Many infectious diseases, especially respiratory diseases, are more frequent and severe among the elderly compared with the younger population. The long-term objective of this project is to compare infection and immunity in young and aged individuals using a mouse model of pulmonary tularemia. The causative agent of tularemia is Francisella tularensis. The biotype A strain of Francisella (Schu4) has been classified as a Category A bioterrorism agent because of its ease of transmission and high mortality rate when inhaled. As such, this project is significant for the areas of both aging and bioweapons. Infection by F.t. novicia and F.t. tularensis (Schu4) will be compared in young adult and aged mice using primarily targeted macroarrays followed by in situ methodologies involving 3 and 4 color fluorescence microscopy and confocal microscopy.
The aims are to perform a kinetic analysis of the infectious disease process in young and aged mice. This will allow a systematic and simultaneous analysis of the immune cells, cytokines, location of the bacteria as it disseminates, and the resulting histopathology. In addition, the protective efficacy of two protective strategies as a result of aging will be tested including the use of attenuated mutants and the use of lL-12 as an adjuvant. The underlying hypothesis is that aged animals will exhibit a delayed innate/adaptive immune response and less protection from therapeutic strategies. The proposed experiments will provide important new insights into immunosenescence, immunity to intracellular respiratory bacteria, and potential strategies should Francisella be used as a bioweapon. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI059703-04
Application #
7033908
Study Section
Special Emphasis Panel (ZRG1-IDM-A (90))
Program Officer
Macchiarini, Francesca
Project Start
2004-04-01
Project End
2009-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
4
Fiscal Year
2006
Total Cost
$345,437
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
800189185
City
San Antonio
State
TX
Country
United States
Zip Code
78249
Sharma, Jyotika; Mares, Chris A; Li, Qun et al. (2011) Features of sepsis caused by pulmonary infection with Francisella tularensis Type A strain. Microb Pathog 51:39-47
Mishra, Bibhuti B; Gundra, Uma Mahesh; Teale, Judy M (2011) STAT6ýýý/ýýý mice exhibit decreased cells with alternatively activated macrophage phenotypes and enhanced disease severity in murine neurocysticercosis. J Neuroimmunol 232:26-34
Mares, Chris A; Sharma, Jyotika; Li, Qun et al. (2011) Defect in efferocytosis leads to alternative activation of macrophages in Francisella infections. Immunol Cell Biol 89:167-72
Gundra, Uma Mahesh; Mishra, Bibhuti B; Wong, Kondi et al. (2011) Increased disease severity of parasite-infected TLR2-/- mice is correlated with decreased central nervous system inflammation and reduced numbers of cells with alternatively activated macrophage phenotypes in a murine model of neurocysticercosis. Infect Immun 79:2586-96
Sharma, Jyotika; Mishra, Bibhuti B; Li, Qun et al. (2011) TLR4-dependent activation of inflammatory cytokine response in macrophages by Francisella elongation factor Tu. Cell Immunol 269:69-73
Mares, Chris A; Sharma, Jyotika; Ojeda, Sandra S et al. (2010) Attenuated response of aged mice to respiratory Francisella novicida is characterized by reduced cell death and absence of subsequent hypercytokinemia. PLoS One 5:e14088
Mares, C A; Ojeda, S S; Li, Q et al. (2010) Aged mice display an altered pulmonary host response to Francisella tularensis live vaccine strain (LVS) infections. Exp Gerontol 45:91-6
Alvarez, Jorge I; Mishra, Bibhuti B; Gundra, Uma Mahesh et al. (2010) Mesocestoides corti intracranial infection as a murine model for neurocysticercosis. Parasitology 137:359-72
Mishra, Bibhuti B; Gundra, Uma Mahesh; Teale, Judy M (2009) Toll-like receptors in CNS parasitic infections. Curr Top Microbiol Immunol 336:83-104
Sharma, Jyotika; Li, Qun; Mishra, Bibhuti B et al. (2009) Lethal pulmonary infection with Francisella novicida is associated with severe sepsis. J Leukoc Biol 86:491-504

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