Role Of Host Defense Peptides Research Articles

Understanding the Roles of Host Defense Peptides in Immune Modulation: From Antimicrobial Action to Potential as Adjuvants.

Host defense peptides are expressed in various immune cells, including phagocytic cells and epithelial cells. These peptides selectively alter innate immune pathways in response to infections by pathogens, such as bacteria, fungi, and viruses, and modify the subsequent adaptive immune environment. Consequently, they play a wide range of roles in both innate and adaptive immune responses. These peptides are of increasing importance due to their broad-spectrum antimicrobial activity and their functions as mediators linking innate and adaptive immune responses. This review focuses on the pleiotropic biological functions and related mechanisms of action of human host defense peptides and discusses their potential clinical applications.

Combating Implant Infections: Shifting Focus from Bacteria to Host.

The widespread use of biomaterials to support or replace body parts is increasingly threatened by the risk of implant-associated infections. In the quest for finding novel anti-infective biomaterials, there generally has been a one-sided focus on biomaterials with direct antibacterial properties, which leads to excessive use of antibacterial agents, compromised host responses, and unpredictable effectiveness in vivo. This review sheds light on how host immunomodulation, rather than only targeting bacteria, can endow biomaterials with improved anti-infective properties. How antibacterial surface treatments are at risk to be undermined by biomaterial features that dysregulate the protection normally provided by critical immune cell subsets, namely, neutrophils and macrophages, is discussed. Accordingly, how the precise modification of biomaterial surface biophysical cues, or the incorporation of immunomodulatory drug delivery systems, can render biomaterials with the necessary immune-compatible and immune-protective properties to potentiate the host defense mechanisms is reviewed. Within this context, the protective role of host defense peptides, metallic particles, quorum sensing inhibitors, and therapeutic adjuvants is discussed. The highlighted immunomodulatory strategies may lay a foundation to develop anti-infective biomaterials, while mitigating the increasing threat of antibacterial drug resistance.

The Network of Colonic Host Defense Peptides as an Innate Immune Defense Against Enteropathogenic Bacteria

Host defense peptides, abundantly secreted by colonic epithelial cells and leukocytes, are proposed to be critical components of an innate immune response in the colon against enteropathogenic bacteria, including Shigella spp., Salmonella spp., Clostridium difficile, and attaching and effacing Escherichia coli and Citrobacter rodentium. These short cationic peptides are bactericidal against both Gram-positive and -negative enteric pathogens, but may also exert killing effects on intestinal luminal microbiota. Simultaneously, these peptides modulate numerous cellular responses crucial for gut defenses, including leukocyte chemotaxis and migration, wound healing, cytokine production, cell proliferation, and pathogen sensing. This review discusses recent advances in our understanding of expression, mechanisms of action and microbicidal and immunomodulatory functions of major colonic host defense peptides, namely cathelicidins, β-defensins, and members of the Regenerating islet-derived protein III (RegIII) and Resistin-like molecule (RELM) families. In a theoretical framework where these peptides work synergistically, aspects of pathogenesis of infectious colitis reviewed herein uncover roles of host defense peptides aimed to promote epithelial defenses and prevent pathogen colonization, mediated through a combination of direct antimicrobial function and fine-tuning of host immune response and inflammation. This interactive host defense peptide network may decode how the intestinal immune system functions to quickly clear infections, restore homeostasis and avoid damaging inflammation associated with pathogen persistence during infectious colitis. This information is of interest in development of host defense peptides (either alone or in combination with reduced doses of antibiotics) as antimicrobial and immunomodulatory therapeutics for controlling infectious colitis.

Expression and Function of Host Defense Peptides at Inflammation Sites.

There is a growing interest in the complex role of host defense peptides (HDPs) in the pathophysiology of several immune-mediated inflammatory diseases. The physicochemical properties and selective interaction of HDPs with various receptors define their immunomodulatory effects. However, it is quite challenging to understand their function because some HDPs play opposing pro-inflammatory and anti-inflammatory roles, depending on their expression level within the site of inflammation. While it is known that HDPs maintain constitutive host protection against invading microorganisms, the inducible nature of HDPs in various cells and tissues is an important aspect of the molecular events of inflammation. This review outlines the biological functions and emerging roles of HDPs in different inflammatory conditions. We further discuss the current data on the clinical relevance of impaired HDPs expression in inflammation and selected diseases.

Evidence that changes in antimicrobial peptides during tuberculosis are related to disease severity, clinical presentation, specific therapy and levels of immune-endocrine mediators

Given the role of host defense peptides (HDPs) in the defensive response against mycobacteria, we analyzed the circulating levels of LL-37, β-defensin-2 and -3 in newly diagnosed patients with pulmonary (PTB) or pleural tuberculosis (PLTB) in whom measurements of pleural fluids were also performed. Severe PTB patients displayed higher circulating amounts of β-defensin-3, statistically different from controls, further decreasing upon antimycobacterial treatment. LL-37 concentrations appeared within the normal range at diagnosis, but tended to increase during treatment, becoming statistically upon its completion in moderate cases. PLTB patients revealed decreased levels of β-defensin-2 in presence of increased amounts of β-defensin-3 and LL-37; in their plasma or pleural fluids. Considering the immune-endocrine dysregulation of tuberculosis, we also performed correlation analysis detecting positive associations between levels of cortisol, IL-6 and β-defensin-3 in plasma from untreated severe patients as did their dehydroepiandrosterone and LL-37 values. Increased presence of β-defensins, may represent an attempt to improve defensive mechanisms; which also take part in the inflammatory reaction accompanying TB, reinforced by the association with immune-endocrine mediators. The divergent profile of PLTB patients, decreased β-defensin-2 but increased β-defensin-3 and LL-37 levels, suggests a differential role of these HDPs in a situation characterized for its better protective response.

Reassessing the Host Defense Peptide Landscape.

Current research has demonstrated that small cationic amphipathic peptides have strong potential not only as antimicrobials, but also as antibiofilm agents, immune modulators, and anti-inflammatories. Although traditionally termed antimicrobial peptides (AMPs) these additional roles have prompted a shift in terminology to use the broader term host defense peptides (HDPs) to capture the multi-functional nature of these molecules. In this review, we critically examined the role of AMPs and HDPs in infectious diseases and inflammation. It is generally accepted that HDPs are multi-faceted mediators of a wide range of biological processes, with individual activities dependent on their polypeptide sequence. In this context, we explore the concept of chemical space as it applies to HDPs and hypothesize that the various functions and activities of this class of molecule exist on independent but overlapping activity landscapes. Finally, we outline several emerging functions and roles of HDPs and highlight how an improved understanding of these processes can potentially be leveraged to more fully realize the therapeutic promise of HDPs.

Pathological Role and Diagnostic Value of Endogenous Host Defense Peptides in Adult and Neonatal Sepsis

Sepsis is a systemic host response to an infection leading to organ failure. This is associated with dynamic expression of endogenous host defense peptides. Dysregulation of these peptides is associated with septic morbidity and mortality. We performed a systematic search of articles indexed in PubMed, ISI Web of Knowledge, EmBase, and Scopus database from inception to October 2016. Both preclinical and clinical studies investigating the role of host defense peptides in pathogenesis and as biomarkers for sepsis were included. Of the available literature, cathelicidin, defensin, and hepcidin are among the best-characterized peptides. These regulate immune response, and crosstalk with pyroptosis and coagulation cascades. The applicability of these peptides as septic biomarkers has been investigated in vitro and in vivo studies. However, numerous studies were based on endotoxemia without an infection, jeopardizing interpretation of the outcomes. Cathelicidin and defensin were frequently reported in adult sepsis while hepcidin in neonatal sepsis. The expression level of these peptides is significantly associated with septic condition. Most of the studies employed a cross-sectional design, precluding the establishment of a temporal relationship between candidate peptide biomarkers and sepsis. Innate defense peptides have been insufficiently evaluated as either diagnostic or prognostic biomarkers. In the future, evaluation of host defense peptides as septic biomarkers may employ a longitudinal design and consider a panel of multiple peptides.

Protecting the boundary: the sentinel role of host defense peptides in the skin

The skin is our primary shield against microbial pathogens and has evolved innate and adaptive strategies to enhance immunity in response to injury or microbial insult. The study of antimicrobial peptide (AMP) production in mammalian skin has revealed several of the elegant strategies that AMPs use to prevent infection. AMPs are inducible by both infection and injury and protect the host by directly killing pathogens and/or acting as multifunctional effector molecules that trigger cellular responses to aid in the anti-infective and repair response. Depending on the specific AMP, these molecules can influence cytokine production, cell migration, cell proliferation, differentiation, angiogenesis and wound healing. Abnormal production of AMPs has been associated with the pathogenesis of several cutaneous diseases and plays a role in determining a patient's susceptibility to pathogens. This review will discuss current research on the regulation and function of AMPs in the skin and in skin disorders.

Antimicrobial Peptides in Innate Immunity against Mycobacteria

Antimicrobial peptides/proteins are ancient and naturallyoccurring antibiotics in innate immune responses in a variety of organisms. Additionally, these peptides have been recognized as important signaling molecules in regulation of both innate and adaptive immunity. During mycobacterial infection, antimicrobial peptides including cathelicidin, defensin, and hepcidin have antimicrobial activities against mycobacteria, making them promising candidates for future drug development. Additionally, antimicrobial peptides act as immunomodulators in infectious and inflammatory conditions. Multiple crucial functions of cathelicidins in antimycobacterial immune defense have been characterized not only in terms of direct killing of mycobacteria but also as innate immune regulators, i.e., in secretion of cytokines and chemokines, and mediating autophagy activation. Defensin families are also important during mycobacterial infection and contribute to antimycobacterial defense and inhibition of mycobacterial growth both in vitro and in vivo. Hepcidin, although its role in mycobacterial infection has not yet been characterized, exerts antimycobacterial effects in activated macrophages. The present review focuses on recent efforts to elucidate the roles of host defense peptides in innate immunity to mycobacteria.

Biological roles of host defense peptides: lessons from transgenic animals and bioengineered tissues

Host defense peptides (HDPs) have long been recognized as microbicidal agents, but their roles as modulators of innate and adaptive immunity have only more recently been appreciated. The study of transgenic animal and tissue models has provided platforms to improve our understanding of the immune modulatory functions of HDPs. Here, the characterization of transgenic animals or tissue models that over-express and/or are deficient for specific HDPs is reviewed. We also attempt to reconcile this data with evidence from human studies monitoring HDP expression at constitutive levels and/or in conjunction with inflammation, infection models, or disease states. We have excluded activities ascribed to HDPs derived exclusively from in vitro experiments. An appreciation of the way that HDPs promote innate immunity or influence the adaptive immune response is necessary in order to exploit their therapeutic or adjuvant potential and to open new perspectives in understanding the basis of immunity. The potential applications for HDPs are discussed.

ROLE OF HOST DEFENSE PEPTIDES OF THE INNATE IMMUNE RESPONSE IN SEPSIS

Innate immune response and its effector molecules have received growing attention in research. Host defense peptides are known to be antimicrobially active. Recently, the peptides have been recognized as potent signaling molecules for cellular effectors of both innate and adaptive immunity. Mammalian peptides in particular revealed immunomodulatory functions, including endotoxin-binding and -neutralizing capacity, chemotactic activities, induction of cytokines and chemokines, promotion of wound healing, and angiogenesis. In sepsis, they present a family of natural substances that can be used in combination with antibiotics to complete a broad-spectrum antimicrobial regimen with endotoxin-neutralizing properties. Although there are side effects, host defense peptides have the potential to be significant reinforcements to the currently available therapeutic options in the future. In this review, we analyze the role of host defense peptides in infection and immune response, and discuss recent efforts to establish host defense peptides as potent novel therapeutic agents for the treatment of sepsis.

Host Defense Peptides and the New Line of Defence Against Multiresistant Infections

Increasing antibiotic resistance has led to an urgent need for new therapeutic approaches. Host defense peptides are known to be antimicrobial and have revealed broad immunomodulatory functions for both innate and adaptive immunity. This review will focus on the role of host defense peptides in infection and immune response and discuss its potential and limitations as a future therapeutical agent.