THE ROLE AND MECHANISM OF PARAHYDROXYBENZOIC ACID DERIVATIVES IN BOVINE TB PATHOGENESIS
Date
2021-11-30
Authors
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