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Bacterial Peptide Recognition and Immune Activation Facilitated by Human Peptide Transporter PEPT2

¹ Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland; ² Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio; ³ Nationwide Children's Research Institute, Columbus, Ohio; ⁴ ACT LLC, Jenkintown, Pennsylvania; and ⁵ Department of Pharmacology, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, Piscataway, New Jersey

Correspondence and requests for reprints should be addressed to Daren L. Knoell, Davis Heart and Lung Research Institute, The Ohio State University, 473 W. 12th Ave., Room 405A, Columbus, OH 43210. E-mail: daren.knoell{at}osumc.edu

Microbial detection requires the recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) that are distributed on the cell surface and within the cytosol. The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family functions as an intracellular PRR that triggers the innate immune response. The mechanism by which PAMPs enter the cytosol to interact with NLRs, particularly muropeptides derived from the bacterial proteoglycan cell wall, is poorly understood. PEPT2 is a proton-dependent transporter that mediates the active translocation of di- and tripeptides across epithelial tissues, including the lung. Using computational tools, we initially established that bacterial dipeptides, particularly -D-glutamyl-meso-diaminopimelic acid (-iE-DAP), are suitable substrates for PEPT2. We then determined in primary cultures of human upper airway epithelia and transiently transfected CHO-PEPT2 cell lines that -iE-DAP uptake was mediated by PEPT2 with an affinity constant of approximately 193 µM, whereas muramyl dipeptide was not transported. Exposure to -iE-DAP at the apical surface of differentiated, polarized cultures resulted in activation of the innate immune response in an NOD1- and RIP2-dependent manner, resulting in release of IL-6 and IL-8. Based on these findings we report that PEPT2 plays a vital role in microbial recognition by NLR proteins, particularly with regard to airborne pathogens, thereby participating in host defense in the lung.

Key Words: human • lung • bacterial • cell surface molecules • acute phase reactants

CLINICAL RELEVANCE This research demonstrates that peptide transporters expressed in human lung epithelia contribute to the uptake of select bacterial peptides, leading to specific activation of innate immune response.

 

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