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 #
5R01HL114858-03
Application #
8687732
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
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Lombard, David B; Zhao, Yingming (2017) ACSF3 and Mal(onate)-Adapted Mitochondria. Cell Chem Biol 24:649-650
Kumar, Surinder; Lombard, David B (2017) Cycling around Lysine Modifications. Trends Biochem Sci 42:501-503
Cho, Chun-Seok; Lombard, David B; Lee, Jun Hee (2017) SIRT3 as a regulator of hepatic autophagy. Hepatology 66:700-702
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
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
Owczarczyk, Anna B; Schaller, Matthew A; Reed, Michelle et al. (2015) Sirtuin 1 Regulates Dendritic Cell Activation and Autophagy during Respiratory Syncytial Virus-Induced Immune Responses. J Immunol 195:1637-46
Reed, M; Morris, S H; Owczarczyk, A B et al. (2015) Deficiency of autophagy protein Map1-LC3b mediates IL-17-dependent lung pathology during respiratory viral infection via ER stress-associated IL-1. Mucosal Immunol 8:1118-30
de Almeida Nagata, Denise E; Demoor, Tine; Ptaschinski, Catherine et al. (2014) IL-27R-mediated regulation of IL-17 controls the development of respiratory syncytial virus-associated pathogenesis. Am J Pathol 184:1807-18
Reed, Michelle; Morris, Susan H; Jang, Sihyug et al. (2013) Autophagy-inducing protein beclin-1 in dendritic cells regulates CD4 T cell responses and disease severity during respiratory syncytial virus infection. J Immunol 191:2526-37

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