Emerging viruses is a term used to describe viruses that have newly appeared in the population or that are rapidly expanding their range. It is important to understand the underlying mechanisms involved in the emergence of new viral pathogens or old viral pathogens with altered pathogenic potential. We have demonstrated that the nutritional status of the host is a driving force for the emergence of new viral variants. Influenza viral infection of a host deficient in selenium (Se), an essential component of the antioxidant enzymes glutathione peroxidases and thioredoxin reductse, leads to increased lung pathology compared to infected Se-adequate hosts. Influenza viruses isolated from Se-deficient hosts developed specific mutations in the viral genome, resulting in a more pathogenic strain of virus. This mutated influenza virus strain was more virulent than the original virus; infection of hosts with normal Se status resulted in enhanced pathology and severe morbidity. The goal of this proposal is to understand the mechanism(s) involved in the role of host nutritional status in promoting viral mutation. Because the mechanism(s) involved are likely to be multi-factorial, we have designed our project to examine 3 different viewpoints: host cellular responses, viral responses, and host inflammatory/innate immune responses. This approach recognizes that the virus itself may be affected by the nutritional status of the host, that the cellular machinery required for viral replication may be affected by the host nutritional status, and finally that the immune response against the virus may also be influenced by host nutritional status. Using murine models as well as a unique in vitro system of differentiated primary human airway epithelial cells, we can address the following questions: 1) How is the natural course of influenza virus evolution altered in the Se-deficient host? 2) How does the host respond to the mutated virus in comparison with the wild type virus? 3) What is the minimum level of host Se required to prevent the mutations from occurring? 4) Does excess vitamin E compensate for a lack of Se in preventing the viral mutations? 5) Does a host deficiency in other antioxidant nutrients (e.g. vitamin C) lead to viral mutations9 6) Can the innate immune response and/or host cellular redox status be correlated with the induction of viral mutations in the Se-deficient host? Taken together, this interdisciplinary project will provide new information on the role of nutrition in driving viral mutations that may ultimately be used in predicting and/or preventing new viral outbreaks.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI055050-01
Application #
6601777
Study Section
Nutrition Study Section (NTN)
Program Officer
Cassetti, Cristina
Project Start
2003-09-30
Project End
2008-01-31
Budget Start
2003-09-30
Budget End
2004-01-31
Support Year
1
Fiscal Year
2003
Total Cost
$225,812
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pediatrics
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Styyyblo, Miroslav; Walton, Felecia S; Harmon, Anne W et al. (2007) Activation of superoxide dismutase in selenium-deficient mice infected with influenza virus. J Trace Elem Med Biol 21:52-62
Beck, Melinda A (2007) Selenium and vitamin E status: impact on viral pathogenicity. J Nutr 137:1338-40
Li, Wei; Beck, Melinda A (2007) Selenium deficiency induced an altered immune response and increased survival following influenza A/Puerto Rico/8/34 infection. Exp Biol Med (Maywood) 232:412-9
Jaspers, I; Zhang, W; Brighton, L E et al. (2007) Selenium deficiency alters epithelial cell morphology and responses to influenza. Free Radic Biol Med 42:1826-37
Sheridan, Patricia A; Zhong, Nianxin; Carlson, Bradley A et al. (2007) Decreased selenoprotein expression alters the immune response during influenza virus infection in mice. J Nutr 137:1466-71
Li, Wei; Maeda, Nobuyo; Beck, Melinda A (2006) Vitamin C deficiency increases the lung pathology of influenza virus-infected gulo-/- mice. J Nutr 136:2611-6