Generating protective antiviral immunity is a complex process that begins in the tissue at the site of infection, amplifies in secondary lymphoid organs such as the lymph nodes (LNs), and, in the best scenario, culminates in viral elimination from infected tissues and the establishment of memory preventing new infections. Despite intense interest in the generation of cellular and humoral immune responses against viral pathogens, the anatomy of the response is imperfectly understood as infection proceeds from peripheral tissues to the draining LN. Inside the LN, differences in the cell types infected by particular viruses and in the location of virus-infected cells can impact generation of the adaptive immune response. The goal of the Viral Immunity and Pathogenesis Unit is to make fundamental discoveries about the processes that shape the creation and execution of antiviral immunity. To understand antiviral immunity in both quantitative and spatial terms, the VIPU utilizes traditional ex vivo immunological and virological techniques along with multicolor fluorescence confocal microscopy of infected tissue sections and intravital multiphoton microscopy (MPM), an imaging modality that directly visualizes virus-infected cells and immune effectors as they move and interact over time in vivo. Using this multi-tiered approach, the VIPU examines three distinct but complementary themes in antiviral immunity: 1) the activation and function of antiviral effector cells within the lymph nodes, 2) the mechanisms of effector cell elimination of virus-infected cells in the tissue, and 3) the downstream effects of viral spread and/or innate immune control at the site of tissue infection. Rather than focus on a single viral pathogen, the VIPU investigates immunity to a wide range of viruses, from large DNA viruses, such as VACV and herpes simplex virus (HSV), to small RNA viruses including ZIKV. We have recently been approved to begin intravital imaging experiments with BSL-3 strains of Chikungunya virus (CHIKV), and we are expanding from our murine infection models to collaboratively examine simian immunodeficiency virus (SIV) and ZIKV-infected non-human primate LNs and tissues. Through the analysis of an array of divergent viruses, we hope to better understand important common and virus-specific factors leading to adaptive immune control in the tissue.

Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Niaid Extramural Activities
Department
Type
DUNS #
City
State
Country
Zip Code
Beura, Lalit K; Mitchell, Jason S; Thompson, Emily A et al. (2018) Intravital mucosal imaging of CD8+ resident memory T cells shows tissue-autonomous recall responses that amplify secondary memory. Nat Immunol 19:173-182
McCarthy, Mary K; Davenport, Bennett J; Reynoso, Glennys V et al. (2018) Chikungunya virus impairs draining lymph node function by inhibiting HEV-mediated lymphocyte recruitment. JCI Insight 3:
Jegaskanda, Sinthujan; Mason, Rosemarie D; Andrews, Sarah F et al. (2018) Intranasal Live Influenza Vaccine Priming Elicits Localized B Cell Responses in Mediastinal Lymph Nodes. J Virol 92:
Hickman, Heather D; Mays, Jacqueline W; Gibbs, James et al. (2018) Influenza A Virus Negative Strand RNA Is Translated for CD8+ T Cell Immunosurveillance. J Immunol 201:1222-1228
Rosshart, Stephan P; Vassallo, Brian G; Angeletti, Davide et al. (2017) Wild Mouse Gut Microbiota Promotes Host Fitness and Improves Disease Resistance. Cell 171:1015-1028.e13
Arbuckle, Jesse H; Gardina, Paul J; Gordon, David N et al. (2017) Inhibitors of the Histone Methyltransferases EZH2/1 Induce a Potent Antiviral State and Suppress Infection by Diverse Viral Pathogens. MBio 8:
Angeletti, Davide; Gibbs, James S; Angel, Matthew et al. (2017) Defining B cell immunodominance to viruses. Nat Immunol 18:456-463
Hickman, Heather D; Pierson, Theodore C (2017) T Cells Take on Zika Virus. Immunity 46:13-14
Hickman, Heather D (2017) New insights into antiviral immunity gained through intravital imaging. Curr Opin Virol 22:59-63