Physiological microbial exposure has the capacity to substantially influence inflammatory responses in vivo

Abstract

Abstract Physiological exposure to microbes profoundly effects the basal immune state, based on data from ‘dirty’ mice with a diverse microbial experience obtained after co-housing with pet store mice. Most T cells in dirty mice and adult humans have an effector/memory phenotype, but specific pathogen free (SPF) mice or newborn humans have few Ag-experienced memory T cells. These differences prompted us to define the acute cytokine/chemokine response in SPF or co-housed inbred C57Bl/6 (B6) mice. Co-housing for 60 d increased the frequency of CD44hi CD8 T cells and led to higher basal serum cytokine/chemokine levels (vs. SPF mice). We then examined to what extent these basal immune differences affected the response to different inflammatory stimuli. Infection of SPF mice with virulent Listeria significantly increased serum cytokines/chemokines (e.g., IFNg, TNF, CXCL1, CXCL10, CCL7) 24–72 h after infection. The same infection produced little-to-no change in the serum of dirty mice, but they had significantly lower bacterial burden. After LPS challenge, SPF and dirty mice had similar increases in serum cytokines/chemokines, but mortality was increased in dirty mice. Lastly, while an increase in serum cytokines/chemokines occurred 6–12 h after sepsis induction (CLP model) in both SPF and dirty mice, they were 2–8-fold higher in dirty mice. Acute lymphopenia was observed in both sets of CLP-treated mice; yet, mortality was higher in CLP-treated dirty mice. Thus, physiological microbial exposure influences the cytokine ‘storm’ and survival suggesting the immune status of the host controls the magnitude of the response and outcome. The data also point out the need to further develop the ‘dirty’ mouse model to complement current studies in SPF mice.