhibitors for these novel targets to combat the life threatening infections.

Topics: Bacterial Infections; Drug Delivery Systems; Humans; Immunosuppressive Agents; Malaria; Sirolimus; Tacrolimus; Tacrolimus Binding Proteins