The daily light/dark cycle has been one of the steadiest environmental factors influencing evolution. Nearly all organisms have adapted their physiology and behavior to a circadian rhythm. Circadian (daily) rhythms refer to physiologic phenomena that oscillate with a period of 24 hours, providing a temporal frame that allows organisms to efficiently program their physiologic tasks and optimize survival. One critical task is the orchestration of effective immune responses that confer protection against pathogens. The innate immune system represents the first line of defense against infection and is triggered by the recognition of conserved pathogen-associated molecular patterns (PAMPs) by specialized pattern-recognition receptors (PRRs) in immune cells. This phenomenon induces the production of cytokines that promote an antiviral state, further activate the immune system, and facilitate the development of the adaptive immune response. Exposure to viral pathogens may be greater at certain times of the day due to the intrinsic daily rhythms of the potential host (e.g., activity, feeding, behavioral rhythms) and/or, in the case of arboviruses, the activity/biting rhythms of the vector carrying the virus. More significantly, systemic circadian-derived signals such as glucocorticoids as well as certain cytokines displaying significant daily variations have been shown to modulate PRR expression and signaling. Thus, there are both teleologically and experimentally based rationales supporting that the efficiency of innate immune recognition mechanisms of viral infection varies throughout the day. The overall objective of this research proposal is to investigate the existence of circadian rhythms in innate immune recognition mechanisms of viral infection and their relevance for viral immunopathogenesis. Using the mouse model and an the NIAID priority pathogen West Nile virus (WNV) as a paradigmatic vector-borne agent we will determine: 1) the daily changes in the expression of PRRs involved in viral recognition in innate immune cells isolated at multiple time points over the light/dark cycle, 2) whether the innate immune response to the activation of viral PRRs with specific PAMPs follows a circadian rhythm, and 3) the significance of these daily rhythms for the antiviral host response by assessing how time of infection influences WNV immunopathogenesis, which has been shown to depend on PRR-mediated innate responses. This proposal tackles the study of a novel, unexplored, and important aspect of the physiologic regulation of innate immune viral recognition mechanisms. Moreover, the information obtained from these studies may be extremely useful for the design and optimization of therapeutic and immunoprophylactic protocols.

Public Health Relevance

West Nile virus, an NIAID category B priority pathogen, emerged in the United States in 1999, causing till date over 11,000 cases of neuroinvasive disease and 1,103 fatalities. Because the threat of emerging viral diseases raises new dangers for public safety, it is critical to gain fundamental knowledge about the physiologic regulation of the antiviral response. Furthermore, anticipating the 24- hour rhythms of innate immune recognition mechanisms of viral infection may be extremely useful for the design and optimization of therapeutic and immunoprophylactic protocols.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Innate Immunity and Inflammation Study Section (III)
Program Officer
Repik, Patricia M
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Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
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Arjona, Alvaro; Silver, Adam C; Walker, Wendy E et al. (2012) Immunity's fourth dimension: approaching the circadian-immune connection. Trends Immunol 33:607-12
Silver, Adam C; Arjona, Alvaro; Walker, Wendy E et al. (2012) The circadian clock controls toll-like receptor 9-mediated innate and adaptive immunity. Immunity 36:251-61
Arjona, Alvaro; Wang, Penghua; Montgomery, Ruth R et al. (2011) Innate immune control of West Nile virus infection. Cell Microbiol 13:1648-58