Hantaviruses are zoonotic agents that are carried by a wide range of rodent host species, are geographically diverse, and cause human disease for which there is currently no cure. The primary goal of this proposal is to better elucidate the cellular and molecular mechanisms mediating host responses to hantavirus infection. Because the CDC classifies hantaviruses as potential biological agents, studies that examine the mechanisms mediating host susceptibility to infectior are required for developing adequate therapies against infection. Sex differences in hantavirus infection are documented in humans and in several rodent reservoir species in which more males are infected than females. Although sex differences in hantavirus infection may reflect dimorphisms in behaviors, such as aggression in rodents or occupation in humans, recent data from our laboratory illustrate that immune responses against infection and virus replication differ between the sexes. After inoculation with Seoul virus (i.e., the naturally occurring hantavirus in Norway rats), male rats exhibit higher antibody responses, shed virus longer and through more routes, and have more viral RNA copies present in target organs, such as the lungs, than females. The expression of antiviral transcriptional factors (e.g., eIF-2alpha, NF-KappaB, IRF, and STAT) is higher in females than males. Upregulation of transcriptional factors, e.g. NF-KappaB, in females may underlie the elevated expression of genes that encode for proinflammatory, chemotactic, and antiviral proteins in females compared with males. Sex differences in hantavirus infection may reflect the effects of steroid receptor signaling pathways on NF-KappaB-mediated signal transduction. The primary aim of this research proposal is to test the hypothesis that steroid hormones, including androgens, estrogens, and glucocorticoids, mediate sex differences in Seoul virus infection through effects on cell signaling pathways.
The aims of this proposal will be met by: 1) characterizing sex differences in the expression and translation of genes thal encode for proinflammatory, antiviral, and chemotactic proteins during the acute and persistent phases of infection; 2) manipulating sex steroids at different times during development, to determine if the expression and translation of genes that encode for proinflammatory, antiviral, and chemotactic proteins are influenced by sex steroids; and 3) assessing whether sex differences inthe expression and translation of genes that encode for proinflammatory, antiviral, and chemotactic proteins are mediated by dimorphisms in glucocorticoid receptor-mediated pathways. Taken together, these studies will provide a comprehensive analysis of how steroid hormones and genes that encode for immunoregulatory proteins interact to affect sex differences in phenotypic responses to infectious diseases and may assist in the development of treatments for qemorrhagic fever viruses that will be successful in both sexes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI054995-04
Application #
7024463
Study Section
Special Emphasis Panel (ZRG1-TMP (01))
Program Officer
Cassetti, Cristina
Project Start
2003-09-01
Project End
2008-02-28
Budget Start
2006-03-01
Budget End
2008-02-28
Support Year
4
Fiscal Year
2006
Total Cost
$399,144
Indirect Cost
Name
Johns Hopkins University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Au, Rebecca Y; Jedlicka, Anne E; Li, Wei et al. (2010) Seoul virus suppresses NF-kappaB-mediated inflammatory responses of antigen presenting cells from Norway rats. Virology 400:115-27
Frisancho-Kiss, Sylvia; Coronado, Michael J; Frisancho, J Augusto et al. (2009) Gonadectomy of male BALB/c mice increases Tim-3(+) alternatively activated M2 macrophages, Tim-3(+) T cells, Th2 cells and Treg in the heart during acute coxsackievirus-induced myocarditis. Brain Behav Immun 23:649-57
Easterbrook, Judith D; Klein, Sabra L (2008) Immunological mechanisms mediating hantavirus persistence in rodent reservoirs. PLoS Pathog 4:e1000172
Easterbrook, Judith D; Klein, Sabra L (2008) Seoul virus enhances regulatory and reduces proinflammatory responses in male Norway rats. J Med Virol 80:1308-18
Easterbrook, Judith D; Klein, Sabra L (2008) Corticosteroids modulate Seoul virus infection, regulatory T-cell responses and matrix metalloprotease 9 expression in male, but not female, Norway rats. J Gen Virol 89:2723-30
Klein, Pamela W; Easterbrook, Judith D; Lalime, Erin N et al. (2008) Estrogen and progesterone affect responses to malaria infection in female C57BL/6 mice. Gend Med 5:423-33
Easterbrook, Judith D; Kaplan, J B; Glass, G E et al. (2008) A survey of rodent-borne pathogens carried by wild-caught Norway rats: a potential threat to laboratory rodent colonies. Lab Anim 42:92-8
Siracusa, Mark C; Overstreet, Michael G; Housseau, Franck et al. (2008) 17beta-estradiol alters the activity of conventional and IFN-producing killer dendritic cells. J Immunol 180:1423-31
Hannah, Michele F; Bajic, Vladimir B; Klein, Sabra L (2008) Sex differences in the recognition of and innate antiviral responses to Seoul virus in Norway rats. Brain Behav Immun 22:503-16
Easterbrook, J D; Kaplan, J B; Vanasco, N B et al. (2007) A survey of zoonotic pathogens carried by Norway rats in Baltimore, Maryland, USA. Epidemiol Infect 135:1192-9

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