Host heterogeneity affects susceptibility of Babesia microti infection using vector-mediated transmission

Human babesiosis is an emerging tick-borne infectious disease in the US that is primarily caused by the intraerythrocytic piroplasm parasite, Babesia microti (Bm). Clinical presentations of babesiosis can range from asymptomatic or mild symptoms to severe or fatal disease. Severe disease is likely dependent on several undefined variables including host and Bm genetics, immune status, and age-dependent variables. Several gaps in our knowledge exist about the characteristics that define protective immunity and the contribution of host genetics to severe Bm infection. Additionally, many studies use artificial transmission methods (needle inoculation) that are insufficient for understanding how Bm naturally affects host health. Therefore, a significant need exists to identify and characterize polymorphic host genes and pathways that drive variability in tick transmitted Bm infection to better understand specific genotypic signatures linked to disease phenotypes. The Collaborative Cross (CC) mouse resource is a vital tool to bridge the gap between host genotype and disease phenotype by enabling high-resolution quantitative trait loci (QTL) mapping of complex traits in both healthy and diseased individuals. Using the CC resource to link disease phenotype to genotype is a major strength of our proposal because the genomes of these mice are fully sequenced and are easily searchable on various online platforms, reducing the need for time consuming and costly sequencing studies. In Aim 1, we will test the hypothesis that host genetic polymorphisms significantly impact tick transmitted Bm infection, including parasitemia levels during acute disease, resolution of infection, and maintenance of hemoglobin levels during infection. Furthermore, we will evaluate whether the impact of host genetics is dependent on the route of infection (needle vs tick transmission) using CC founder strains. We expect the CC founder strains will exhibit marked heterogeneity in disease phenotype (parasitemia and hemoglobin levels), in response to tick transmission of Bm. In Aim 2, we will perform initial mapping of impactful QTL regions that were found to be associated with Bm pathogenesis. CC recombinant (CC-RI/RIX) strains will be selected based on strains that provide the most comprehensive genomic coverage of the CC founder strains and represent specific disease phenotypes related to acute parasitemia levels, mulitiple versus single waves of parasitemia, resolution of infection, and hemoglobin levels. We expect to detect QTLs of 10% effect size or greater based on previous infection models using the CC mouse resource, however if this is not observed it may suggest that a large number of genetic polymorphisms with small effect size are important for differences in Bm pathogenesis which will be important and valuable new information. These aims are complimentary, but not dependent on one another as our preliminary data has shown that needle inoculation has a strong impact on host genetic polymorphisms. The use of CC mice to identify host QTLs important for regulating parasitemia is an innovative approach that has never been applied to Bm and our findings will provide crucial insights into Bm pathogenesis. Project Number: 1R21AI185273-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Danielle Tufts | Institution: UNIVERSITY OF PITTSBURGH AT PITTSBURGH, PITTSBURGH, PA | Award Amount: $250,573 | Activity Code: R21 | Study Section: Transmission of Vector-Borne and Zoonotic Diseases Study Section [TVZ] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21AI18527301A1