Carving a Niche for Antibacterial α-Defensins when Craving
Authors: Elisabeth G. Foerster, Stephen E. Girardin
Journal: Cell Host & Microbe (2019)

In this issue of Cell Host & Microbe, Liang et al., 2019Liang S. Guo X.-K. Ou J. Huang R. Xue Q. Zhang B. Chung Y. Wu W. Dong C. Yang X. Hu X. Nutrient sensing by the intestinal epithelium orchestrates mucosal antimicrobial defense via translational control of Hes1.Cell Host Microbe. 2019; 25 (this issue): 706-718Abstract Full Text Full Text PDF Scopus (14) Google Scholar show that α-defensins in the gastrointestinal tract sustain defenses to enteric pathogens during starvation. mTOR-dependent sensing of nutrient loss promotes production of an α-defensin regulator, which sustains α-defensin levels, loss of which increases lethality during bacterial infection. In this issue of Cell Host & Microbe, Liang et al., 2019Liang S. Guo X.-K. Ou J. Huang R. Xue Q. Zhang B. Chung Y. Wu W. Dong C. Yang X. Hu X. Nutrient sensing by the intestinal epithelium orchestrates mucosal antimicrobial defense via translational control of Hes1.Cell Host Microbe. 2019; 25 (this issue): 706-718Abstract Full Text Full Text PDF Scopus (14) Google Scholar show that α-defensins in the gastrointestinal tract sustain defenses to enteric pathogens during starvation. mTOR-dependent sensing of nutrient loss promotes production of an α-defensin regulator, which sustains α-defensin levels, loss of which increases lethality during bacterial infection. In 1977, M.J. Murray and M.B. Murray hypothesized that “starvation represses and refeeding activates certain infections,” speculating that resistance to infection is required during times of famine to assure human survival (Murray and Murray, 1977Murray M.J. Murray A.B. Starvation suppression and refeeding activation of infection. An ecological necessity?.Lancet. 1977; 1: 123-125Abstract PubMed Scopus (42) Google Scholar). A recent study of feeding behaviors during infection in mice showed that disease-induced anorexia was indeed protective in Listeria monocytogenes infection, yet detrimental in a viral infection (Wang et al., 2016Wang A. Huen S.C. Luan H.H. Yu S. Zhang C. Gallezot J.D. Booth C.J. Medzhitov R. Opposing effects of fasting metabolism on tissue tolerance in bacterial and viral inflammation.Cell. 2016; 166: 1512-1525.e12Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar). Furthermore, an enteric bacterial pathogen has been found to regulate its host’s feeding behavior, which both protected the host from systemic disease and allowed for pathogen dissemination (Rao et al., 2017Rao S. Schieber A.M.P. O’Connor C.P. Leblanc M. Michel D. Ayres J.S. Pathogen-mediated inhibition of anorexia promotes host survival and transmission.Cell. 2017; 168: 503-516.e12Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). Nevertheless, not much has been known about the response to an infection that arises during a period of acute nutrient deprivation, an important question addressed by Liang et al., 2019Liang S. Guo X.-K. Ou J. Huang R. Xue Q. Zhang B. Chung Y. Wu W. Dong C. Yang X. Hu X. Nutrient sensing by the intestinal epithelium orchestrates mucosal antimicrobial defense via translational control of Hes1.Cell Host Microbe. 2019; 25 (this issue): 706-718Abstract Full Text Full Text PDF Scopus (14) Google Scholar in their recent work on antimicrobial proteins (AMPs) in starvation. The first sensors of a gastrointestinal infection and nutrient deprivation are intestinal epithelial cells (IECs). Due to continuous exposure to the resident intestinal microbiota as well as potentially pathogenic ingested microorganisms, the intestinal epithelium has evolved to form a protective barrier to shield the body from intestinal luminal contents. Reinforcing this barrier are AMPs, a diverse family of bactericidal and/or bacteriostatic molecules including, among others, C-type lectins and α-defensins. C-type lectins, which include the regenerating islet-derived 3 (Reg3) family, are formed by various IEC subtypes, whereas α-defensins are exclusively produced by Paneth cells located at the small intestinal crypt base. α-defensins are packaged into secretory vesicles as propeptides and cleaved by matrix-metalloproteinase 7 (MMP7) into their bioactive form (Peterson and Artis, 2014Peterson L.W. Artis D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis.Nat. Rev. Immunol. 2014; 14: 141-153Crossref PubMed Scopus (1639) Google Scholar). Interestingly, mice deficient in MMP7 have previously been shown to be more susceptible to infection with the enteric pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) (Wilson et al., 1999Wilson C.L. Ouellette A.J. Satchell D.P. Ayabe T. López-Boado Y.S. Stratman J.L. Hultgren S.J. Matrisian L.M. Parks W.C. Regulation of intestinal α-defensin activation by the metalloproteinase matrilysin in innate host defense.Science. 1999; 286: 113-117Crossref PubMed Scopus (909) Google Scholar). IECs respond to nutrient starvation in part through the mechanistic target of the rapamycin (mTOR) pathway. mTOR integrates the cellular response to both internal and environmental signals, including cell stress, energy status, and the availability of growth factors, oxygen, and amino acids. Downstream of mTOR lie major cell metabolic pathways, both lipid and protein synthesis as well as the catabolic autophagic pathway. Active mTOR results in eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) and S6 kinase 1 (S6K1) phosphorylation, allowing for protein translation and upregulation of anabolic processes. In the event of nutrient starvation, mTOR is inhibited, resulting in a stop in translation and, in parallel, initiation of autophagy (Laplante and Sabatini, 2012Laplante M. Sabatini D.M. mTOR signaling in growth control and disease.Cell. 2012; 149: 274-293Abstract Full Text Full Text PDF PubMed Scopus (6136) Google Scholar). In this issue of Cell Host & Microbe, Liang et al., 2019Liang S. Guo X.-K. Ou J. Huang R. Xue Q. Zhang B. Chung Y. Wu W. Dong C. Yang X. Hu X. Nutrient sensing by the intestinal epithelium orchestrates mucosal antimicrobial defense via translational control of Hes1.Cell Host Microbe. 2019; 25 (this issue): 706-718Abstract Full Text Full Text PDF Scopus (14) Google Scholar propose an additional mTOR-regulated pathway that mediates protection against bacterial infection. Liang et al., 2019Liang S. Guo X.-K. Ou J. Huang R. Xue Q. Zhang B. Chung Y. Wu W. Dong C. Yang X. Hu X. Nutrient sensing by the intestinal epithelium orchestrates mucosal antimicrobial defense via translational control of Hes1.Cell Host Microbe. 2019; 25 (this issue): 706-718Abstract Full Text Full Text PDF Scopus (14) Google Scholar elegantly explored the role and regulation of α-defensins in bacterial infection during nutrient deprivation. Upon 32 hours of starvation, both Reg3 proteins and mature α-defensins were downregulated at the protein level. This downregulation was sustained by the Reg3 family throughout starvation. The levels of mature α-defensins, on the other hand, were increased back to baseline after 72 hours of starvation, while pro-α-defensins had remained unchanged throughout, suggesting that regulation occurred at the step of maturation. This was supported by MMP7 transcript and protein levels that followed the same V-shaped pattern as the mature α-defensins (summarized in Figure 1). Crucially, starved MMP7−/− mice, which lack mature α-defensins, were more susceptible to oral infection with S. Typhimurium than their starved wild-type counterparts. MMP7−/− mice lost more weight, had a higher bacterial burden, and displayed decreased survival, indicating an important role for α-defensins in protecting from bacterial infection during starvation. This phenotype was dependent on the state of starvation; in contrast to previous findings, the authors did not see a difference in disease burden at baseline (Wilson et al., 1999Wilson C.L. Ouellette A.J. Satchell D.P. Ayabe T. López-Boado Y.S. Stratman J.L. Hultgren S.J. Matrisian L.M. Parks W.C. Regulation of intestinal α-defensin activation by the metalloproteinase matrilysin in innate host defense.Science. 1999; 286: 113-117Crossref PubMed Scopus (909) Google Scholar). Experimental evidence delineating the starvation response of the two AMP sub-families showed that transcription of Reg3 family genes was dependent on interleukin-22 (IL-22) and toll-like receptor (TLR) signaling through myeloid differentiation primary response 88 (MyD88). Both IL-22 and MyD88 signaling were decreased upon starvation due to restriction of microbial abundance by nutrient limitation. Interestingly, MMP7 transcription was also dependent on these pathways, explaining why mature α-defensins were decreased early in starvation. However, this did not account for the later increase in MMP7 levels in starvation, which replenished mature α-defensin production; as such, the authors sought out other transcriptional regulators of MMP7. They found that atonal basic helix-loop-helix (bHLH) transcription factor 1 (Atoh1), a master transcription factor of the secretory cell lineage, directly led to MMP7 transcription; coincidentally, Atoh1 expression was upregulated with nutrient starvation. Hairy and enhancer of split 1 (Hes1) has been well established as a transcriptional repressor of Atoh1 during IEC lineage differentiation, inhibiting secretory cell specification while promoting absorptive enterocyte differentiation (Noah and Shroyer, 2013Noah T.K. Shroyer N.F. Notch in the intestine: regulation of homeostasis and pathogenesis.Annu. Rev. Physiol. 2013; 75: 263-288Crossref PubMed Scopus (126) Google Scholar). Indeed, Hes1-deficient mice sustained MMP7 expression and mature α-defensins throughout nutrient deprivation. Taking into consideration that the mTOR pathway functions to integrate stimuli such as nutrient deprivation, Liang et al., 2019Liang S. Guo X.-K. Ou J. Huang R. Xue Q. Zhang B. Chung Y. Wu W. Dong C. Yang X. Hu X. Nutrient sensing by the intestinal epithelium orchestrates mucosal antimicrobial defense via translational control of Hes1.Cell Host Microbe. 2019; 25 (this issue): 706-718Abstract Full Text Full Text PDF Scopus (14) Google Scholar tested whether upstream mTOR inhibition was regulating the Hes1-Atoh1 interaction. Indeed, they found Hes1 to be translationally targeted downstream of mTOR inhibition, which resulted in decreased Hes1 protein levels. Finally, this effect could be countered by amino acid and/or glucose re-feeding following starvation. The study by Liang et al., 2019Liang S. Guo X.-K. Ou J. Huang R. Xue Q. Zhang B. Chung Y. Wu W. Dong C. Yang X. Hu X. Nutrient sensing by the intestinal epithelium orchestrates mucosal antimicrobial defense via translational control of Hes1.Cell Host Microbe. 2019; 25 (this issue): 706-718Abstract Full Text Full Text PDF Scopus (14) Google Scholar provides convincing evidence of a non-redundant role for α-defensins in the mammalian gastrointestinal tract. Their novel findings show that α-defensins possibly evolved to protect from infection during a physiological state of starvation, highlighting a crucial window for α-defensin-mediated immunity. This corroborates work done by Becker et al., 2010Becker T. Loch G. Beyer M. Zinke I. Aschenbrenner A.C. Carrera P. Inhester T. Schultze J.L. Hoch M. FOXO-dependent regulation of innate immune homeostasis.Nature. 2010; 463: 369-373Crossref PubMed Scopus (253) Google Scholar in Drosophila that showed starvation-induced AMP expression dependent on FOXO, a key regulator of metabolism and the stress response. Together, these studies suggest an evolutionarily conserved role of specific AMPs during periods of nutrient starvation that require tight regulation of energy expenditure. It would be of interest to explore additional physiological states that similarly target the mTOR pathway, such as cell stress, and how these states affect AMP regulation. Different disease states that affect nutrient absorption may thus be dependent on a similar α-defensin response. In addition, mTOR-independent effects on the downstream Hes1-Atoh1 interaction may result in a similar AMP phenotype. Interestingly, Crohn’s disease patients have decreased α-defensins (Wehkamp et al., 2005Wehkamp J. Salzman N.H. Porter E. Nuding S. Weichenthal M. Petras R.E. Shen B. Schaeffeler E. Schwab M. Linzmeier R. et al.Reduced Paneth cell α-defensins in ileal Crohn’s disease.Proc. Natl. Acad. Sci. U S A. 2005; 102: 18129-18134Crossref PubMed Scopus (803) Google Scholar), which may contribute to susceptibility to bacterial infection during states of nutrient malabsorption. Furthering our understanding of α-defensin mediated protection would give us insight into better therapeutics for these patients. In conclusion, nutrient sensing regulates production of mature α-defensins through Hes1 repression followed by Atoh1 de-repression, MMP7 expression, and, ultimately, α-defensin cleavage. This carves out a niche for α-defensins in the innate immune defense during a nutrient-starved state. Nutrient Sensing by the Intestinal Epithelium Orchestrates Mucosal Antimicrobial Defense via Translational Control of Hes1Liang et al.Cell Host & MicrobeApril 30, 2019In BriefMetabolic and antimicrobial programs are integrated to ensure proper immunity during stress. Liang et al. show that during nutrient fluctuations, antimicrobial peptide α-defensin and its processing enzyme MMP7 are functionally sustained via translational attenuation of the transcriptional repressor Hes1. This MMP7-α-defensin axis provides essential protection against enteric infections during nutrient deprivation. Full-Text PDF Open Archive