Host Defense Peptides: Functions and Applications

Host defense peptides (HDPs) are molecules produced by the innate immune system that act as a natural barrier against infection. Found in virtually all forms of life, these small peptides provide a rapid, broad-spectrum defense against invading organisms like bacteria, viruses, and fungi. Their presence across life forms points to their ancient evolutionary origins.

Origins and Classification of Host Defense Peptides

In humans, HDPs are found on surfaces exposed to the outside world, such as the skin, lungs, and intestinal lining, where they provide an immediate chemical shield. Specialized immune cells, like neutrophils and macrophages, also produce and store these peptides, ready for release at sites of infection.

The classification of HDPs is based on their three-dimensional structure and amino acid composition. Major structural classes include peptides that form α-helices, those that assemble into β-sheets, and others with extended or linear shapes. Another defining feature is the overall positive electrical charge of HDPs, which facilitates their attraction to the negatively charged surfaces of microbes.

Among the most well-studied families of HDPs in humans are defensins and cathelicidins. Defensins are small peptides that form a stable β-sheet structure. Cathelicidins, such as the human peptide LL-37, are produced as larger precursor molecules that are cleaved to release the active, often α-helical, peptide. These two families exemplify the structural diversity of HDPs.

Antimicrobial Modes of Action

HDPs eliminate microbes by targeting the microbial cell membrane, which is fundamentally different from human cell membranes. This selectivity allows HDPs to kill invaders without causing significant harm to the host’s own tissues. The peptides work by physically disrupting the integrity of the microbial barrier.

One mechanism involves forming pores in the microbial membrane. In the “barrel-stave” model, HDPs insert into the membrane and group together to form a channel. In the “toroidal pore” model, the peptides and membrane lipids bend to create a water-filled channel that spans the membrane, causing leakage of essential cellular contents.

A different method is the “carpet model,” where HDPs accumulate on the microbial membrane surface. Once a certain concentration is reached, the peptides cause the membrane to dissolve in a detergent-like manner. Some HDPs can also cross the microbial membrane to interfere with internal processes like DNA, RNA, or protein synthesis. For example, human β-defensin 3 inhibits the construction of the bacterial cell wall.

Modulation of the Immune Response

Beyond their direct killing capabilities, HDPs are active participants in shaping the broader immune response. They function as signaling molecules that recruit and activate other immune cells. This immunomodulatory capacity connects the immediate, innate immune response with the more specialized, adaptive immune system.

One immunomodulatory function is chemotaxis, the process of attracting immune cells to an infection site. The human cathelicidin LL-37, for example, attracts neutrophils, monocytes, and T cells. Human β-defensins can recruit dendritic cells, which initiate the adaptive immune response, ensuring the site is quickly populated with cells capable of clearing the pathogen.

HDPs also regulate inflammation. They influence the production of cytokines, proteins that control other immune cells. This regulation can enhance the inflammatory response to fight infection or suppress it to prevent tissue damage. Furthermore, some HDPs can bind to and neutralize bacterial toxins like lipopolysaccharide (LPS), which can cause a dangerous inflammatory reaction.

Clinical Potential and Drug Development

The properties of HDPs make them promising candidates for new therapeutic agents. Because they kill microbes through physical mechanisms, it is less likely for pathogens to develop resistance compared to conventional antibiotics. This feature is valuable in an era of growing antimicrobial resistance (AMR). Researchers are exploring HDPs and their synthetic derivatives for use as novel antimicrobial drugs.

Potential applications for HDP-based therapies are diverse. They are being investigated as treatments for bacterial, fungal, and viral infections, as agents to break down bacterial biofilms, and as promoters of wound healing. Their immunomodulatory functions suggest they could also be used to manage inflammatory conditions or as anticancer agents. For instance, the peptide OP-145, a synthetic HDP, has undergone clinical trials for treating chronic middle ear infections.

Despite their promise, developing HDPs into effective drugs presents several challenges. They can be broken down quickly in the body, may be costly to produce, and can be toxic to host cells at high concentrations. Scientists are working to overcome these hurdles by modifying the peptides to improve their stability and selectivity. Strategies include substituting amino acids, changing their structure from linear to circular, and using nanotechnology for delivery.