Pulmonary inflammation and injury is a frequent (and, in some instances, lethal) outcome of virus infections of the respiratory tract. Respiratory virus infection triggers a coordinated response from the host innate and adaptive immune systems. The host response is essential for virus clearance and recovery, but is also a significant cause of pulmonary injury that can accompany virus elimination. Relevant recent examples of this are the immune-mediated lung inflammation/injury observed in human infections with the SARS coronavirus and the H5N1 avian influenza viruses. The long-term goal of Project 1 is to define and characterize the interactions between cells of the innate immune system i.e. dendritic cells, monocyte/ macrophage, NK cells and adaptive immune effector T lymphocytes (Tej in the process of virus clearance and in the control of inflammation/injury during experimental virus infection of the respiratory tract. The foundation for this application is our recent and unexpected findings in the murine model of type A influenza infection that anti-viral effector T-cells (both CD4 +Te and more prominently CDS +Te) infiltrating the infected lungs produce high levels of the anti-inflammatory/regulatory cytokines IL-10 during the Te response to infection and virus elimination. Furthermore, we found that blocking the effect of Te-derived IL- 10 during infection results in increased pulmonary inflammation and lethal injury. Our evidence further suggests that this Te-derived IL-10 plays a central role in controlling the level of lung inflammation/injury produced by mononuclear cells infiltrating the infected lungs in response to virus infection and the proinflammatory mediators released by virus- immune (Te). We wish to analyze the expression and regulation of IL-10 and specifically Te-derived IL-10 in the infected lungs and the impact of this cytokine on the control of virus clearance and lung inflammation/injury.
The aims of Project 1 are: 1. To evaluate the cellular sources and effects of IL-10 on influenza virus infection;2. To analyze the regulation of IL-10 production by Te during influenza infection;3. To determine the impact of viral infection on the production of Te-derived IL- 10. The proposed studies are designed to complement ongoing related studies in Projects 2, 3 and 4.

Public Health Relevance

The studies proposed in this project will provide new insight on how the immune system controls the severity of the inflammation and tissue injury associated with elimination of infectious virus from the body.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI083024-05
Application #
8474684
Study Section
Special Emphasis Panel (ZAI1-BDP-I)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$270,246
Indirect Cost
$76,397
Name
University of Virginia
Department
Type
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Teoh, Jeffrey J; Gamache, Awndre E; Gillespie, Alyssa L et al. (2016) Acute Virus Control Mediated by Licensed NK Cells Sets Primary CD8+ T Cell Dependence on CD27 Costimulation. J Immunol 197:4360-4370
Jiang, Li; Yao, Shuyu; Huang, Su et al. (2016) Type I IFN signaling facilitates the development of IL-10-producing effector CD8(+) T cells during murine influenza virus infection. Eur J Immunol 46:2778-2788
DeBerge, Matthew P; Ely, Kenneth H; Wright, Peter F et al. (2015) Shedding of TNF receptor 2 by effector CD8⁺ T cells by ADAM17 is important for regulating TNF-α availability during influenza infection. J Leukoc Biol 98:423-34
Kim, Taeg S; Hanak, Mark; Trampont, Paul C et al. (2015) Stress-associated erythropoiesis initiation is regulated by type 1 conventional dendritic cells. J Clin Invest 125:3965-80
Krueger, Peter D; Kim, Taeg S; Sung, Sun-Sang J et al. (2015) Liver-resident CD103+ dendritic cells prime antiviral CD8+ T cells in situ. J Immunol 194:3213-22
Ramana, Chilakamarti V; DeBerge, Matthew P; Kumar, Aseem et al. (2015) Inflammatory impact of IFN-γ in CD8+ T cell-mediated lung injury is mediated by both Stat1-dependent and -independent pathways. Am J Physiol Lung Cell Mol Physiol 308:L650-7
Steinke, John W; Liu, Lixia; Turner, Ronald B et al. (2015) Immune surveillance by rhinovirus-specific circulating CD4+ and CD8+ T lymphocytes. PLoS One 10:e0115271
Moser, Emily K; Sun, Jie; Kim, Taeg S et al. (2015) IL-21R signaling suppresses IL-17+ gamma delta T cell responses and production of IL-17 related cytokines in the lung at steady state and after Influenza A virus infection. PLoS One 10:e0120169
Moser, Emily K; Hufford, Matthew M; Braciale, Thomas J (2014) Late engagement of CD86 after influenza virus clearance promotes recovery in a FoxP3+ regulatory T cell dependent manner. PLoS Pathog 10:e1004315
DeBerge, Matthew P; Ely, Kenneth H; Enelow, Richard I (2014) Soluble, but not transmembrane, TNF-α is required during influenza infection to limit the magnitude of immune responses and the extent of immunopathology. J Immunol 192:5839-51

Showing the most recent 10 out of 48 publications