Human Enteric Defensin 5 PromotesShigellaInfection of Macrophages

Abstract

Human α-defensins are 3- to 5-kDa disulfide-bridged peptides with a multitude of antimicrobial activities and immunomodulatory functions. Recent studies show that human enteric α-defensin 5 (HD5), a host defense peptide important for intestinal homeostasis and innate immunity, aids the highly infectious enteropathogen Shigella in breaching the intestinal epithelium in vitro and in vivo. Whether and how HD5 influences Shigella infection of resident macrophages following its invasion of the intestinal epithelium remain poorly understood. Here, we report that HD5 greatly promoted phagocytosis of Shigella by macrophages by targeting the bacteria to enhance bacterium-to-cell contacts in a structure- and sequence-dependent fashion. Subsequent intracellular multiplication of phagocytosed Shigella led to massive necrotic cell death and release of the bacteria. HD5-promoted phagocytosis of Shigella was independent of the status of the type 3 secretion system. Furthermore, HD5 neither inhibited nor enhanced phagosomal escape of Shigella. Collectively, these findings confirm a potential pathogenic role of HD5 in Shigella infection of not only epithelial cells but also macrophages, illuminating how an enteropathogen exploits a host protective factor for virulence and infection.

Defensin-driven viral evolution

“…One hypothesis to explain these observations is that resistance stems from evolutionary pressure imposed by enteric α-defensins during fecal-oral transmission. Consistent with this hypothesis, rather than kill the enteric bacterial pathogen shigella, HD5 was recently found to promote its cell binding and infection [ 19 , 20 ]. Moreover, enteric α-defensins play a role in shaping the microbial communities of the gastrointestinal tract through differential susceptibility of commensal bacteria to defensin killing [ 21 – 23 ].…”

“…An alternative model whereby enhancement occurs through increased internalization or more efficient uncoating cannot be formally excluded but is not supported by any of our studies to date. Because shigella is another gastrointestinal pathogen that appropriates HD5 to facilitate infection [ 19 , 20 ], the ability of enteric pathogens to co-opt defensins to promote adhesion may be common.…”

Defensin-driven viral evolution

“…Increased cell binding likely occurs by neutralizing the repulsive forces of the electronegative capsid in proximity to the cell membrane [15], although HD5 could also bridge interactions between the virus and cellular lipids, glycans, or an unidentified HD5-specific receptor. A similar mechanism has been shown in shigella, another gastrointestinal pathogen that appropriates HD5 to facilitate infection [19, 20]. In addition, only viruses containing hexons in which all of the HVRs are from one serotype are enhanced, including a recently published HAdV-5 chimera containing all of the HVRs of HAdV-48 hexon [32].…”

“…One hypothesis to explain these observations is that resistance stems from evolutionary pressure imposed by enteric α-defensins during fecal-oral transmission. Consistent with this hypothesis, rather than kill the enteric bacterial pathogen shigella, HD5 was recently found to promote its cell binding and infection [19, 20]. And, enteric α-defensins play a role in shaping the microbial communities of the gastrointestinal tract through differential susceptibility of commensal bacteria to defensin killing [21-23].…”

Antimicrobial Peptides: Virulence and Resistance Modulation in Gram-Negative Bacteria

“…Because host cells also exhibit an anionic charge, it has been proposed that human AMPs such as the enteric α-Defensin 5 (HD-5) are used as a scaffold between the bacteria and the host cells [77,78]. In addition, a subinhibitory concentration of human defensin 5 increases the phagocytosis of S. flexneri by human macrophages, leading to increased cytotoxicity and lysis of the macrophages [79]. Therefore, S. flexneri, which is devoid of the major adhesion apparatus, subverts the human immune system and exploits AMPs' properties to adhere and invade human epithelial cells.…”