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MBio Oct 2023Members of the coiled-coil-helix-coiled-coil-helix (CHCH) domain protein family are transported into the mitochondrial intermembrane space, where they play important...
Members of the coiled-coil-helix-coiled-coil-helix (CHCH) domain protein family are transported into the mitochondrial intermembrane space, where they play important roles in the biogenesis and function of the organelle. Unexpectedly, the ATP synthase of the apicomplexan harbors CHCH domain-containing subunits of unknown function. As no other ATP synthase studied to date contains this class of proteins, characterizing their function will be of broad interest to the fields of molecular parasitology and mitochondrial evolution. Here, we demonstrate that that two ATP synthase subunits containing CHCH domains are required for parasite survival and for stability and function of the ATP synthase. We also show that knockdown disrupts multiple aspects of the mitochondrial morphology of and that mutation of key residues in the CHCH domains caused mis-localization of the proteins. This work provides insight into the unique features of the apicomplexan ATP synthase, which could help to develop therapeutic interventions against this parasite and other apicomplexans, such as the malaria-causing parasite .
Topics: Animals; Toxoplasma; Mitochondria; Proteins; Parasites; Nitric Oxide Synthase; Adenosine Triphosphate; Protozoan Proteins; Mitochondrial Proteins
PubMed: 37796022
DOI: 10.1128/mbio.01769-23 -
The Kelch13 compartment contains highly divergent vesicle trafficking proteins in malaria parasites.PLoS Pathogens Dec 2023Single amino acid changes in the parasite protein Kelch13 (K13) result in reduced susceptibility of P. falciparum parasites to artemisinin and its derivatives (ART)....
Single amino acid changes in the parasite protein Kelch13 (K13) result in reduced susceptibility of P. falciparum parasites to artemisinin and its derivatives (ART). Recent work indicated that K13 and other proteins co-localising with K13 (K13 compartment proteins) are involved in the endocytic uptake of host cell cytosol (HCCU) and that a reduction in HCCU results in reduced susceptibility to ART. HCCU is critical for parasite survival but is poorly understood, with the K13 compartment proteins among the few proteins so far functionally linked to this process. Here we further defined the composition of the K13 compartment by analysing more hits from a previous BioID, showing that MyoF and MCA2 as well as Kelch13 interaction candidate (KIC) 11 and 12 are found at this site. Functional analyses, tests for ART susceptibility as well as comparisons of structural similarities using AlphaFold2 predictions of these and previously identified proteins showed that vesicle trafficking and endocytosis domains were frequent in proteins involved in resistance or endocytosis (or both), comprising one group of K13 compartment proteins. While this strengthened the link of the K13 compartment to endocytosis, many proteins of this group showed unusual domain combinations and large parasite-specific regions, indicating a high level of taxon-specific adaptation of this process. Another group of K13 compartment proteins did not influence endocytosis or ART susceptibility and lacked detectable vesicle trafficking domains. We here identified the first protein of this group that is important for asexual blood stage development and showed that it likely is involved in invasion. Overall, this work identified novel proteins functioning in endocytosis and at the K13 compartment. Together with comparisons of structural predictions it provides a repertoire of functional domains at the K13 compartment that indicate a high level of adaption of endocytosis in malaria parasites.
Topics: Animals; Antimalarials; Plasmodium falciparum; Parasites; Protozoan Proteins; Drug Resistance; Malaria, Falciparum; Mutation
PubMed: 38039338
DOI: 10.1371/journal.ppat.1011814 -
Cells Oct 2023Tuft cells have recently emerged as the focus of intense interest following the discovery of their chemosensory role in the intestinal tract, and their ability to... (Review)
Review
Tuft cells have recently emerged as the focus of intense interest following the discovery of their chemosensory role in the intestinal tract, and their ability to activate Type 2 immune responses to helminth parasites. Moreover, they populate a wide range of mucosal tissues and are intimately connected to immune and neuronal cells, either directly or through the release of pharmacologically active mediators. They are now recognised to fulfil both homeostatic roles, in metabolism and tissue integrity, as well as acting as the first sensors of parasite infection, immunity to which is lost in their absence. In this review we focus primarily on the importance of tuft cells in the intestinal niche, but also link to their more generalised physiological role and discuss their potential as targets for the treatment of gastrointestinal disorders.
Topics: Animals; Intestinal Mucosa; Helminths; Parasitic Diseases; Parasites; Immunity
PubMed: 37887321
DOI: 10.3390/cells12202477 -
Proceedings. Biological Sciences Jan 2024Environmental temperature fundamentally shapes insect physiology, fitness and interactions with parasites. Differential climate warming effects on host versus parasite...
Environmental temperature fundamentally shapes insect physiology, fitness and interactions with parasites. Differential climate warming effects on host versus parasite biology could exacerbate or inhibit parasite transmission, with far-reaching implications for pollination services, biocontrol and human health. Here, we experimentally test how controlled temperatures influence multiple components of host and parasite fitness in monarch butterflies () and their protozoan parasites . Using five constant-temperature treatments spanning 18-34°C, we measured monarch development, survival, size, immune function and parasite infection status and intensity. Monarch size and survival declined sharply at the hottest temperature (34°C), as did infection probability, suggesting that extreme heat decreases both host and parasite performance. The lack of infection at 34°C was not due to greater host immunity or faster host development but could instead reflect the thermal limits of parasite invasion and within-host replication. In the context of ongoing climate change, temperature increases above current thermal maxima could reduce the fitness of both monarchs and their parasites, with lower infection rates potentially balancing negative impacts of extreme heat on future monarch abundance and distribution.
Topics: Animals; Humans; Butterflies; Parasites; Host-Parasite Interactions; Extreme Heat; Apicomplexa
PubMed: 38228180
DOI: 10.1098/rspb.2023.2305 -
Proceedings of the National Academy of... Jul 2023To ensure their survival in the human bloodstream, malaria parasites degrade up to 80% of the host erythrocyte hemoglobin in an acidified digestive vacuole. Here, we...
To ensure their survival in the human bloodstream, malaria parasites degrade up to 80% of the host erythrocyte hemoglobin in an acidified digestive vacuole. Here, we combine conditional reverse genetics and quantitative imaging approaches to demonstrate that the human malaria pathogen employs a heteromultimeric V-ATPase complex to acidify the digestive vacuole matrix, which is essential for intravacuolar hemoglobin release, heme detoxification, and parasite survival. We reveal an additional function of the membrane-embedded V-ATPase subunits in regulating morphogenesis of the digestive vacuole independent of proton translocation. We further show that intravacuolar accumulation of antimalarial chemotherapeutics is surprisingly resilient to severe deacidification of the vacuole and that modulation of V-ATPase activity does not affect parasite sensitivity toward these drugs.
Topics: Animals; Humans; Antimalarials; Adenosine Triphosphatases; Vacuoles; Malaria, Falciparum; Plasmodium falciparum; Parasites
PubMed: 37463201
DOI: 10.1073/pnas.2306420120 -
Nature Communications Aug 2023The gut microbiota is a crucial modulator of Plasmodium infection in mosquitoes, including the production of anti-Plasmodium effector proteins. But how the...
The gut microbiota is a crucial modulator of Plasmodium infection in mosquitoes, including the production of anti-Plasmodium effector proteins. But how the commensal-derived effectors are translocated into Plasmodium parasites remains obscure. Here we show that a natural Plasmodium blocking symbiotic bacterium Serratia ureilytica Su_YN1 delivers the effector lipase AmLip to Plasmodium parasites via outer membrane vesicles (OMVs). After a blood meal, host serum strongly induces Su_YN1 to release OMVs and the antimalarial effector protein AmLip into the mosquito gut. AmLip is first secreted into the extracellular space via the T1SS and then preferentially loaded on the OMVs that selectively target the malaria parasite, leading to targeted killing of the parasites. Notably, these serum-induced OMVs incorporate certain serum-derived lipids, such as phosphatidylcholine, which is critical for OMV uptake by Plasmodium via the phosphatidylcholine scavenging pathway. These findings reveal that this gut symbiotic bacterium evolved to deliver secreted effector molecules in the form of extracellular vesicles to selectively attack parasites and render mosquitoes refractory to Plasmodium infection. The discovery of the role of gut commensal-derived OMVs as carriers in cross-kingdom communication between mosquito microbiota and Plasmodium parasites offers a potential innovative strategy for blocking malaria transmission.
Topics: Animals; Phosphatidylcholines; Parasites; Plasmodium; Biological Transport; Culicidae
PubMed: 37620328
DOI: 10.1038/s41467-023-40887-6 -
Proceedings of the National Academy of... Jul 2023The malaria parasite has a nonphotosynthetic plastid called the apicoplast, which contains its own genome. Regulatory mechanisms for apicoplast gene expression remain...
The malaria parasite has a nonphotosynthetic plastid called the apicoplast, which contains its own genome. Regulatory mechanisms for apicoplast gene expression remain poorly understood, despite this organelle being crucial for the parasite life cycle. Here, we identify a nuclear-encoded apicoplast RNA polymerase σ subunit (sigma factor) which, along with the α subunit, appears to mediate apicoplast transcript accumulation. This has a periodicity reminiscent of parasite circadian or developmental control. Expression of the apicoplast subunit gene, , together with apicoplast transcripts, increased in the presence of the blood circadian signaling hormone melatonin. Our data suggest that the host circadian rhythm is integrated with intrinsic parasite cues to coordinate apicoplast genome transcription. This evolutionarily conserved regulatory system might be a future target for malaria treatment.
Topics: Animals; Apicoplasts; Parasites; Cues; Plasmodium falciparum; Malaria; Protozoan Proteins
PubMed: 37406097
DOI: 10.1073/pnas.2214765120 -
PLoS Neglected Tropical Diseases Oct 2023Trichomonas vaginalis is a human infective parasite responsible for trichomoniasis-the most common, non-viral, sexually transmitted infection worldwide. T. vaginalis...
Trichomonas vaginalis is a human infective parasite responsible for trichomoniasis-the most common, non-viral, sexually transmitted infection worldwide. T. vaginalis resides exclusively in the urogenital tract of both men and women. In women, T. vaginalis has been found colonizing the cervix and vaginal tract while in men it has been identified in the upper and lower urogenital tract and in secreted fluids such as semen, urethral discharge, urine, and prostatic fluid. Despite the over 270 million cases of trichomoniasis annually worldwide, T. vaginalis continues to be a highly neglected organism and thus poorly studied. Here we have developed a male mouse model for studying T. vaginalis pathogenesis in vivo by delivering parasites into the murine urogenital tract (MUT) via transurethral catheterization. Parasite burden was assessed ex-vivo using a nanoluciferase-based gene expression assay which allowed quantification of parasites pre- and post-inoculation. Using this model and read-out approach, we show that T. vaginalis can be found within MUT tissue up to 72 hrs post-inoculation. Furthermore, we also demonstrate that parasites that exhibit increased parasite adherence in vitro also have higher parasite burden in mice in vivo. These data provide evidence that parasite adherence to host cells aids in parasite persistence in vivo and molecular determinants found to correlate with host cell adherence in vitro are applicable to infection in vivo. Finally, we show that co-inoculation of T. vaginalis extracellular vesicles (TvEVs) and parasites results in higher parasite burden in vivo. These findings confirm our previous in vitro-based predictions that TvEVs assist the parasite in colonizing the host. The establishment of this pathogenesis model for T. vaginalis sets the stage for identifying and examining parasite factors that contribute to and influence infection outcomes.
Topics: Male; Humans; Female; Animals; Mice; Trichomonas vaginalis; Parasites; Trichomonas Infections; Vagina; Extracellular Vesicles
PubMed: 37871037
DOI: 10.1371/journal.pntd.0011693 -
Journal of Biochemistry Dec 2023Iron is involved in many biochemical processes including oxygen transport, ATP production, DNA synthesis and antioxidant defense. The importance of iron also applies to... (Review)
Review
Iron is involved in many biochemical processes including oxygen transport, ATP production, DNA synthesis and antioxidant defense. The importance of iron also applies to Leishmania parasites, an intracellular protozoan pathogen causing leishmaniasis. Leishmania are heme-auxotrophs, devoid of iron storage proteins and the heme synthesis pathway. Acquisition of iron and heme from the surrounding niche is thus critical for the intracellular survival of Leishmania inside the host macrophages. Moreover, Leishmania parasites are also exposed to oxidative stress within phagolysosomes of macrophages in mammalian hosts, and they need iron superoxide dismutase for overcoming this stress. Therefore, untangling the strategy adopted by these parasites for iron acquisition and utilization can be good targets for the development of antileishmanial drugs. Here, in this review, we will address how Leishmania parasites acquire and utilize iron and heme during infection to macrophages.
Topics: Animals; Leishmania; Iron; Parasites; Leishmaniasis; Heme; Mammals
PubMed: 37830941
DOI: 10.1093/jb/mvad082 -
Proceedings of the National Academy of... Jul 2023Crozier's paradox suggests that genetic kin recognition will not be evolutionarily stable. The problem is that more common tags (markers) are more likely to be...
Crozier's paradox suggests that genetic kin recognition will not be evolutionarily stable. The problem is that more common tags (markers) are more likely to be recognized and helped. This causes common tags to increase in frequency, eliminating the genetic variability that is required for genetic kin recognition. Two potential solutions to this problem have been suggested: host-parasite coevolution and multiple social encounters. We show that the host-parasite coevolution hypothesis does not work as commonly assumed. Host-parasite coevolution only stabilizes kin recognition at a parasite resistance locus if parasites adapt rapidly to hosts and cause intermediate or high levels of damage (virulence). Additionally, when kin recognition is stabilized at a parasite resistance locus, this can have an additional cost of making hosts more susceptible to parasites. However, we show that if the genetic architecture is allowed to evolve, meaning natural selection can choose the recognition locus, genetic kin recognition is more likely to be stable. The reason for this is that host-parasite coevolution can maintain tag diversity at another (neutral) locus by genetic hitchhiking, allowing that other locus to be used for genetic kin recognition. These results suggest a way that host-parasite coevolution can resolve Crozier's paradox, without making hosts more susceptible to parasites. However, the opportunity for multiple social encounters may provide a more robust resolution of Crozier's paradox.
Topics: Animals; Parasites; Selection, Genetic; Adaptation, Physiological; Virulence; Host-Parasite Interactions; Biological Evolution
PubMed: 37463213
DOI: 10.1073/pnas.2220761120