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GENES, IN ADDITION TO TOLL-LIKE RECEPTOR 2, PLAY A ROLE IN ANTIBACTERIAL DEFENSE TO STREPTOCOCCAL PNEUMONIA
HOLLINGSWORTH, J. W., K. BERMAN, G. WHITEHEAD, E. M. TEKIPPE, M. IAN I. GILMOUR, AND D. SCHWARTZ. GENES, IN ADDITION TO TOLL-LIKE RECEPTOR 2, PLAY A ROLE IN ANTIBACTERIAL DEFENSE TO STREPTOCOCCAL PNEUMONIA. Presented at American Thoracic Society Annual Meeting, San Diego, CA, May 19 - 24, 2006.
Streptococcus infection in human populations continues to be a major cause of morbidity and mortality. To evaluate the effect of genetic background and toll-like receptor 2 (TLR2) on antibacterial defense to streptococcal infection, eight genetically diverse strains of mice (129/SvImJ, A/J, BALB/cJ, C3H/HeJ, C57BL/6J, CAST/Ei, DBA/2J, and FVB/NJ) and tlr2-deficient (C57BL/6tlr2-/-) mice were infected with three doses of Streptococcus zooepidemicus (500, 5,000, or 50,000 colony forming units) by oropharyngeal aspiration. There was a range of susceptibility between the strains at each dose and time point (6, 24, and 96 hours). At the lowest dose, the 129/SvImJ and C3H/HeJ strains had significantly higher bacterial counts than other strains, at all three time points after infection. In contrast, A/J, FVB, DBA, and CAST/Ei were relatively resistant to infection at low dose of innoculum. At the medium dose, 129/SvImJ and C3H/HeJ strains had higher bacterial counts, while A/J, BALB/cJ, and DBA/2J strains to show an overall decrease in streptococcal growth. Following inoculation with the highest dose of Streptococcus, there were minimal differences between strains, suggesting the protective impact of modifier genes can be overcome. Next we specifically studied the role of TLR2, which is known to mediate host response to gram-positive bacterial wall components, but not thought to be associated with pulmonary antibacterial defense to live Streptococcal infection. TLR2-deficient animals demonstrated increased bacterial load with reduced cytokines at late time points with medium to high doses of innoculation. Overall, we identify late antibacterial defense to be TLR2-dependent, as well as, more general vulnerable (129/SvlmJ and C3H/Hej) and resistant (A/J and DBA) mouse strains to Streptococcal lung infection. These results demonstrate innate differences in pulmonary host defense to Streptococcus zooepidemicus is dependent on TLR2 and background strain, which support the role of novel genes in the clearance of bacterial pathogens.
Acknowledgements: Authors gratefully receive support from the National Institute of Environmental Health Services (ES12717, ES11961) and the National Institute of Allergy and Infectious Diseases (AI058161). We appreciate our continued collaboration with S. Akira (Osaka University), who provided the genetically engineered mice. This is an abstract of a proposed presentation and does not necessarily reflect EPA policy.