Project : USDA ARS

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Research Project: Control Strategies for Bovine Babesiosis

2023 Annual Report

Objectives
This project aims to develop a risk mitigation plan to reduce threats associated with bovine babesiosis for the U.S. livestock industry. To develop bovine babesiosis control strategies, there are significant knowledge gaps regarding Babesia-mammalian-tick host interactions that need to be addressed. These gaps include a lack of understanding of Babesia stage-specific protein expression, limited knowledge regarding drug therapy efficacy and safety, and genetic conservation among geographically distinct Babesia isolates. Additionally, little progress has been made on characterizing the mechanisms regulating a protective immune response to bovine babesiosis, understanding the risk of introducing pathogens into disease-free regions by wildlife, and rapidly changing environmental factors. This plan will address these knowledge gaps by developing diagnostic assays for detecting cattle infected with Babesia spp., discovery and testing of potential Babesia antigen targets expressed by the parasite during its development within cattle or tick vectors, development of efficacious and safe treatment regimens to control babesiosis, characterizing the immune response to Babesia and identification of targets that can be used to develop a vaccine, and developing mathematical models to predict the spread of bovine babesiosis parasites into U.S. herds. This project will address the following objectives. Objective 1: Develop intervention strategies to minimize the impact of bovine babesiosis outbreaks, to include vaccine and therapeutic development to prevent clinical disease or block transmission of bovine babesiosis. Sub-objective 1A: Improve molecular and serologic diagnostic assays for bovine babesiosis. Sub-objective 1B: Evaluate the capacity of bovine antibodies against Babesia gamete and kinete surface antigens to minimize the impact of bovine babesiosis outbreaks. Sub-objective 1C: Assess the efficacy of chemotherapeutic approaches to eliminate Babesia pathogens and disrupt transmission. Objective 2: Characterize the immune response to infection with Babesia bovis, to include identifying targets that can be used as correlates of protection and examining age-specific differences. Sub-objective 2A: Investigate age-specific immune response differences to acute Babesia bovis infection between naïve young calves and adult cattle. Sub-objective 2B: Identify Babesia bovis proteins required to induce an immune response that mitigates disease severity. Objective 3: Develop predictive models of potential Babesia disease spread in the United States to assist in mitigating potential future outbreaks. Sub-objective 3A: Develop prediction models of potential Babesia parasite spread into the United States.

Approach
Objective 1: Develop intervention strategies to minimize the impact of bovine babesiosis outbreaks, to include vaccine and therapeutic development to prevent clinical disease or block transmission of bovine babesiosis. Goals: The research will focus on developing strategies for mitigating or preventing bovine babesiosis outbreaks. Specifically, 1) develop cost-effective diagnostic assays for detecting cattle infected with B. bovis and/or B. bigemina, which are major threats to the U.S. cattle industry, 2) evaluate bovine antibodies against Babesia tick stage-specific parasites for their capacity to prevent transmission and reduce acute disease, and 3) identify efficient drug(s) to clear infection to minimize the impact of bovine babesiosis outbreaks. Objective 2: Characterize the immune response to infection with Babesia bovis, to include identifying targets that can be used as correlates of protection and examining age-specific differences. Goals: The research will focus on a comprehensive characterization of the immune response of calves to infection with B. bovis and defining cytokines/chemokines associated with reduced disease severity. Also, Babesia surface proteins will be identified and utilized to understand immune mechanisms responsible for controlling Babesia infection within the mammalian host. The outcome will provide a strong foundation for future Babesia subunit vaccine development. Objective 3: Develop predictive models of potential Babesia disease spread in the United States to assist in mitigating potential future outbreaks. Goal: The research focus will be to develop and validate models that better predict areas at risk of Babesia parasite introduction into the United States.

Progress Report
The current research plan (2090-32000-040-000D) addresses critical gaps in our knowledge concerning diagnosis, pathogenesis, transmissibility, chemotherapy, and vaccine development for bovine babesiosis, a lethal disease that affects cattle in many parts of the world. In support of Objective 1, progress has been made on all sub-objectives. For Sub-objective 1A, ARS researchers in Pullman, Washington, improved molecular diagnostic assays to detect Babesia parasites from infected animals. The optimized molecular diagnostic methods were applied to evaluate babesiosis incidence in an endemic area in Egypt. Proteins were expressed to determine if antibodies from infected animals react with the recombinant version of protein. For Subobjective 1B, animals were vaccinated with recombinant protein to determine if antibodies prevent parasite transmission. The results demonstrated that immunized animals prevent tick infection and, consequently, block parasite transmission to susceptible animals. In support of Sub-objective 1C, additional babesicidal drugs were tested in in vitro conditions to determine drug efficacy. In support of Objective 2, progress has been made in all sub-objectives. For Sub-objective 2A, results demonstrated bovines vaccinated with live parasites were protected against disease. For both adults and young bovines, the result demonstrated the live parasite vaccine caused mild disease, and all vaccinated animals recovered. In addition, all vaccinated animals survived against challenge with a lethal dose of virulent parasites. For Sub-objective 2B, parasite proteins were identified and categorized, in order to be tested as potential vaccine candidates. Parasite genomes from different strains have been sequenced. Recombinant proteins are being expressed to test if they can be recognized by bovine antibody derived from experimentally infected and protected bovines. In support of Objective 3, progress has also been made. For Sub-objective 3A, new data sets were collected, and modeling was initiated to predict the potential for tick and parasite spread. Distribution data of wildlife hosts known to support cattle fever ticks in Texas (white-tailed deer [Odocoileus virginianus] and nilgai [Bosephalus tragocamelus]), were collected to determine the potential exposure of cattle to ticks at the wildlife-livestock interface. In addition, historical cattle fever tick distribution data have been collected to identify climate change and weather patterns factors that may affect tick distributions. Also, humidity and temperature data were collected to evaluate their impact on animal and tick distribution. For subordinate projects, substantial progress was obtained including testing infection of ticks fed on animals vaccinated with parasite proteins related to Sub-objective 1B and expression of proteins for vaccine development related to Sub-objective 2B.

Accomplishments
1. Identification of vaccine and druggable targets to prevent transmission of bovine babesiosis. Bovine babesiosis, a lethal disease that affects cattle in many parts of the world, is transmitted efficiently by tick vectors. It has been estimated that if these parasites spread in the United States, they may be responsible for the death of approximately 90% of naïve adult cattle exposed, thus causing tremendous economic losses in the affected areas. A lack of knowledge about expression of protein families during different life stages of the parasite hinders vaccine development. ARS researchers at Pullman, Washington, have characterized a family of proteins known as the “Thrombospondin-related anonymous protein” (TRAP) family. Members of the TRAP family are likely involved in host cell invasion and parasite development and are differentially expressed by Babesia parasites within cattle and ticks. These results can be used in vaccine development to assist the livestock industry to control bovine babesiosis and, consequently, prevent significant economic burden to cattle producers.

2. A balanced proinflammatory and anti-inflammatory immune response are important for protection against acute bovine babesiosis. Parasites transmitted by tick vectors are causative agents of bovine babesiosis, a disease that negatively impacts the cattle industry and food safety around the world. Understanding the components of the immune system associated with the prevention of bovine babesiosis following immunization is fundamental for vaccine development. ARS researchers in Pullman, Washington, determined that neutrophils, monocytes, and T lymphocytes coupled with a balanced pro- and anti-inflammatory immune response are important for preventing disease. These results are critical for evaluating subunit vaccine candidates and designing effective vaccines to prevent bovine babesiosis, which would improve animal health and production worldwide. These findings have direct implications for designing vaccines and control programs to reduce the negative impact of bovine babesiosis on the cattle industry.

U.S. DEPARTMENT OF AGRICULTURE

Animal Disease Research: Pullman, WA