Vaccination has been the most widely used strategy to protect against viral infections. The establishment of immunological memory is critical for the success of vaccines against future infections. However, the molecular mechanisms underlying the persistence of immunological memory cells in response to vaccines remain to be elucidated. We have found that autophagy plays a critical role in the long-term survival of memory B cells against influenza virus infection in mice. Compared to nave B cells and germinal center B cells, memory B cells display elevated levels of basal autophagy with increased expression of genes that regulate autophagy initiation or autophagosome maturation. Mice with deficiency of autophagy in B cells show accelerated cell death in memory B cells after immunization with influenza, and fail to generate protective secondary antibody responses when re-challenged with the virus, resulting in high viral loads, widespread lung destruction and increased fatality. This suggests that autophagy is required for the survival of virus-specific memory B cells. Experiments are proposed to test the hypothesis that promoting autophagy can enhance the efficacy of vaccination against viral infections through the protection of memory B cells. The following studies are proposed: 1) To determine the mechanisms for active autophagy in memory B cells induced by influenza vaccination; 2) To investigate the mechanisms for autophagy in the protection of memory B cells induced by vaccination against influenza viruses; and 3) To determine whether induction of autophagy can boost immunological memory to influenza vaccination. In the long term, the knowledge gained from the study will be employed to develop novel strategies for boosting the efficacy of vaccination against viral pathogens by promoting the generation and maintenance of immunological memory cells in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI116644-03
Application #
9390031
Study Section
Vaccines Against Microbial Diseases Study Section (VMD)
Program Officer
Lane, Mary Chelsea
Project Start
2016-12-01
Project End
2020-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Methodist Hospital Research Institute
Department
Type
DUNS #
185641052
City
Houston
State
TX
Country
United States
Zip Code
77030
Sandoval, Hector; Kodali, Srikanth; Wang, Jin (2018) Regulation of B cell fate, survival, and function by mitochondria and autophagy. Mitochondrion 41:58-65
Kimata, Jason T; Rice, Andrew P; Wang, Jin (2016) Challenges and strategies for the eradication of the HIV reservoir. Curr Opin Immunol 42:65-70