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Infection by Trypanosoma cruzi, the protozoan parasite that causes Chagas disease, depends on reactive oxygen species (ROS), which has been described to induce parasite proliferation in mammalian host cells. It is unknown how the parasite manages to increase host ROS levels. Here, we found that intracellular T. cruzi forms release in the host cytosol its major cyclophilin of 19 kDa (TcCyp19). Parasites depleted of TcCyp19 by using CRISPR/Cas9 gene replacement proliferate inefficiently and fail to increase ROS, compared to wild type parasites or parasites with restored TcCyp19 gene expression. Expression of TcCyp19 in L6 rat myoblast increased ROS levels and restored the proliferation of TcCyp19 depleted parasites. These events could also be inhibited by cyclosporin A, (a cyclophilin inhibitor), and by polyethylene glycol‐linked to antioxidant enzymes. TcCyp19 was found more concentrated in the membrane leading edges of the host cells in regions that also accumulate phosphorylated p47phox, as observed to the endogenous cyclophilin A, suggesting some mechanisms involved with the translocation process of the regulatory subunit p47phox in the activation of the NADPH oxidase enzymatic complex. We concluded that cyclophilin released in the host cell cytosol by T. cruzi mediates the increase of ROS, required to boost parasite proliferation in mammalian hosts. [ABSTRACT FROM AUTHOR]

Is the etiological agent of American trypanosomiasis, or Chagas disease, and is transmitted mainly by blood-sucking reduviid insects in endemic countries. The parasites in the tissues, associated with an immune response, contribute to the chronic symptoms of the disease. The Brazilian physician Carlos Chagas first discovered the parasite and defined its life cycle, vector, and disease symptoms. [Extracted from the article]

Summary Kinetoplastids cause Chagas disease, human African trypanosomiasis, and leishmaniases. Current treatments for these diseases are toxic and inefficient, and our limited knowledge of drug targets and inhibitors has dramatically hindered the development of new drugs. Here we used a chemogenetic approach to identify new kinetoplastid drug targets and inhibitors. We conditionally knocked down Trypanosoma brucei inositol phosphate (IP) pathway genes and showed that almost every pathway step is essential for parasite growth and infection. Using a genetic and chemical screen, we identified inhibitors that target IP pathway enzymes and are selective against T. brucei . Two series of these inhibitors acted on T. brucei inositol polyphosphate multikinase (IPMK) preventing Ins(1,4,5)P3 and Ins(1,3,4,5)P4 phosphorylation. We show that IPMK is functionally conserved among kinetoplastids and that its inhibition is also lethal for Trypanosoma cruzi . Hence, IP enzymes are viable drug targets in kinetoplastids, and IPMK inhibitors may aid the development of new drugs. [ABSTRACT FROM AUTHOR]

Parasitic diseases affect millions of individuals worldwide, mainly in low-income regions. There is no cure for most of these diseases, and the treatment relies on drugs that have side effects and lead to drug resistance, emphasizing the urgency to find new treatments. Snake venom has been gaining prominence as a rich source of molecules with antiparasitic potentials, such as phospholipases A 2 (PLA 2 s). Here, we compile the findings involving PLA 2 s with antiparasitic activities against helminths, Plasmodium , Toxoplasma , and trypanosomatids. We indicate their molecular features, highlighting the possible antiparasitic mechanisms of action of these proteins. We also demonstrate interactions between PLA 2 s and some parasite membrane components, shedding light on potential targets for drug design that may provide better treatment for the illnesses caused by parasites. Despite treatments available (most of them inefficient), human parasitic diseases are still affecting millions of individuals worldwide. Snake venoms are a rich source of bioactive molecules (small molecules, peptides, and proteins) potentially useful for various biotechnological applications. PLA 2 s, important snake-venom components, have striking features that make this class of proteins an excellent candidate to be used as anti-infectious agents. Recent data suggest that both Asp49 and Lys49 svPLA 2 s can promote pharmacological effects regardless of their catalytic activity. [ABSTRACT FROM AUTHOR]