Conceptual Perspectives: Bacterial Antimicrobial Peptide Induction as a Novel Strategy for Symbiosis with the Human Host.

Santosh K. Ghosh,Hisashi Fujioka,Aaron Weinberg,Thomas S. McCormick,Zhimin Feng,Renate Lux

doi:10.3389/fmicb.2018.00302

Abstract

Human beta defensins (hBDs) are small cationic peptides, expressed in mucosal epithelia and important agents of innate immunity, act as antimicrobial and chemotactic agents at mucosal barriers. In this perspective, we present evidence supporting a novel strategy by which the oral bacterium Fusobacterium nucleatum induces hBDs and other antimicrobial peptides (AMPs) in normal human oral epithelial cells (HOECs) and thereby protects them from other microbial pathogens. The findings stress (1) the physiological importance of hBDs, (2) that this strategy may be a mechanism that contributes to homeostasis and health in body sites constantly challenged with bacteria and (3) that novel properties identified in commensal bacteria could, one day, be harnessed as new probiotic strategies to combat colonization of opportunistic pathogens. With that in mind, we highlight and review the discovery and characterization of a novel lipo-protein, FAD-I (Fusobacterium Associated Defensin Inducer) associated with the outer membrane of F. nucleatum that may act as a homeostatic agent by activating endogenous AMPs to re-equilibrate a dysregulated microenvironment. FAD-I has the potential to reduce dysbiosis-driven diseases at a time when resistance to antibiotics is increasing. We therefore postulate that FAD-I may offer a new paradigm in immunoregulatory therapeutics to bolster host innate defense of vulnerable mucosae, while maintaining physiologically responsive states of inflammation.

Highlights

Symbiosis is a relationship between two organisms; it can be mutualistic where both the bacteria and the host benefit, or commensalistic where the bacteria benefits while the host is unharmed
We propose that Human beta defensins (hBDs)-2 is playing a major role in mucosal protection, we cannot rule out the possibility of synergy with other inducible epithelial cell derived antimicrobial peptides (AMPs)
We discovered that F. nucleatum can promote the expression of the cathelicidin AMP, LL-37, FIGURE 1 | (A–D) Representative F. nucleatum (A,C) and P. gingivalis (B,D) susceptibility to hBD-2 (A,B) and−3 (C,D), 2 × 105 bacteria were incubated with recombinant hBD-2 and 3 anaerobically, for 3 h, followed by serial dilutions and plating on sheep red blood agar plates

Summary

INTRODUCTION

Symbiosis is a relationship between two organisms; it can be mutualistic where both the bacteria and the host benefit, or commensalistic where the bacteria benefits while the host is unharmed. We present a novel strategy by the commensal organism F. nucleatum, whereby this ubiquitous Gram-negative colonizer of the human oral cavity induces hBD-2 expression in oral epithelial cells; along with expression and release of CCL20 and LL37, which, as a consequence, confers protection to the cells from the opportunistic pathogen P. gingivalis. Previous studies by others and our data to date support the principle that F. nucleatum has evolved to create a “heightened state of readiness” of the epithelium it inhabits without promoting notable inflammatory cytokine responses This does not necessarily mean that F. nucleatum maintains the similar degree of “symbiosis” in other body sites, as the organism has been reported to infect vulnerable sites outside the oral cavity (Bolstad et al, 1996; Williams et al, 2003), and more recently has been shown to be associated with esophageal (Yamamura et al, 2016), colon (Castellarin et al, 2012), and oral cancers (Schmidt et al, 2014; Al-Hebshi et al, 2017). Could F. nucleatum be a key commensal that promotes “physiological” inflammation, tweaking the host mucosa to generate physiological levels of innate response agents that contribute to homeostasis? Could FAD-I have the ability to promote epigenetic changes directly or induce an HDAC inhibitor that in conjunction with FAD-I contribute to selective “physiologically” relevant innate responses?

CONCLUSIONS AND FUTURE PERSPECTIVES

Findings

ETHICS STATEMENT