In addition to neutralization, antibodies (Abs) represent a critical bridge between the adaptive and innate immune system, as they mediate their activity by harnessing and instructing the innate immune system on how to clear the antigen to which they are bound. The ability of Abs to provide specificity to the innate immune system is tightly regulated by: a) the isotype of the antibody (Ab), and b) the glycan structure attached at the asparagine 297 within the CH2-domain of the Ab heavy chain. While Ab engineering has revolutionized the efficacy of monoclonal Abs through the optimization of Ab glycan structures for the treatment of malignancies and autoimmune disorders, little is known about how Ab glycosylation may be harnessed in vivo through vaccination to provide enhanced protection against infectious diseases. Accumulating evidence suggests that natural modulation of the Ab-glycan occurs under inflammatory conditions, dramatically altering the activity of an Ab. However, little is known about the mechanism(s) that regulates Ab-glycosylation, how the immune system naturally exploits this humoral activity, and how it may be harnessed to potentiate Ab-antiviral activity. Given that innate immune recruiting Abs are detectable in early HIV infection, are enriched in long-term non-progressors, and correlate with enhanced HIV control, the PI hypothesizes that the "rules" for eliciting innate immune recruiting Abs, with specific glycans in vivo, can be learned from natural infection. Thus in this proposal, the PI will hone in on the B cell biology of glycosylation to define a) the mechanism by which Ab-glycosylation is tuned naturally in spontaneous controllers, b) define the mechanism by which glycosylation in B cells is regulated, and c) determine whether Ab-glycosylation is "remembered" following immunization. Together, knowledge gained from these studies will provide critical insights into the mechanism by which Ab-effector functions are regulated, and will lead to the generation of new strategies to potentiate the antiviral activity of vaccine inducd Abs.

Public Health Relevance

This proposal aims to define the mechanism(s) regulating antibody glycosylation in B cells. These studies may identify new strategies to specifically tune B cell responses during vaccination to induce antibodies with enhanced antiviral activity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI102660-01
Application #
8408897
Study Section
Special Emphasis Panel (ZAI1-DR-A (M1))
Program Officer
Embry, Alan C
Project Start
2012-07-01
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$609,875
Indirect Cost
$259,875
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Ackerman, Margaret E; Mikhailova, Anastassia; Brown, Eric P et al. (2016) Polyfunctional HIV-Specific Antibody Responses Are Associated with Spontaneous HIV Control. PLoS Pathog 12:e1005315
Lu, Lenette L; Chung, Amy W; Rosebrock, Tracy R et al. (2016) A Functional Role for Antibodies in Tuberculosis. Cell 167:433-443.e14
Sips, M; Krykbaeva, M; Diefenbach, T J et al. (2016) Fc receptor-mediated phagocytosis in tissues as a potent mechanism for preventive and therapeutic HIV vaccine strategies. Mucosal Immunol 9:1584-1595
Mahan, Alison E; Jennewein, Madeleine F; Suscovich, Todd et al. (2016) Antigen-Specific Antibody Glycosylation Is Regulated via Vaccination. PLoS Pathog 12:e1005456
Barouch, Dan H; Alter, Galit; Broge, Thomas et al. (2015) Protective efficacy of adenovirus/protein vaccines against SIV challenges in rhesus monkeys. Science 349:320-4