How Antimicrobial Peptides Fight Viruses and Inflammation
Understanding nature’s antibiotic
Bacterial drug resistance can lead to serious consequences. Antibiotics, while beneficial in some cases, have lost their antibacterial ability as abuse has risen and drug-resistance increases. Antimicrobial peptides (AMPs), are a wide-ranging class of defensive molecules part of the innate immune system, acting as the first resistance to foreign invaders. They are an indispensable source to treat various microbes, including those that are drug resistant.
Here’s how antimicrobial peptides fight viruses and inflammation:
Your immune system uses a variety of techniques to defend against microorganism invaders. The first line of defense is to send AMPs, which exist in various organisms. When derived from mammals, there are two major classes of amphipathic AMPs in human respiratory lining fluid: defensins and cathelicidins. Both help to ward off infection.
AMPs are expressed through mucosal and glandular secretions, found in oral fluids, such as saliva, gingival crevicular fluid and can be used for diagnostic significance of oral health. The enhanced level of oral cathelicidins is associated with inflammatory conditions, like gingivitis and immune disorders like oral lichen planus.
What are the advantages of antimicrobial peptides?
AMPs fight disease and injury naturally and are a safer option than traditional antibiotics. They are more important now than ever before since finding new antibiotics can be difficult; even impossible for drug-resistant viruses and bacteria. These peptides interact with bacteria by neutralizing them. They puncture and destroy bacterial membranes, reducing the chance of bacterial drug resistance.
Little Peptides, Big Impact
The human cathelicidin antimicrobial peptide LL37 is an amphipathic cationic peptide (1). This peptide is known to have direct antimicrobial and antiviral behaviors with dual host defense functions; it kills bacteria and promotes inflammation (4). Cathelicidins mediate both pro- and anti-inflammatory responses. When inflammation occurs, chemicals from the body’s white blood cells are released into the affected area.
These peptides can act as a barrier to (and destroy) cancer cells (5). They do this by inserting themselves into the membranes, forming ion channels to eventually destroy the cancer cells (5). They can eliminate pathogenic microbes, modulate host immune responses, and promote wound healing, playing a crucial role in innate and adaptive immunity.
Other important AMPs include: defensins, lysozymes, and lactoferrin.
Defensins are released by mucosal and glandular secretions, expressed in intestinal emphatical cells and stored in neutrophils – type of white blood cell that protects from infections. They play an important role against invading microbes rapidly. They act against bacteria, fungi, or viruses by binding to their membranes and destroying microbial membrane integrity.
Lysozymes are an enzyme that accelerates the destruction of the cell walls of certain bacteria.
Lactoferrin is a protein found in mucosal or glandular secretions, i.e. tears, saliva, respiratory tract, with bactericidal and iron-binding properties. This helps limit the growth of bacteria and fungi, disrupting microbial membranes and limiting the effectivity of some viruses.
How do antimicrobial peptides work with the immune system?
There are two categories of the immune system: innate and adaptive. The innate immune system is a rapid defense system, protecting the body against antigens immediately (or within hours) of their arrival. This happens when the innate immune system signals AMPs to attack foreign cells in the body.
Adaptive immunity is more complex since the antigen must first be processed and recognized. After the antigen is assessed, the immune system produces an army of immune cells to attack the antigen. Adaptive immunity includes a memory function, building immunity to specific pathogens for future infections.
How are antimicrobial peptides expressed?
Gene expression is like an instructional manual in DNA that is converted into functional production of proteins. There are two key steps involved in expression: transcription and translation. The regulation of gene expression is the process by which expression of genes is controlled (induced or repressed) at the cell level in a time under a certain condition (3). This basic process occurs within the cell, including cell development and differentiation.
Transcriptional and post-transcriptional – the control of gene expression at the RNA level – processing regulates expression of human cathelicidin peptides, such as the active form LL37 released from neutrophils (2). This complex process involves adding layers of control including chromatin remodeling, nucleosome positioning, histone modifications, DNA-binding regulatory proteins such as transcription factors and noncoding RNA (3).
Gene expression is controlled at multiple cellular levels including: the messenger RNA (mRNA) level (transcriptional and post-transcriptional) and protein level (translation regulation and posttranslational degradation). Once RNA is transcribed, it must be processed to create a mature RNA that is ready to be translated.
A large part of the human genome constitutes noncoding elements classified as small noncoding RNAs (sncRNAs) and long noncoding RNAs (lncRNAs) and predicted to play an important role in post-transactional regulation (3).
The expression and processing of LL37 is associated with AMP expression with human diseases including inflammatory bowel disease, lung cancer, asthma, cystic fibrosis, chronic obstructive pulmonary disease, Alzheimer’s disease, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis, atherosclerosis, rosacea, psoriasis, and atopic dermatitis (2).
1) Kościuczuk, E. M., Lisowski, P., Jarczak, J., Strzałkowska, N., Jóźwik, A., Horbańczuk, J., Bagnicka, E. (2012, December). Cathelicidins: family of antimicrobial peptides. A review. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3487008/
2) Gudmundsson, G. H., Agerberth, B., Odeberg, J., Bergman, T., Olsson, B., & Salcedo, R. (2004, August 31). The Human Gene FALL39 and Processing of the Cathelin Precursor to the Antibacterial Peptide LL‐37 in Granulocytes. FEBS Press. Retrieved from https://febs.onlinelibrary.wiley.com/doi/full/10.1111/j.1432-1033.1996.0325z.x
3) Ghedira, K. (2018, October 10). Introductory Chapter: A Brief Overview of Transcriptional and Post-transcriptional Regulation. IntechOpen. Retrieved from https://www.intechopen.com/books/transcriptional-and-post-transcriptional-regulation/introductory-chapter-a-brief-overview-of-transcriptional-and-post-transcriptional-regulation
4) De, Y., Chen, Q., Schmidt, A. P., Anderson, G. M., Wang, J. M., & Wooters, J. J. Oppenheim, and O. Chertov. 2000. LL-37, the neutrophil granule-and epithelial cellderived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells. J. Exp. Med, 192, 1069-1074. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/11015447
5) Lei, J., Sun, L., Huang, S., Zhu, C., Li, P., He, J., … He, Q. (2019, July 15). The antimicrobial peptides and their potential clinical applications. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684887/