Viral infections induce higher morbidity and mortality in older people than in younger individuals. Based on both experimental and clinical studies, this disease burden is thought to be due to declining immune responses. However, our published work supported by the last cycle of the award challenges this paradigm as we found that older mice exhibit dysregulated immune responses during viral infection that induce immune pathology. This dysregulation consists of exaggerated IL-17 responses produced by natural killer T (NKT) cells, innate immune lymphocytes that respond rapidly to pathogens, coupled to defective type I interferon (IFN) responses by plasmacytoid dentritic cells (pDCs), sentinel immune cells that aid viral clearance. This defective viral clearance synergizes with the age-elevated IL-17 responses leading to severe liver inflammation and death. During non-lethal systemic viral infections, exaggerated inflammatory responses (i.e., IL-6 production) by NKT-cells coupled with defective type I IFN responses by pDCs induce an inflammatory environment that skews adaptive immune CD4+ T cells to an IL-17 producing phenotype. We have also observed the age-elevated IL-17 response coupled to defective type I IFNs in other viral infections such as in localized influenza lung infections. Here, we propose to study the underlying cellular and molecular mechanisms for dysregulation of immune responses with aging by using murine models to determine 1) if exaggerated inflammatory responses by NKT cells coupled to defective pDC responses are critical for the generation of IL-17 anti-viral CD4+ T cells during systemic herpes viral infections with aging;and 2) whether exaggerated IL-17 responses by aged NKT cells coupled with impaired type I IFN responses by pDCs also induce immune pathology during influenza viral lung infection. Our work will greatly differ from mainstream research in the field and may lead to novel anti-inflammatory therapies to improve immunity to viral infections with aging.

Public Health Relevance

Current paradigms indicate that older people suffer from viral infections more than young people due to declining immune function. However, our studies show that in aged mice the course of viral infection is affected due to dysregulated immune responses. We propose to examine the factors that, with aging, lead to both exaggerated and defective immune responses to viral infection, which could lead to novel therapies to improve the outcome of viral infections in older people.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG028082-06A1
Application #
8436926
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Fuldner, Rebecca A
Project Start
2006-04-01
Project End
2017-08-31
Budget Start
2012-09-30
Budget End
2013-08-31
Support Year
6
Fiscal Year
2012
Total Cost
$290,471
Indirect Cost
$115,591
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Wong, Christine K; Smith, Candice A; Sakamoto, Koji et al. (2017) Aging Impairs Alveolar Macrophage Phagocytosis and Increases Influenza-Induced Mortality in Mice. J Immunol 199:1060-1068
Colvin, Monica M; Smith, Candice A; Tullius, Stefan G et al. (2017) Aging and the immune response to organ transplantation. J Clin Invest 127:2523-2529
Mori, Daniel N; Shen, Hua; Galan, Anjela et al. (2016) Aged B cells alter immune regulation of allografts in mice. Eur J Immunol 46:2650-2658
Braza, Faouzi; Brouard, Sophie; Chadban, Steve et al. (2016) Role of TLRs and DAMPs in allograft inflammation and transplant outcomes. Nat Rev Nephrol 12:281-90
Jane-Wit, Dan; Fang, Caodi; Goldstein, Daniel R (2016) Innate immune mechanisms in transplant allograft vasculopathy. Curr Opin Organ Transplant 21:253-7
Spahn, Jessica H; Li, Wenjun; Bribriesco, Alejandro C et al. (2015) DAP12 expression in lung macrophages mediates ischemia/reperfusion injury by promoting neutrophil extravasation. J Immunol 194:4039-48
Shen, Hua; Heuzey, Elizabeth; Mori, Daniel N et al. (2015) Haptoglobin enhances cardiac transplant rejection. Circ Res 116:1670-9
Mori, Daniel N; Kreisel, Daniel; Fullerton, James N et al. (2014) Inflammatory triggers of acute rejection of organ allografts. Immunol Rev 258:132-44
Elpek, Kutlu G; Cremasco, Viviana; Shen, Hua et al. (2014) The tumor microenvironment shapes lineage, transcriptional, and functional diversity of infiltrating myeloid cells. Cancer Immunol Res 2:655-67
Wong, Christine; Goldstein, Daniel R (2013) Impact of aging on antigen presentation cell function of dendritic cells. Curr Opin Immunol 25:535-41

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