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.
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.
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|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|
|Ely, Kenneth H; Matsuoka, Mitsuo; DeBerge, Matthew P et al. (2014) Tissue-protective effects of NKG2A in immune-mediated clearance of virus infection. PLoS One 9:e108385|
|DeBerge, Matthew P; Ely, Kenneth H; Enelow, Richard I (2014) Soluble, but not transmembrane, TNF-? is required during influenza infection to limit the magnitude of immune responses and the extent of immunopathology. J Immunol 192:5839-51|
|Kim, Taeg S; Gorski, Stacey A; Hahn, Steven et al. (2014) Distinct dendritic cell subsets dictate the fate decision between effector and memory CD8(+) T cell differentiation by a CD24-dependent mechanism. Immunity 40:400-13|
|Yoo, Jae-Kwang; Braciale, Thomas J (2014) IL-21 promotes late activator APC-mediated T follicular helper cell differentiation in experimental pulmonary virus infection. PLoS One 9:e105872|
|Yoo, Jae-Kwang; Kim, Taeg S; Hufford, Matthew M et al. (2013) Viral infection of the lung: host response and sequelae. J Allergy Clin Immunol 132:1263-76; quiz 1277|
|Braciale, Thomas J; Hahn, Young S (2013) Immunity to viruses. Immunol Rev 255:5-12|
|Gorski, Stacey Ann; Hahn, Young S; Braciale, Thomas J (2013) Group 2 innate lymphoid cell production of IL-5 is regulated by NKT cells during influenza virus infection. PLoS Pathog 9:e1003615|
|Goh, Celeste; Narayanan, Sowmya; Hahn, Young S (2013) Myeloid-derived suppressor cells: the dark knight or the joker in viral infections? Immunol Rev 255:210-21|
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