The lack of effective vaccines and therapeutic treatments for many viruses presents a significant health concern. Host defenses against viruses require adaptive immune functions provided by both B cells and T cells, but the cellular and molecular processes that control the functions and cell fate decisions of these cells are incompletely understood. Although the persistence of viral antigens, the cytokine milieu in local microenvironments, the concentration and placement of immune cells in lymphoid and non-lymphoid organs, and the availability and type of co-stimulation can all dramatically affect the ultimate biological outcome of an immune response to virus infection or vaccination, it is unclear how these factors are controlled or how viruses manipulate each of these factors to evade or subvert immunity. These basic knowledge gaps limit our ability to rationally design new vaccines and develop interventions to treat virus-mediated diseases. Therefore the overall goal of this U19 Program is to determine how various types of virus infections (chronic-systemic, acute-systemic, and acute-mucosal) affect the factors described above and lead to specific types of immune responses that may be beneficial or pathologic. In order to meet this goal, five labs with complementary expertise in human and mouse antiviral immunology will work collaboratively to address some of these key unresolved issues in antiviral immunity. In Project 1, Troy Randall at UAB will determine how Tfh responses are controlled by IL-2 signaling and availability. In Project 2, Allan Zajac at UAB will determine how antiviral CD8+ T cells responses are controlled by adhesion molecules and T cell clustering. In Project 3, Frances Lund at UAB will determine how antiviral B cell responses are controlled by IFN? signaling and availability. In Project 4, Nicole Baumgarth of UC Davis will determine how natural and induced antiviral IgM responses are controlled. These projects will be facilitated by Core A - Administration and Biostatistics (Troy Randall), Core B - Viral Stocks and Reagents (Frances Lund), and Core C - Human Immunology (Frances Eun-Hyung Lee, Emory). Importantly, all projects will be able to examine virus-specific B and T cells using tetramer reagents developed by Core B. In addition, although many of the mechanistic studies in each project will be performed using mouse models, the projects will also test key hypotheses in humans via interactions with the Human Immunology Core (Core C).

Public Health Relevance

The lack of effective vaccines and therapeutic treatments for many viruses presents a significant health concern. Therefore the overall goal of this U19 Program is to determine how various types of virus infections (chronic-systemic, acute-systemic, and acute-mucosal) affect specific types of immune responses and ultimately lead to protection or pathology. In order to meet this goal, five labs at three universities with complementary expertise in human and mouse antiviral immunology will work collaboratively to address some of the key unresolved issues in antiviral immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI109962-01
Application #
8653359
Study Section
Special Emphasis Panel (ZAI1-ZL-I (J1))
Program Officer
Miller, Lara R
Project Start
2014-08-01
Project End
2019-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$2,100,001
Indirect Cost
$458,602
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Nguyen, Trang T T; Graf, Beth A; Randall, Troy D et al. (2017) sIgM-Fc?R Interactions Regulate Early B Cell Activation and Plasma Cell Development after Influenza Virus Infection. J Immunol 199:1635-1646
Savage, Hannah P; Yenson, Vanessa M; Sawhney, Sanjam S et al. (2017) Blimp-1-dependent and -independent natural antibody production by B-1 and B-1-derived plasma cells. J Exp Med 214:2777-2794
Nguyen, Trang T T; Kläsener, Kathrin; Zürn, Christa et al. (2017) The IgM receptor Fc?R limits tonic BCR signaling by regulating expression of the IgM BCR. Nat Immunol 18:321-333
Meza-Perez, Selene; Randall, Troy D (2017) Immunological Functions of the Omentum. Trends Immunol 38:526-536
Botta, Davide; Fuller, Michael J; Marquez-Lago, Tatiana T et al. (2017) Dynamic regulation of T follicular regulatory cell responses by interleukin 2 during influenza infection. Nat Immunol 18:1249-1260
Baumgarth, Nicole (2017) A Hard(y) Look at B-1 Cell Development and Function. J Immunol 199:3387-3394
Nellore, Anoma; Randall, Troy D (2016) Narcolepsy and influenza vaccination-the inappropriate awakening of immunity. Ann Transl Med 4:S29
Tian, Yuan; Cox, Maureen A; Kahan, Shannon M et al. (2016) A Context-Dependent Role for IL-21 in Modulating the Differentiation, Distribution, and Abundance of Effector and Memory CD8 T Cell Subsets. J Immunol 196:2153-66
Nguyen, Trang T T; Baumgarth, Nicole (2016) Natural IgM and the Development of B Cell-Mediated Autoimmune Diseases. Crit Rev Immunol 36:163-177
Tian, Yuan; Mollo, Sarah B; Harrington, Laurie E et al. (2016) IL-10 Regulates Memory T Cell Development and the Balance between Th1 and Follicular Th Cell Responses during an Acute Viral Infection. J Immunol 197:1308-21

Showing the most recent 10 out of 22 publications