The regulation of anti-viral immune responses in the lung is dependent upon the ability to efficiently and appropriately recognize pathogenic signals and promote the proper and non-pathogenic response to clear the viral infection. Respiratory syncytial virus (RSV) is an especially pathogenic virus that can induce morbidity at all ages, especially in infants and those with underlying lung conditions. Recent data has indicated that a critical innate immune pathway that is functional for pathogen recognition is autophagy. This omnipresent process provides all cells the ability to not only preserve resources but transport pathogen components to the proper immune recognition molecules, PAMPs. Our studies have identified that recognition of RSV infection by dendritic cells (DC) depends upon autophagy for the most appropriate, nonpathogenic response in the lungs. Thus, our overall hypothesis is that RSV infection responses depend upon autophagy to generate an effective immune response through the induction of critical innate cytokines in APC within the lungs. We will test this hypothesis using both in vitro and in vivo analyses with our RSV infection model and extend the findings to demonstrate that autophagy-mediated recognition of the viral infection dictates that direction of the acquired immune response, lending to the severity of the response. Using specific gene knockdown and genetically deficient mice, including Beclin +/- and LC3B-/- mice, we will explore how the absence of autophagy mechanisms alters anti-RSV responses in vitro and in vivo. Subsequently, we will further explore an important mechanism of initiation of the autophagy responses by examining a NAD deacetylase, sirt1, known to initiate autophagosome formation. Using our established model of RSV infection that recapituates several aspects of human disease, including mucus hypersecretion, physiologic changes (AHR) and a pathogenic cytokine profile, these investigations will be able to thoroughly characterize the mechanistic changes associated with these critical pathways. Thus, these studies will explore several novel and topical pathways that can not only further define the mechanisms that promote pulmonary mucosal immune responses, but expand our understanding of rationale vaccine design for RSV.

Public Health Relevance

Respiratory syncytial virus (RSV) infections can not only cause significant disease during primary infection of infants but also exacerbation of chronic pulmonary disease in children and adults with underlying pulmonary problems, including asthma and COPD. The better understanding of how RSV immune responses are initated for minimal pathology, such as we observe with autophagy, will allow better therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL114858-04
Application #
8871569
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Blaisdell, Carol J
Project Start
2012-08-01
Project End
2016-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
4
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Ting, Hung-An; de Almeida Nagata, Denise; Rasky, Andrew J et al. (2018) Notch ligand Delta-like 4 induces epigenetic regulation of Treg cell differentiation and function in viral infection. Mucosal Immunol 11:1524-1536
Bringman-Rodenbarger, Lauren R; Guo, Angela H; Lyssiotis, Costas A et al. (2018) Emerging Roles for SIRT5 in Metabolism and Cancer. Antioxid Redox Signal 28:677-690
Kumar, Surinder; Lombard, David B (2018) Functions of the sirtuin deacylase SIRT5 in normal physiology and pathobiology. Crit Rev Biochem Mol Biol 53:311-334
Fonseca, Wendy; Lukacs, Nicholas W; Ptaschinski, Catherine (2018) Factors Affecting the Immunity to Respiratory Syncytial Virus: From Epigenetics to Microbiome. Front Immunol 9:226
Kumar, Surinder; Lombard, David B (2017) Cycling around Lysine Modifications. Trends Biochem Sci 42:501-503
Ting, Hung-An; Schaller, Matthew A; de Almeida Nagata, Denise E et al. (2017) Notch Ligand Delta-like 4 Promotes Regulatory T Cell Identity in Pulmonary Viral Infection. J Immunol 198:1492-1502
Cho, Chun-Seok; Lombard, David B; Lee, Jun Hee (2017) SIRT3 as a regulator of hepatic autophagy. Hepatology 66:700-702
Giblin, William; Lombard, David B (2017) Sirtuin 6 Builds a Wall Against Inflammation, Trumping Diabetes. Diabetes 66:2535-2537
Kumar, Surinder; Lombard, David B (2017) For Certain, SIRT4 Activities! Trends Biochem Sci 42:499-501
Fonseca, W; Lucey, K; Jang, S et al. (2017) Lactobacillus johnsonii supplementation attenuates respiratory viral infection via metabolic reprogramming and immune cell modulation. Mucosal Immunol 10:1569-1580

Showing the most recent 10 out of 20 publications