Host-Microbe Competition for Zinc in the Inflamed Gut
- Author(s): Liu, Janet Zhen-Yi
- Advisor(s): Raffatellu, Manuela
- et al.
Salmonella enterica serovar Typhimurium is a common food-borne pathogen that causes localized enteritis in healthy individuals. A general host strategy to limit the growth of bacterial pathogens is to produce factors to limit the availability of metal nutrients such as iron and zinc, a concept termed “nutritional immunity”. Calprotectin is one such host-produced antimicrobial protein that binds and sequesters zinc and manganese ions from resident and invading microbes. It has been shown in previous studies that the two subunits of calprotectin, S100a8 and S100a9, are highly up-regulated during S. Typhimurium gastroenteritis, suggesting calprotectin is highly expressed during S. Typhimurium infection.
Despite this, S. Typhimurium replicates to high numbers in the inflamed gut. We therefore hypothesize S. Typhimurium is resistant to calprotectin-mediated zinc withholding, and that this is one of the mechanisms exploited by this pathogen to thrive in the inflamed gut. Using a mouse model of S. Typhimurium gastroenteritis, we found that calprotectin induction does not inhibit S. Typhimurium proliferation in the inflamed gut. S. Typhimurium overcomes calprotectin-mediated zinc chelation by expressing a high affinity zinc transporter, ZnuABC, thereby promoting its own growth over competing microbes. A znuA mutant exhibited a severe colonization defect in competition with wild-type S. Typhimurium. This colonization defect is diminished in the absence of either calprotectin or inflammation.
ZnuABC is also expressed by E. coli Nissle 1917 (E. coli Nissle), a probiotic that has been shown to be able to reduce S. Typhimurium levels in the inflamed gut. We hypothesized that zinc transporters such as ZnuABC are also important for E. coli Nissle probiotic activity and demonstrated that a zinc transporter mutant E. coli Nissle was unable to reduce S. Typhimurium colonization. Furthermore, the ability of E. coli Nissle to reduce S. Typhimurium colonization was dependent on the presence of host calprotectin protein, as E. coli Nissle was unable to reduce S. Typhimurium colonization in calprotectin-deficient mice. These findings have broadened our understanding about the role of zinc in health and disease and have important implications for understanding the mechanisms of probiotic activity and pathogen colonization.