T-cell immunity is known to wane with old age, and this defect is likely to impair protection against primary infection with a wide variety of pathogens. New results from the Nikolich lab strongly suggest that defects in effector T-cell differentiation underlie the age-related susceptibility to the West Nile virus (WNV). Moreover, preliminary results suggest that similar defects may exist in old mice infected with vaccinia virus (VACV). While much remains to be learned about the basic biology of this defect(s), its phenotypic manifestation is the reduced expression of the key effector molecules of the lytic pathway (Perforin/Granzyme B) and IFNy. Dr. Nikolich has made numerous important contributions to the biology of CDS T-cells in adult and aged organisms in the context of immunity and infection, and will deploy his knowledge and leadership skills to lead this Project and the entire P01.
Aims are : (i) to investigate the mechanistic features and the breadth of the putative common T-cell defect(s) that underlie age-related susceptibility to different bioattack agents (by broadening the studies to Listeria, monkeypox and Francisella models);(ii) to examine whether therapy of effector T-cell maturation can be achieved by correcting lytic complex and IFNy defects and whether such intervention can restore protective immunity to old mice. In collaboration with Projects 1.1, 1.2 &1.3, we shall then synthesize the results and knowledge to select the most efficient treatment(s);and (iii) to test in aged monkeys he most efficacious treatment validated in rodents, using the monkeypox virus model.

Public Health Relevance

Protection of the elderly and other populations especially vulnerable to bioattack or an emerging disease outbreak represents a considerable challenge in biodefense. Above experiments will study basic biology and practical aspects of T-cell activation in old age, and will test candidate treatments to broadly protect the elderly and, hopefully, other vulnerable populations by immunomodulation with or without concomitant vaccination.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZAI1-DDS-M)
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Oregon Health and Science University
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Smith, Jessica L; Stein, David A; Shum, David et al. (2014) Inhibition of dengue virus replication by a class of small-molecule compounds that antagonize dopamine receptor d4 and downstream mitogen-activated protein kinase signaling. J Virol 88:5533-42
Trobaugh, Derek W; Gardner, Christina L; Sun, Chengqun et al. (2014) RNA viruses can hijack vertebrate microRNAs to suppress innate immunity. Nature 506:245-8
Haick, Anoria K; Rzepka, Joanna P; Brandon, Elizabeth et al. (2014) Neutrophils are needed for an effective immune response against pulmonary rat coronavirus infection, but also contribute to pathology. J Gen Virol 95:578-90
Gibbs, David L; Gralinski, Lisa; Baric, Ralph S et al. (2014) Multi-omic network signatures of disease. Front Genet 4:309
Gardner, Christina L; Hritz, Jozef; Sun, Chengqun et al. (2014) Deliberate attenuation of chikungunya virus by adaptation to heparan sulfate-dependent infectivity: a model for rational arboviral vaccine design. PLoS Negl Trop Dis 8:e2719
Josset, Laurence; Tchitchek, Nicolas; Gralinski, Lisa E et al. (2014) Annotation of long non-coding RNAs expressed in collaborative cross founder mice in response to respiratory virus infection reveals a new class of interferon-stimulated transcripts. RNA Biol 11:875-90
Nikolich-┼Żugich, Janko (2014) Aging of the T cell compartment in mice and humans: from no naive expectations to foggy memories. J Immunol 193:2622-9
Engelmann, Flora; Josset, Laurence; Girke, Thomas et al. (2014) Pathophysiologic and transcriptomic analyses of viscerotropic yellow fever in a rhesus macaque model. PLoS Negl Trop Dis 8:e3295
Pal, Pankaj; Fox, Julie M; Hawman, David W et al. (2014) Chikungunya viruses that escape monoclonal antibody therapy are clinically attenuated, stable, and not purified in mosquitoes. J Virol 88:8213-26
Fontaine, Krystal A; Camarda, Roman; Lagunoff, Michael (2014) Vaccinia virus requires glutamine but not glucose for efficient replication. J Virol 88:4366-74

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