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* Division of Dermatology, Department of Medicine, University of California San Diego and VA San Diego Healthcare Center, San Diego;
Division of Infectious Disease, Department of Pediatrics, University of California San Diego, San Diego, California, USA;
Cellular and Molecular Microbiology Division, Medical Microbiology and Hygiene Department, University of Tubingen, Tubingen, Germany; and
Institute of Basic Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan
1Correspondence: Mail Code 9111B, 3350 La Jolla Village Dr., San Diego, CA 92161, USA. E-mail: rgallo{at}vapop.ucsd.edu
Antimicrobial peptides (AMPs) have been shown in animal and human systems to be effective natural antibiotics. However, it is unclear how they convey protection; they often appear inactive when assayed under culture conditions applied to synthetic antibiotics. This inactivation has been associated with loss of function in physiological concentrations of NaCl or serum. In this study we show that the balance of host ionic conditions dictate microbial sensitivity to AMPs. Carbonate is identified as the critical ionic factor present in mammalian tissues that imparts the ability of AMPs such as cathelicidins and defensins to kill at physiological NaCl concentrations. After adapting to carbonate-containing solutions, global changes occur in Staphylococcus aureus and Escherichia coli structure and gene expression despite no change in growth rate. Our findings show that changes in cell wall thickness and Sigma factor B expression correspond to the increased susceptibility to the AMP LL-37. These observations provide new insight into the factors involved in enabling function of innate immune effector molecules, and suggest that discovery of new antimicrobials should specifically target pathogens as they exist in the host and not the distinctly different phenotype of bacteria grown in culture broth.—Dorschner, R. A., Lopez-Garcia, B., Peschel, A., Kraus, D., Morikawa, K., Nizet, V., Gallo, R. L. The mammalian ionic environment dictates microbial susceptibility to antimicrobial defense peptides.
Key Words: leukocyte recruitment • cathelicidin • AMP activity • dermatitis
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