Natural, evolutionarily conserved Host Defense Peptides (HDPs) offer enormous potential to improve pathogen killing and therefore hold promise as therapeutics. HDPs are short, cationic, and amphiphilic peptides encoded in the genome of all living organisms. HDPs have not only a direct antimicrobial, antiviral, and anti-fungi activity but also have documented anti-biofilm activity. HDPs have a broad range of relevant functions in both innate and adaptive immunity but also regulate inflammation and thereby contribute to pathogen clearance by the host. They also modulate several biological signaling pathways related to processes such as wound healing and autoimmune disease. Critically, their multiple simultaneous mechanisms of action and their reduced half-life make emergence of resistance against these peptides unlikely. These peptides are secreted by host innate immune and epithelial cells, but the isolation of native peptides is often tedious, inefficient and may not conserve the natural peptide structure require for optimal therapeutic efficacy. Alternatively, most of the currently used HDPs are produced by chemical synthesis or by recombinant production using prokaryotic or eukaryotic cells.

According to the World Health Organization, antimicrobial resistance (AMR) is the single greatest challenge of our time. There is an urgent need to both support the host immune response to promote resilience against infection but also to harness evolutionarily conserved, effective mechanisms of natural immunity for enhanced therapeutic purposes. HDPs have important potential applications across these critical areas.

Although HDP antimicrobial activity has been broadly explored using both synthetic and recombinant peptides, new roles in immunity and specifically the regulation of inflammation are still emerging. In this regard, studies on the immunomodulatory capacity of HDPs, including peptides of non-human origin, would contribute to the generation of a very valuable knowledge base for the development of HDP-based therapies. Although occurring widely across the animal and plant kingdoms, their sequence and resulting property variability have made the bioinformatic prediction of functional peptide domains challenging.

The empirical comparison of synthetic and recombinant HDP versions would be highly valuable to determine how methods of production may contribute to functional differences in peptide activity. In addition, the production conditions for HDPs require optimization to facilitate their scalability for future therapeutic applications. Also, the small size of HDPs makes them highly susceptible to proteolytic degradation and they have a short half-life which needs to be further improved using stabilisation techniques including nanoencapsulation.

This Research Topic aims to cover scientific findings on the emergent roles of HDPs across species, and specifically include recent research on the design, production, and purification of HDPs by recombinant production or chemical synthesis. Facilitating a sharing of scientific thinking in this critical area and a convergence of production and analytical techniques for functional analysis, this Research Topic will contribute to improved understanding of HDP roles in the immune system across species and signpost collective innovations to advance future biomedical applications.

In this collection, we welcome the submission of Original Research, Review, Mini Review and perspective articles to cover the following specific questions:

• Bioinformatic discovery, computational modeling and prediction of functional domains in novel HDPs of human and non-human origin.

• Comparison and characterization of the immunomodulatory activity of synthetic and recombinant HDPs.

• Functional characterisation of immune-related functions of synthetic and recombinant HDPs.

• Combinatorial functional characterisation of HDPs.

• Optimization of production processes of HDPs with immune-related functions.

• Strategies to increase the stability of HDPs with immune-related functions using approaches including nanotechnology.

• New applications of synthetic and recombinant HDPs with immune-related functions.

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Frontiers in Immunology

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