|Ren, Zhihong - JM USDA HNRCA @ TUFTS|
|Gay, Raina - JM USDA HNRCA @ TUFTS|
|Thomas, Adam - JM USDA HNRCA @ TUFTS|
|Pae, Munkyong - JM USDA HNRCA @ TUFTS|
|Logsdon, Lauren - TUFTS SCHOOL OF MEDICINE|
|Mecsas, John - TUFTS SCHOOL OF MEDICINE|
Submitted to: Journal of Medical Microbiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: August 28, 2009
Publication Date: November 1, 2009
Citation: Ren, Z., Gay, R., Thomas, A., Pae, M., Wu, D., Logsdon, L., Mecsas, J., Meydani, S. 2009. Effect of Age on Susceptibility to Salmonella typhimurium Infection in C57BL/6 Mice: Role of the Immune System. Journal of Medical Microbiology. 58:1559-1567. Interpretive Summary: Aging is associated with a decline in immune system to function; therefore, the elderly are more inclined to develop infections more frequently, and the courses of diseases are generally more severe and cause higher death rates. Statistics from the World Health Organization showed a 400-fold increase in deaths attributed to gastrointestinal infections in the elderly in comparison to the young adult population. Patients over 60 years of age comprise 25% of all hospitalizations for gastroenteritis and account for 85% of the deaths attributed to diarrhea. Salmonella infections, which affect the gastrointestinal system, are one of the most common food borne infections worldwide. It is estimated that 200 million to 1.3 billion cases of intestinal disease including 3 million deaths due to Salmonella occur each year worldwide. An estimated 1.4 million Salmonella infections, result in 168,000 visits to physicians, 15,000 hospitalizations and 580 deaths annually in US. Information on age-related increase in susceptibility to ST and the immune system’s specific response to this microorganism are lacking. In this study, we used streptomycin (strep)-pretreated C57BL/6 mice to develop a mouse model that would demonstrate age-related differences in susceptibility and immune response to ST. After young and old mice were orally given high or low doses of ST, we noted that old mice had significantly greater ST colonization in the intestinal tract and other organs including the liver and the spleen. Old mice had significantly higher weight loss than young mice on days 1 and 2 after being infected. Further, old mice had significantly higher mortality and shorter time to mortality in response to low dose ST. In summary, strep-treated C57BL/6 old mice are more susceptible to ST infection than young mice, which might be due to impaired immune response ST infection compared to young mice. In conclusion, the higher susceptibility of aged mice to ST infection could be due to their decreased ability to effectively increase their production of two cytokines, Interferon gamma (IFN-gamma) and Tumor Necrosis Factor-alpha (TNF-alpha) in response to ST as well as to maintain the number of macrophages (immune cells that digest harmful substances). These studies showing the immune system response to a specific organism like Salmonella could lead to methods of specific support to the immune system of the aged to assist them in fighting and overcoming this and other infections that affect the gastrointestinal system.
Technical Abstract: Aging is associated with a decline in immune function, which predisposes the elderly to higher incidence of infections. Enterocolitis caused by Salmonella typhimurium (ST) infection is a common foodborne disease in the US. However, information on the mechanism of age-related increase in susceptibility to ST is lacking. In particular little is known regarding the role of the immune response in this regard. This is in part due to lack of an appropriate rodent model for old age groups. In this study, we employed the streptomycin (strep)-pretreated C57BL/6 mice to develop a mouse model that would demonstrate age-related difference in susceptibility and immune response to ST. After young and old mice were inoculated orally with high (3×10**8 cfu) or low (1 ×10**6 cfu) doses of ST, old mice had significantly greater ST colonization in ileum, colon, peyer’s patches, spleen and liver. Old mice had significantly higher weight loss than young mice on days 1 and 2 postinfection. The LD50 for old strep-pretreated mice was less than young infected mice. Furthermore, old mice had significantly higher mortality and shorter time to mortality in response to low dose ST. Ex vivo production of IFN-gamma and TNF-alpha in spleen and mesenteric lymph node (MLN) from old ST infected mice was significantly less than those from young infected mice. In summary, strep-treated C57BL/6 old mice are more susceptible to ST infection than young mice, which might be due to impaired IFN-gamma and TNF-alpha production in response to ST infection compared to young mice.