Published April 28, 2020
Terry D. Connell, PhD, professor of microbiology and immunology, is leading research into the capacity of several bacterial molecules (LT-IIa, LT-IIb) to modulate immune responses to foreign antigens.
He is principal investigator on a two-year study titled “Identification of New Ribosylation-Dependent Immunoregulatory Factors” that has been funded for $275,000 in direct costs by the National Institute of Allergy and Infectious Diseases.
“If we immunize mice with an antigen that usually fails to evoke a strong immune response to that antigen, but in the presence of either LT-IIa or LT-IIb, two proteins expressed by certain strains of the bacterium Escherichia coli, the immune response to that antigen is greatly enhanced,” Connell says.
He notes agents such as LT-IIa and LT-IIb, which have the capacity to enhance both mucosal and systemic immune response to weak antigens, are denoted “adjuvants.”
“Clinically, some prospective vaccines have not evoked protection to the targeted pathogen due to the fact that the antigens from the pathogen that are included in the vaccine are not highly immunogenic,” Connell says.
“If that vaccine, however, could be co-administered in the presence of our adjuvants, that vaccine might be much more effective in protecting against disease since a strong immune response to the antigens would have been evoked,” he adds.
Connell’s lab has published that a putative vaccine against ricin toxin, a potential bioterrorist agent, and which failed in a Phase I clinical trial, is much improved when mixed with LT-IIb due to enhanced production of ricin-specific neutralizing antibodies in an animal model.
Biochemically, LT-IIa and LT-IIb are ADP-ribosylating agents, which means that the adjuvants are known to transfer an ADP-ribosyl unit to GSα, a regulatory protein that, once ADP-ribosylated, induces high level production of cyclic adenosine monophosphate (cAMP) by the cells’ adenylate cyclase enzyme.
“We can replicate that cAMP response by adding forskolin, a drug that also stimulates production of cAMP in the cell. But, forskolin does not exhibit adjuvant properties,” Connell says.
That data suggested that LT-IIa and LT-IIb were likely ADP-ribosylating some other protein in the cell other than GSα, he notes.
“In this grant, we propose to identify the non-GSα protein(s) that are ADP-ribosylated in cells by LT-IIa and LT-IIb,” Connell says.
“Our hypothesis is that there is an unknown immunoregulatory pathway in immune cells that is regulated by ADP-ribosylation,” he adds. “If that hypothesis is correct, it would open a very novel avenue of research in immunology.”
Connell notes that identification of a new immunomodulatory pathway for enhancing immune responses to antigens could be useful in development of new and more effective vaccines.
Jun Qu, PhD, professor of pharmaceutical sciences in UB’s School of Pharmacy and Pharmaceutical Sciences, is co-investigator on the grant.
Qu also holds an appointment as a research associate professor in the Department of Biochemistry.
Other investigators on the grant from the Department of Microbiology and Immunology are: