B cells are the central source of long-term humoral immune responses to viral pathogens, but also serve critical regulatory functions during adaptive CD4+ T cell responses. It is unknown whether B cells contribute significantly to viral immune responses beyond antibody production or whether their manipulation can hasten or enhance immune responses. Important for emerging infections and biodefense, we have recently shown that B cells are essential for optimal CD4+ T cell priming during bacteria challenge. By contrast, monoclonal antibody (mAb)-induced B cell depletion augments Th1-type cellular immune responses in other models. This unexpected observation is explained by the identification of a potent regulatory B cell subset that dramatically attenuates Th1 immune responses and autoimmunity. We have labeled this phenotypically unique B cell subset that also secretes IL-10 as "B10" cells, which represent ~1% of total spleen B cells in young mice, and <1% of circulating human B cells. B10 cell numbers within tissues increase significantly in mice with autoimmunity and age. Thus, humoral and CD4+ T cell immune responses are balanced by both positive and negative B cell regulation. We have also identified a critical signaling pathway that is required For B10 cell survival in vivo. MAbs that inhibit this B cell-restricted survival signal induce rapid and semiselective B10 cell depletion in vivo, which has an adjuvant-like effect that enhances humoral antibody responses to T cell-dependent model antigens and Thl-type CD4+ T cell immune responses. Thus, B10 cells regulate both humoral and Th1 immune responses. We have also developed a humanized mAb to the same survival target and generated transgenic mice expressing the human survival receptor that will facilitate preclinical translation of these basic studies into human studies. The ability to manipulate B cell contributions to humoral and cell-mediated immunity by mAb treatment offers a new strategy for accelerating mmune responses during acute pathogen challenge. The focus of our proposed studies is to identify the extent that B cells and the B10 subset modulate humoral and cellular immune responses to alphaviruses, and to determine how B cells can be manipulated for therapeutic benefit and vaccine development.

Public Health Relevance

Alphaviruses present in the Americas are considered to be potential bioterrorism agents, and an alphavirus Tom Africa has initiated an major ongoing epidemic in Asia. Very little is known about the role of B cells in these and other infections, and their resulting immunopathology, other than antibody production. Thus, basic studies of B cell biology are necessary to understand how to develop optimal therapies and vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057157-11
Application #
8437239
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
11
Fiscal Year
2013
Total Cost
$308,159
Indirect Cost
$50,114
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Ashbrook, Alison W; Lentscher, Anthony J; Zamora, Paula F et al. (2016) Antagonism of the Sodium-Potassium ATPase Impairs Chikungunya Virus Infection. MBio 7:
Bowles, R D; Karikari, I O; VanDerwerken, D N et al. (2016) In vivo luminescent imaging of NF-κB activity and NF-κB-related serum cytokine levels predict pain sensitivities in a rodent model of peripheral neuropathy. Eur J Pain 20:365-76
Alayli, Farah; Scholle, Frank (2016) Dengue virus NS1 enhances viral replication and pro-inflammatory cytokine production in human dendritic cells. Virology 496:227-36
Bates, John T; Pickens, Jennifer A; Schuster, Jennifer E et al. (2016) Immunogenicity and efficacy of alphavirus-derived replicon vaccines for respiratory syncytial virus and human metapneumovirus in nonhuman primates. Vaccine 34:950-6
Fibriansah, Guntur; Tan, Joanne L; Smith, Scott A et al. (2015) A highly potent human antibody neutralizes dengue virus serotype 3 by binding across three surface proteins. Nat Commun 6:6341
de St Maurice, Annabelle; Grijalva, Carlos G; Fonnesbeck, Christopher et al. (2015) Racial and Regional Differences in Rates of Invasive Pneumococcal Disease. Pediatrics 136:e1186-94
Roberts, Lydia M; Ledvina, Hannah E; Tuladhar, Shraddha et al. (2015) Depletion of alveolar macrophages in CD11c diphtheria toxin receptor mice produces an inflammatory response. Immun Inflamm Dis 3:71-81
Smith, Scott A; Silva, Laurie A; Fox, Julie M et al. (2015) Isolation and Characterization of Broad and Ultrapotent Human Monoclonal Antibodies with Therapeutic Activity against Chikungunya Virus. Cell Host Microbe 18:86-95
Pulendran, Bali (2015) The varieties of immunological experience: of pathogens, stress, and dendritic cells. Annu Rev Immunol 33:563-606
Price, Aryn A; Sampson, Timothy R; Ratner, Hannah K et al. (2015) Cas9-mediated targeting of viral RNA in eukaryotic cells. Proc Natl Acad Sci U S A 112:6164-9

Showing the most recent 10 out of 375 publications