Location: Ruminant Diseases and Immunology Research
Project Number: 5030-32000-236-000-D
Project Type: In-House Appropriated
Start Date: Oct 1, 2021
End Date: Sep 30, 2026
Objective 1: Define the virulence determinants and mechanisms used by Mannheimia haemolytica, Pasteurella multocida, Mycoplasma bovis and Mycoplasma mycoides cluster agents to cause disease in ruminant species. Subobjective 1.1: Identify microbial mechanisms used by commensal bacteria to become pathogens. Subobjective 1.2: Identify the mechanisms of bacterial colonization of the host. Objective 2: Determine the host-pathogen interactions associated with infection with Mannheimia haemolytica, Pasteurella multocida, Mycoplasma bovis and Mycoplasma mycoides cluster agents, including development of animal models. Subobjective 2.1: Continue the development of animal disease models to study respiratory disease complex. Subobjective 2.2: Identify the host factors that drive the early innate immune response to bacterial infection. Subobjective 2.3: Characterize functional genomics of the host associated with respiratory infection. Objective 3: Develop intervention strategies to prevent or treat respiratory infections that minimizes the development of antibiotic resistant bacteria. This includes the development of easily administered vaccines and developing and evaluating immune-modulators to prevent and/or treat respiratory disease. Subobjective 3.1: Develop and test vaccines that induce early immunity in young animals. Subobjective 3.2: Develop and test vaccines that induce early mucosal immunity in young animals. Objective 4: Following identification of virulence determinants, utilize synthetic genome and other approaches to engineer Mycoplasma mycoides cluster agents for enhancing the understanding of disease pathogenesis and for use as potential vaccines. Subobjective 4.1: To determine if hydrogen peroxide (H2O2) is a virulence determinant in-vivo. Subobjective 4.2: Identify MmmSC virulence determinants and vaccine targets through NextGen genomic sequencing and analysis using archived, newly obtained MmmSC field and experimental strains. Subobjective 4.3: Identify MmmSC virulence determinants and vaccine targets through NextGen transcriptomic sequencing and analysis of bacteria and host during infection. Subobjective 4.4: To develop a synthetic genomic live attenuated vaccine (LAV) approach. Subobjective 4.5: Development of a subunit vaccine. Objective 5: Determine the role of surface lipoproteins for vaccine enhancement of disease in Mycoplasma mycoides subsp. mycoides small colony.
Binding of bacteria to mucosal surfaces, and evasion of host innate, and adaptive immunity are critical to successful colonization and maintenance of infection. Identification of key molecular players in these interactions should enable potentially effective intervention strategies. We plan to utilize a coordinated, multipronged approach to characterize molecular mechanisms promoting respiratory bacterial colonization, adherence, and persistence in cattle. While much knowledge has been gained from studying individual pathogens, less is known concerning co-infections involving bacterial and viral pathogens. Given the expertise of our research team, we will focus on BHV-1 and BRSV as the viral pathogens, and Mannheimia haemolytica, Pasteurella multocida, and Mycoplasma bovis as the bacterial agents. Mycoplasma mycoides was added to this project by the USDA Animal Health NPLs in response to congressional appropriations. A research team from the University of Connecticut will carry out objectives related to M. mycoides cluster agents in collaboration with ARS researchers. We will continue the development of experimental animal models and specific mutants to describe molecular mechanisms enabling bacteria to colonize the respiratory tract and examine influences of primary viral infection on secondary bacterial infections. Bacterial genes or gene products so identified, will be used for developing and testing novel vaccines and/or immunomodulators. The overriding goal is to reduce or eliminate BRDC, which will substantially benefit producers. However, as specific pathogens involved in BRDC can cause significant disease in wild ruminants, there are aspects of this plan that include isolates from those species. For example, M. bovis has emerged in bison, causing substantial economic losses and threatening stability of heritage herds. Therefore, strategies to reduce respiratory disease in wildlife will be valuable to the public interest in sustaining these populations, as well as reduce economic losses to producers.