Cul4b in generation of protective antibody responses
Name:
Dr. Emily Moser
Email
emily.moser@medicine.ufl.edu
Phone
(804) 304-1842
Faculty Department/Division
Pulmonary, Critical Care, and Sleep Medicine
This project is primarily:
Basic
Research Project Description:
Influenza A virus is a serious global health threat, causing approximately 36,000 deaths per year in the United States alone. The primary intervention against influenza infection is vaccination to induce protective antibodies. Vaccines are less effective in certain groups with weakened germinal center responses, e.g. elderly and immunocompromised individuals. Programming of the antibody response occurs in specialized niches in lymphoid tissue called germinal centers. Using mice lacking Cul4b in B cells (Cul4bf/fMB1Cre/+ mice), we have discovered that the enzyme Cul4b is essential for germinal center expansion and formation of protective antibody responses after Influenza vaccination. The proposed research project will define the role of Cul4b in germinal center and antibody responses after influenza vaccination. Results from these studies will aid in the design of new vaccines that enhance the Cul4b pathway, unleashing robust antibody responses in populations with weakened immune systems.
Cul4b is a ubiquitin ligase that facilitates cell cycle and repair or DNA damage, although its role has never been investigated in B cells. In order to become long-lived plasma cells capable of producing high affinity antibodies germinal center B cells must undergo somatic hypermutation, induced by Activation Induced Cytidine Deaminase (AID). We hypothesize that Cul4b is required for GC B cell expansion in the presence of somatic hypermutation-induced DNA damage, and elimination of AID will restore GC B cell expansion in Cul4bf/fMB1Cre/+ mice. To test this, we have crossed Cul4bf/fMB1Cre/+ mice to AIDf/f mice, which deletes AID in Cre-expressing cells and thereby eliminate somatic hypermutation. We have separately generated Cul4b+/+AIDf/fMB1cre/+ mice, to serve as controls. The student will immunize these mice with an influenza mRNA vaccine to induce GCs, then quantify influenza-specific GC B cells at the peak of the GC response (day 14) in secondary lymphoid tissues using flow cytometry. Because AID deficient mice develop larger GCs than WT mice54,55, the correct comparison is Cul4bf/fAIDf/fMB1cre/+ vs. Cul4b+/+AIDf/fMB1cre.
Expected outcomes and interpretation: We expect that AID deficiency will restore the magnitude of influenza-specific GC B cells after vaccination in mice with Cul4b deficient B cells. This result would support the idea that Cul4b is essential for repair of DNA damage in GC B cells undergoing somatic hypermutation.
Funded by the American Lung Association Innovator Award, 2022-2024 “Improving germinal center responses to influenza A virus vaccination through a novel ubiquitin ligase pathway”
Relevant publications:
Wang Y, Manzi M, Feswick A, Renshaw L, Oliver PM, Tibbetts SA, Moser EK. B cell expression of E3 ubiquitin ligase Cul4b promotes chronic gammaherpesvirus infection in vivo. J Virol. 2023 Nov 14:e0100823. doi: 10.1128/jvi.01008-23. Epub ahead of print. PMID: 37962378.
Dar AA, Sawada K, Dybas JM, Moser EK, Lewis EL, Park E, Fazelinia H, Spruce LA, Ding H, Seeholzer SH, Oliver PM. The E3 ubiquitin ligase Cul4b promotes CD4+ T cell expansion by aiding the repair of damaged DNA. PLoS Biol. 2021 Feb 1;19(2):e3001041. doi: 10.1371/journal.pbio.3001041. PMID: 33524014; PMCID: PMC7888682.
Does this project have an international component or travel?
No
The role of complement in aspergillosis
Name:
Dr. Luis Sordo Vieira
Email
Luis.sordovieira@medicine.ufl.edu
Phone
(586) 744-1236
Faculty Department/Division
Pulmonary, Critical Care, and Sleep Medicine
This project is primarily:
Basic
Research Project Description:
Invasive aspergillosis is among the most common fungal infections in immunocompromised patients. With the increasing number of susceptible patients, the development of host-centric interventions is of paramount importance. This project will focus on the effects of C5a signaling, a key effector molecule of the complement system, on human monocyte derived dendritic cells in the context of fungal infection. The student will learn basic laboratory skills and carry some of the fundamental in vitro experiments.
Park SJ, Mehrad B. Innate immunity to Aspergillus species. Clin Microbiol Rev. 2009 Oct;22(4):535-51. doi: 10.1128/CMR.00014-09. PMID: 19822887; PMCID: PMC2772361.
Does this project have an international component or travel?
No