Repository logo
 

THE ROLE AND MECHANISM OF PARAHYDROXYBENZOIC ACID DERIVATIVES IN BOVINE TB PATHOGENESIS

Date

2021-11-30

Journal Title

Journal ISSN

Volume Title

Publisher

ORCID

Type

Thesis

Degree Level

Doctoral

Abstract

Bovine tuberculosis (bTB), caused by Mycobacterium bovis imposes a significant financial burden on the global cattle industry. Although considerable effort is being spent developing vaccines for bTB disease prevention and control, a licensed vaccine for use in cattle has yet to emerge. Mycobacterial cell envelope antigens are known to interact with the host immune system and contribute to TB pathogenesis. Thus, a better understanding of the effects of M. bovis cell envelope antigens on the bovine immune system will aid the rational development of effective bTB vaccines. In this thesis, I first report a comparative analysis of the immune-stimulatory effects of various fractions of the M. bovis cell envelope on bovine dendritic cells (bDCs), which are key immune cells required for TB control by the host. I found that the cell surface sugar extract (CSSE) fraction is the least immune-stimulatory suggesting that this fraction might contain an immunosuppressive molecule. Given that CSSE fractions of the M. tuberculosis complex are enriched in phenolic glycans, including para-hydroxy benzoic acid derivatives (p-HBADs), which are known to have immunosuppressive properties, I then examined the immunomodulatory effects of p-HBAD-1, the major p-HBAD made by M. bovis on bDCs. I found that p-HBAD-1 has opposing effects in non-primed and IFN-γ primed bDCs in vitro. In non-primed bDCs, p-HBAD-1 induces a tolerogenic response, while a pro-inflammatory response is observed with IFN-γ primed bDCs. These findings suggest that M. bovis p-HBAD-1 is an immune-regulatory molecule that might have a dual function in bTB pathogenesis. Finally, I successfully prepared plasmid constructs required to disrupt the gene encoding a key enzyme involved in p-HBAD synthesis in M. bovis. These will be used in future efforts to generate an M. bovis mutant deficient in p-HBAD-1 for detailed studies in animal models of TB.

Description

Keywords

Mycobacterium bovis, Parahydroxybenzoic acid derivatives, Immune response, Immune tolerance, Pathogenesis.

Citation

Degree

Doctor of Philosophy (Ph.D.)

Department

Veterinary Microbiology

Program

Veterinary Microbiology

Part Of

item.page.relation.ispartofseries

DOI

item.page.identifier.pmid

item.page.identifier.pmcid