Viral respiratory tract infections are among the leading causes of hospitalization, economic loss, and mortality in the US and worldwide. With the continued threat from emerging pathogens as well as complications from more common respiratory viruses, understanding these infections and their accompanying host responses remain a major priority for global public health. In particular, efforts must also be made to understand these infections within the context of an aging population. While modern germ theory has greatly reduced its burden, infectious disease remains the fourth leading cause of death in aging adults. Coupled with the robust increase in aged populations over the next two decades, these factors highlight the importance of understanding the interplay between infection and the senescent host. While significant progress has been made in understanding the age-related deficiency in adaptive immunity, much less is understood about tissue specific and innate immune cell function in the aging host. Therefore, these studies take a systems based approach to characterize and examine the early tissue-specific and innate immune responses to respiratory virus infection within the context of aging. Utilizing severe acute respiratory syndrome coronavirus (SARS-CoV), the proposal seeks to compare young, middle-aged, and aged mice in order to identify, confirm, and validate major change in pathway and immune activation that contribute to enhanced susceptibility and can be exploited for therapeutic treatment. In addition, the project extends examination into primary human airway and immune cells in order to confirm and validate in vivo finding. Finally, efforts will be made to explore th contribution of broad epigenetic changes to differential responses in young and aged models. Together, these approaches will yield important findings critical to understanding and treating current and future respiratory virus infections in aged populations.

Public Health Relevance

Using systems based approaches, we directly compare young and aged model of SARS-CoV infection in order to identify differentially activated pathways and immune cell functions that contribute to enhanced susceptibility in senescent hosts. Utilizing drug and genetic approaches, we validate these findings and seek to establish novel therapeutics that mitigate age-related susceptibility to respiratory viral pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Career Transition Award (K99)
Project #
1K99AG049092-01A1
Application #
8891093
Study Section
Neuroscience of Aging Review Committee (NIA)
Program Officer
Fuldner, Rebecca A
Project Start
2015-07-15
Project End
2017-05-31
Budget Start
2015-07-15
Budget End
2016-05-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Menachery, Vineet D; Schäfer, Alexandra; Burnum-Johnson, Kristin E et al. (2018) MERS-CoV and H5N1 influenza virus antagonize antigen presentation by altering the epigenetic landscape. Proc Natl Acad Sci U S A 115:E1012-E1021
Agnihothram, Sudhakar; Menachery, Vineet D; Yount Jr, Boyd L et al. (2018) Development of a Broadly Accessible Venezuelan Equine Encephalitis Virus Replicon Particle Vaccine Platform. J Virol 92:
Menachery, Vineet D; Graham, Rachel L; Baric, Ralph S (2017) Jumping species-a mechanism for coronavirus persistence and survival. Curr Opin Virol 23:1-7
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Menachery, Vineet D; Mitchell, Hugh D; Cockrell, Adam S et al. (2017) MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis. MBio 8:
Menachery, Vineet D; Gralinski, Lisa E; Mitchell, Hugh D et al. (2017) Middle East Respiratory Syndrome Coronavirus Nonstructural Protein 16 Is Necessary for Interferon Resistance and Viral Pathogenesis. mSphere 2:
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