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Research Project: Development of Detection and Control Strategies for Bovine Babesiosis and Equine Piroplasmosis

Location: Animal Disease Research

Title: Advances in understanding of the immune response to mycobacterial pathogens and vaccines through use of cattle and Mycobacterium avium subsp. paratuberculosis as a prototypic mycobacterial pathogen

item DAVIS, WIILIAM - Washington State University
item ABDELLRAZEQ, GABER - Washington State University
item MAHMOUD, ASMAA - Washington State University
item PARK, KUN-TAEK - Inje University
item ELNAGGAR, MAHMOUD - Washington State University
item DONOFRIO, GAETANO - University Of Parma
item HULUBEI, VICTORIA - Washington State University
item Fry, Lindsay

Submitted to: Vaccines
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/23/2021
Publication Date: 9/26/2021
Citation: Davis, W.C., Abdellrazeq, G.S., Mahmoud, A.H., Park, K., Elnaggar, M.M., Donofrio, G., Hulubei, V., Fry, L.M. 2021. Advances in understanding of the immune response to mycobacterial pathogens and vaccines through use of cattle and Mycobacterium avium subsp. paratuberculosis as a prototypic mycobacterial pathogen. Vaccines. 9(10). Article 1085.

Interpretive Summary: The development of a vaccine to protect cattle from Johnes Disease, caused by Mycobacterium avium subsp. paratuberculosis, is of urgent importance to reduce animal losses and improve meat and milk yields from cattle. Protective immunity to this organism requires the development of functional CD4+ helper T cell- and CD8+ cytotoxic T lymphocyte (CTL) responses. In this review, we summarize work to develop and test a subunit vaccine for M. avium subsp. paratuberculosis. The review includes discussion of the discovery of the importance of the relA gene in M. avium subsp. paratuberculosis survival and immune response evasion, and the discovery of a protective candidate vaccine antigen within the relA gene, known as MMP. The review also discusses progress made in the development of improved reagents and T-cell assays for use in studying the immune system of cattle and other livestock species.

Technical Abstract: Progress toward development of a vaccine that limits progression of Mycobacterium avium subsp. paratuberculosis (Map) infection to clinical disease, or that induces sterile immunity, has been incremental and closely associated with increases in knowledge on the origins of Map, evidence that Map is a pathogen with a broad host range that includes humans, and enhanced understanding of mechanisms that regulate the immune response to mycobacterial pathogens. As discussed in the present review, it is not clear exactly when the first lineage of mycobacteria acquired the genes that facilitated survival in vertebrate hosts. These events occurred before the dawn of civilization and the lifestyle transition from hunter-gatherers to nomadic pastoralists that domesticated animals for use in farming. However, phylogenomics has facilitated tracing of the evolution and expansion of mycobacterial species that have become pathogens of humans and livestock. A better understanding of the factors regulating the immune response to mycobacterial pathogens has developed in parallel with advances in the understanding of the immune system of humans and animals, especially cattle. Use of cattle as a model species to study the immune response to mycobacteria, with Map as a prototype mycobacterium for comparative studies, have yielded data showing a gene involved in regulating the stringent response, relA, is an Achilles’s heel for mycobacterial pathogens. Deletion of relA abrogates the capacity of Map to establish a persistent infection. Immunization with a relA deletion mutant leads to development of CD8 cytotoxic T cells (CTL) with ability to kill intracellular bacteria. Immunization with an M. bovis Calmette-Guérin (BCG) relA deletion mutant also elicits development of CTL with identical activity. Analysis of the immune response to the Map relA deletion mutant has shown the target of the immune response is a 35 kD membrane protein. The studies conducted thus far suggest it will be possible to use relA deletion mutants as attenuated vaccines for different lineages of mycobacterial pathogens and subsequently, to identify peptide targets for the development of peptide-based vaccines. Methods developed to conduct comparative studies on the immune response to mycobacterial pathogens in cattle can also be used with other species including humans.