Human babesiosis is a tick-borne multisystem disease, and current treatments have both adverse side effects and a significant rate of drug failure. Lawres et al. report that endochin-like quinolones, in combination with atovaquone, cure experimental babesiosis in immunodeficient mice.
Babesia microti, a tick-transmitted, intraerythrocytic protozoan parasite circulating mainly among small mammals, is the primary cause of human babesiosis. While most cases are transmitted by Ixodes ticks, the disease may also be transmitted through blood transfusion and perinatally. A comprehensive analysis of genome composition, genetic diversity, and gene expression profiling of seven B. microti isolates revealed that genetic variation in isolates from the Northeast United States is almost exclusively associated with genes encoding the surface proteome and secretome of the parasite. Furthermore, we found that polymorphism is restricted to a small number of genes, which are highly expressed during infection. In order to identify pathogen-encoded factors involved in host-parasite interactions, we screened a proteome array comprised of 174 B. microti proteins, including several predicted members of the parasite secretome. Using this immuno-proteomic approach we identified several novel antigens that trigger strong host immune responses during the onset of infection. The genomic and immunological data presented herein provide the first insights into the determinants of B. microti interaction with its mammalian hosts and their relevance for understanding the selective pressures acting on parasite evolution.
Highlights d Obesity accelerates oncogenic Kras-driven pancreatic ductal tumorigenesis in mice d Genetic or dietary weight loss intercepts pancreatic cancer progression d Obesity is associated with aberrant pancreatic islet cholecystokinin expression d Islet cholecystokinin overexpression drives pancreatic ductal cancer development
The positioning of chromosomes in the nucleus of a eukaryotic cell is highly organized and has a complex and dynamic relationship with gene expression. In the human malaria parasite Plasmodium falciparum, the clustering of a family of virulence genes correlates with their coordinated silencing and has a strong influence on the overall organization of the genome. To identify conserved and species-specific principles of genome organization, we performed Hi-C experiments and generated 3D genome models for five Plasmodium species and two related apicomplexan parasites. Plasmodium species mainly showed clustering of centromeres, telomeres, and virulence genes. In P. falciparum, the heterochromatic virulence gene cluster had a strong repressive effect on the surrounding nuclear space, while this was less pronounced in Plasmodium vivax and Plasmodium berghei, and absent in Plasmodium yoelii. In Plasmodium knowlesi, telomeres and virulence genes were more dispersed throughout the nucleus, but its 3D genome showed a strong correlation with gene expression. The Babesia microti genome showed a classical Rabl organization with colocalization of subtelomeric virulence genes, while the Toxoplasma gondii genome was dominated by clustering of the centromeres and lacked virulence gene clustering. Collectively, our results demonstrate that spatial genome organization in most Plasmodium species is constrained by the colocalization of virulence genes. P. falciparum and P. knowlesi, the only two Plasmodium species with gene families involved in antigenic variation, are unique in the effect of these genes on chromosome folding, indicating a potential link between genome organization and gene expression in more virulent pathogens.
by guest on July 10, 2020 http://www.jbc.org/ Downloaded from Figure 1. Continuous in vitro culture of B. duncani in hamster RBCs and transfer to human RBCs. A, parasitemia expressed as the percentage of hamster RBCs infected by the parasite at 1, 2, and 3 days post-inoculation (DPI) in a representative experiment. Columns represent mean Ϯ S.E. (error bars) of six biological replicates. B, micrograph of the intracellular development of cultured B. duncani in hamster RBCs in a Giemsa-stained smear prepared at 3 days post-inoculation. The parasitemia was 15% in this sample. C, transfer of B. duncani to human RBCs. B. duncani-infected hamster RBCs (haRBCs) were freshly harvested and maintained in culture in the presence of human RBCs (hRBCs). Left, free merozoites and infected haRBCs. Right, successful development of B. duncani in hRBCs. Human RBCs are distinguishable from haRBCs by their larger size and darker staining. ACCELERATED COMMUNICATION: In vitro culture of B. duncani
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