Komodo Dragons and Reptilian Antimicrobial Peptides: Addressing Emergent Problems with Prehistoric Solutions

As a small child, from the point I could articulate sentences, I expressed an interest in dinosaurs. A short time later this interest led to a fascination with other reptiles. This did not stem from such creatures being weird or inciting fear or excitement, I just liked the aesthetics of their appearances. Thus, it is not surprising that I started doing art depicting reptiles from an early age. Of course, I thoroughly enjoyed learning all I could about my subjects. As a result, over the course of my life, I amassed a collection of hundreds of relevant books, I have obtained two degrees in biological sciences, pursued a career in herpetology, engaged in independent field research of reptiles in multiple countries, and built a portfolio of artwork often depicting reptiles. In my current job, I work with venomous snakes.

 

Among all extant reptiles, I must admit my favorite species is Varanus komodoensis, the Komodo Dragon. Along with its charismatic physiognomy comes a shopping list of exceptional characteristics: extreme size; dental/feeding convergences with predatory dinosaurs; surprisingly high levels of cognition; play behaviour; a hyper-carnivorous diet including large prey and carrion; an often-lethal bite; and surprising resilience. In examining the interplay between the last two of these characteristics, one of the greatest attributes of this species, as well as other reptiles, is indicated. This will become clearer as I elaborate below.

 

Most people would probably be disappointed to learn the static bite force of a Komodo Dragon  is surprisingly weak; on a typical dragon the adductors close the jaws with about as much force as that of an angry house cat. However that unimpressive bite is accompanied with a myriad of characteristics that will impart a death sentence on creatures that find some section of their anatomy being accommodated by those jaws.  

 

The teeth of an adult Komodo Dragon are scalpel-shaped, serrated blades (a condition known as ziphodont), very similar to the dentition of many big predatory dinosaurs. Furthermore, those teeth are arranged in an arc to concomitantly lacerate, allowing the maxillae to essentially function as giant serrated blades. Once a Komodo dragon grasps an item in its jaws, it’s neck musculature is brought into play. Laterocaudal yanking results in a defleshing stroke for larger prey; smaller prey, if too small to swallow whole, are subjected to violent thrashing. 

 

The saliva of a Komodo dragon is toxic and has been documented to disrupt clotting at wound-sites. It is also known to contain proteins associated with paralysis, lowering blood pressure, and induction of hypothermia. 

 

For decades researchers have stated that Komodo Dragons utilize a septic bite to bring down prey, but that supposition has recently become a point of controversy. A 2013 investigation indicated the bacterial community of a Komodo Dragon’s mouth was not drastically different from that of other carnivores. However, it should be noted all specimens examined in that study, were zoo captives. Nonetheless, whether due to the dragon’s oral microflora or infection from environmental microbes, animals that escape from a Komodo Dragon’s initial bite often find themselves languishing with a gangrenous wound.

 

In any case, in the course of interacting with their own species, Komodo Dragons frequently turn their formidable weaponry upon one another. This is not just limited to cannibalism (up to 10% of a Komodo Dragon’s diet may be smaller Komodo Dragons) and intraspecific fighting, but occurs courtship as well; the process often involves biting and scratching the nape of the neck, thighs and lower back. I recall a female V. komodoensis at one institution I worked at was lacerated to the bone as a result of such activity. Other than in the cannibalism, the parties involved often continue often recover and carry on with their lives with little apparent effect. Whether or not Komodo Dragons have a particularly septic bite, it is remarkable that injured individuals do not seem to get serious infection from environmental microbes as they probe carrion with their heads and neck, and also crawl through warm, muddy water contaminated with fecal matter. There is definitely something rather extraordinary about their immune system.

 

While Komodo Dragons engage in a lifestyle that seemingly puts them at higher risk for gaping lacerations and infection than many other creatures, other reptiles often survive extensive injuries that would likely result in a human succumbing to infection, among other issues.

 

For example, crocodilians sometimes receive fairly horrific bite injuries in social interactions, occasionally suffering open wounds and lost limbs. Clinical studies of crocodilian bites on humans have found that such injuries often result in serious infections from environmental microbes, as well as those occupying the croc’s mouth.  Yet, in most agonistic encounters, crocs rarely have such problems. As intraspecific biting is widespread among modern crocodilian taxa, and paleopathologies consistent with such behavior are known in fossils from extinct dyrosaurs (a clade modern crocs diverged from during the early Jurassic), they have apparently been getting away with this behavior for more than 180 million years.

 

In many lizards a seemingly major avenue for infection is tail loss (autotomy). This phenomenon gets a lot of attention due to the regeneration that follows. However, prior to that regeneration, the animal may have a fairly significant cross-section of its internal anatomy exposed to the external environment, especially in cases where autotomy has occurred in the most proximal regions of the tail. However, researchers have noted that infection and/or inflammation at the wound site is rare.

 

Another infection risk, as well as a lesser known defensive characteristic, among some geckos species is regional integumentary loss; This is not the kind of skin-loss that happens in moulting where a shiny new layer of scales is exposed; this involves extensive integument loss resulting exposure of underlying tissue giving the impression of de-skinned chicken flesh. An article discussing the phenomenon stated that integument loss would seem to put the animals at greater risk for infection. This mechanism may be present in distantly related lizard species, as a researcher conducting on insular populations of an Anole mentioned encountering incidents of integument loss observed in the course of capturing specimens. 

 

There’s also plenty of anecdotal evidence for infection resistance in a number of reptile taxa. A recent example is a photo that went viral which shows a “zombie” short-horned lizard (Phrynosoma hernandesi) with a gaping wound exposing a good portion of its axial skeleton. Judging from the photo, other than the massive hole, the animal does not appear to be terribly distressed, and the researcher who took the photo reported the animal was not dead. This led to multiple anecdotes posted reporting reptiles surviving injuries that would likely result in human would succumb to infection, among other issues, without intensive medical intervention, including mention by a researcher of a snake that survived an injury from an automobile that that resulted in its heart being displaced on the outside of its body.

 

Much of Komodo Dragon’s, as well as other reptiles’, success in dealing with such wounds has been attributed to their innate immune system, a large component of which are antimicrobial peptides (AMPs).  Various crocodilian derived AMPs have been demonstrated to possess properties with potential to kill a wide range of pathogens that impact humans, including methicillin-resistant Staphylococcus aureus (MRSA), HIV, and Candida albicans. In 2014, one of the first investigations of the Komodo Dragon’s innate immune system found that serum from its blood inhibited growth in some bacteria species and obliterated others. AMPs of both, Komodo Dragons and crocs, are being examined as a potential tool in dealing with the rising prevalence of multi-drug resistant microbes. 

 

A promising development came in a study where investigators identified a potential AMP from Komodo Dragon plasma, dubbed VK25, and subsequently engineered a synthetic version of it created by reversing the of two N-terminal amino acids. This synthetic AMP, named DRGN-1, was evaluated against VK-25 and LL-37, a human AMP. DRGN-1 yielded more desirable results than VK-25, LL-37, and the control treatment in most aspects. In the study, DRGN-1 performed remarkably well: it had a significant inhibitory effect on S. aureus and Pseudomonas aeruginosa bacterial biofilm formation; it was found to impart no cytotoxic effects on human HEKa keratinocytes; Application of DRGN-1 to infected HEKa cells, resulted in great reduction in number of internalized bacteria as well as decreased P. aeruginosa-induced apoptotic cell death; Finally, wounds on mouse models demonstrated faster healing and more rapid closure where DRGN-1 was used than in any other treatment. Interestingly, in this study, VK25 did not exhibit significant antimicrobial activity as predicted. At the conclusion, the authors suggest that DRGN-1 may be very useful as a topical treatment for wounds. 

 

It will be fascinating to see what developments come from future studies investigating reptile AMPs. The results of which may lessen the threat of many multi-drug resistant microbes, mitigate immunodeficiencies, or result in new forms of first-aid; discussion of reptile AMP-derived treatments in articles often mentions potential delivery in the form of topical treatments and/or pills. However, I wonder what may result from engineering cells to actually produce certain reptile AMPs. Fairly soon, I hope some of my independent projects will begin to yield some insight into this; I am currently working on transfecting mammalian cells to produce a reptile AMP from a description in a recent paper detailing innate immunity genes of Komodo Dragons, as well as the synthetic DRGN-1. 

 

Simply transfecting mammalian cells with plasmids containing a Komodo Dragon DNA sequence is something I engage in to satisfy my overwhelming curiosity and as a form of artistic expression. However, if it, to any extent, results in expression of those AMPs – to  emulate in the slightest what is arguably the most impressive feature of my favorite extant taxon – in my opinion, that is one of the damned coolest things that can be done in this day and age.

 

Even if my projects don’t yield publishable data, it is my hope that discussion such as this will draw attention to the idea and lead others to further research the concept; I believe there is the potential for highly beneficial developments to come from it.

 

Selected Sources/Further Reading:

D’Amore, Domenic. (2005). Feeding in the Komodo Dragon, VARANUS KOMODOENSIS: Taphonomic and functional implications of ziphodont dentition. Journal of Vertebrate Paleontology. 25. 49A-49A

https://www.researchgate.net/publication/295383019_FEEDING_IN_THE_KOMODO_DRAGON_VARANUS_KOMODOENSIS_TAPHONOMIC_AND_FUNCTIONAL_IMPLICATIONS_OF_ZIPHODONT_DENTITION

 

A.M. Bauer & A. P. Russell (1992) The evolutionary significance of regional integumentary loss in island geckos: a complement to caudal autotomy, Ethology Ecology & Evolution, 4:4, 343-358, DOI: 10.1080/08927014.1992.9523127

 

Zombie Lizards and Hearty Snakes

https://snakeymama.blogspot.com/2019/09/zombie-lizard-and-hearty-snakes.html?fbclid=IwAR2dbQ2yxsrGdiA4u0m553DoyFYv5VjjEcPojV47vla_oecrsh6cI9a6xAE

 

Antibiotic factors in crocodile and alligator blood

http://crocodilian.blogspot.com/2008/04/antibiotic-factors-in-crocodile-and.html

 

van Hoek M. L. (2014). Antimicrobial peptides in reptiles. Pharmaceuticals (Basel, Switzerland), 7(6), 723–753. doi:10.3390/ph7060723

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4078517/

 

van Hoek, M. L., Prickett, M. D., Settlage, R. E., Kang, L., Michalak, P., Vliet, K. A., & Bishop, B. M. (2019). The Komodo dragon (Varanus komodoensis) genome and identification of innate immunity genes and clusters. BMC genomics, 20(1), 684. doi:10.1186/s12864-019-6029-y

https://bmcgenomics.biomedcentral.com/articles/10.1186/s12864-019-6029-y

 

Chung, E.M.C., Dean, S.N., Propst, C.N. et al. (2017). Komodo dragon-inspired synthetic peptide DRGN-1 promotes wound-healing of a mixed-biofilm infected wound. npj Biofilms Microbiomes 3, 9 doi:10.1038/s41522-017-0017-2

https://www.nature.com/articles/s41522-017-0017-2