Cathelicidins Across Species

LL-37 and Vitamin D

30+ mammalian cathelicidins

At least 30 cathelicidin family members have been identified across mammalian species, each adapted to the specific pathogen challenges of its host.

Kosciuczuk et al., Molecular Biology Reports, 2012

Kosciuczuk et al., Molecular Biology Reports, 2012

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Humans have exactly one cathelicidin: LL-37, a 37-amino-acid peptide that serves as a front-line weapon against bacterial, viral, and fungal invaders. Pigs have 11. Cattle have at least 7. Even the Tasmanian devil, an endangered marsupial with no placenta and an immune system that must protect hairless, jellybean-sized newborns from infection, has multiple cathelicidins with antimicrobial activity that surpasses LL-37 against certain pathogens.^[1] For a broader look at human LL-37 biology, see the guide to LL-37 and vitamin D.

The diversity of cathelicidins across the animal kingdom is not academic trivia. Each species' cathelicidin repertoire reflects millions of years of selective pressure from the pathogens it faces. Understanding these differences is reshaping how researchers design new antimicrobial drugs and revealing fundamental principles about how innate immunity works.

The Cathelicidin Family: One Gene, Many Solutions

All cathelicidins share a common architecture: a signal peptide, a conserved cathelin-like domain, and a variable C-terminal antimicrobial domain. The cathelin domain is remarkably similar across species, serving as a molecular chaperone that keeps the antimicrobial peptide inactive until it is needed. The antimicrobial domain, the business end of the molecule, is where evolution has done its work.^[2]

This architecture means the cathelicidin gene family is ancient. Homologs appear in mammals, birds, reptiles, amphibians, and fish, placing the gene family's origins at over 500 million years ago. Despite this shared ancestry, the mature antimicrobial peptides have diverged dramatically. Some are alpha-helical (LL-37, CRAMP, PMAP-36). Others are proline-rich (porcine PR-39) or disulfide-bonded (protegrins). A few are tryptophan-rich (indolicidin from cattle). This structural diversity reflects the enormous variety of microbial threats that different species face.^[2]

The number of cathelicidin genes also varies. Humans, mice, rats, and guinea pigs each have a single cathelicidin gene. Pigs have 11. Cattle, sheep, and goats have 7 or more. The reasons for this difference are not fully understood, but one hypothesis connects it to the types of epithelial surfaces each species must defend: animals with large, exposed mucosal surfaces (rumen, extensive intestinal tract) may benefit from a more diverse antimicrobial toolkit.

Head-to-Head: How Species Compare Under Identical Conditions

One of the most informative studies in this field tested cathelicidins from multiple species under standardized conditions, eliminating the variability that makes cross-study comparisons unreliable.

Coorens et al. (2017) compared 12 cathelicidins from 6 species: human LL-37, murine CRAMP, canine K9CATH, three equine cathelicidins (eCATH-1, -2, -3), three chicken cathelicidins (CATH-1, -2, -3), and three porcine cathelicidins (PMAP-23, PMAP-36, PR-39). Every peptide was tested against the same bacteria, in the same media, at the same concentrations.^[3]

The results revealed several surprises. Under physiological salt conditions (mimicking the body's internal environment), most cathelicidins lost substantial antimicrobial activity against gram-negative E. coli. But activity against methicillin-resistant Staphylococcus aureus (MRSA) was actually enhanced under these same conditions for several peptides. This finding has direct implications for drug development: the conditions under which a peptide is tested fundamentally change which peptides appear most promising.

The study also compared immune-modulatory functions: Toll-like receptor activation, chemokine induction, and regulation of phagocytosis. These functions diverged across species as much as antimicrobial activity did. Human LL-37 was the strongest inhibitor of lipopolysaccharide (LPS)-induced immune activation despite binding LPS only weakly. Porcine PMAP-36 bound LPS strongly but was less effective at dampening the inflammatory response. This disconnect between LPS binding and anti-inflammatory activity challenges the assumption that these properties are directly linked.^[3]

Different Killing Mechanisms

A follow-up study by Scheenstra et al. (2019) used transmission electron microscopy to visualize exactly how three representative cathelicidins kill E. coli, and found fundamentally different mechanisms.^[4]

Porcine PMAP-36, with its highly cationic charge (+13), caused rapid and catastrophic membrane destruction. Bacterial cells literally burst open. Chicken CATH-2 produced a different pattern: the outer membrane blebbed and separated, but killing appeared to involve intracellular targets beyond simple membrane disruption. Human LL-37 produced yet another pattern, with bacteria showing signs of internal disorganization without the dramatic membrane destruction seen with PMAP-36.

These observations matter because they suggest that cathelicidins from different species could potentially complement each other. A drug design strategy that combines membrane-disrupting and intracellular-targeting mechanisms might be harder for bacteria to resist than either approach alone. For more on how LL-37 disrupts bacterial membranes and biofilms, see the dedicated article.

Primate Cathelicidins: Evolution in Action

Zelezetsky et al. (2006) sequenced cathelicidin genes from 20 primate species and found that the antimicrobial domain is under strong positive selection, meaning evolution actively favors mutations that change the peptide's structure and function. This is the molecular signature of an arms race between host immune peptides and pathogen defenses.^[5]

The study mapped structural changes across the primate phylogenetic tree onto antimicrobial potency. Species whose cathelicidins had diverged most from the ancestral sequence often showed the greatest shifts in which bacteria they could kill. Some primate cathelicidins gained activity against certain pathogens while losing it against others, consistent with adaptation to local microbial environments.

The cathelin domain, by contrast, was highly conserved across all 20 species. This domain's role as a molecular chaperone and potential immune signaling module appears to be under stabilizing selection, its function too important to tolerate variation.

Marsupial Cathelicidins: Protecting Vulnerable Newborns

Marsupial cathelicidins represent a natural experiment in immune defense. Marsupial neonates are born after extremely short gestation (as little as 12 days in some species) without a functional adaptive immune system. They are hairless, blind, and immunologically naive, developing for weeks to months in the mother's pouch.

Peel et al. (2016) identified cathelicidins in the Tasmanian devil (Sarcophilus harrisii) and found antimicrobial activity against a panel of bacteria. Tasmanian devil cathelicidins showed potent activity, with some variants outperforming human LL-37 against specific gram-negative pathogens.^[1]

A 2025 study expanded this work to characterize cathelicidins across multiple marsupial species and reconstruct predicted ancestral sequences using phylogenetic methods. The ancestral marsupial cathelicidins displayed broader antimicrobial spectra than their modern descendants: 85% of ancestral peptides were active against at least two bacterial genera, compared to only 41% of extant versions.^[6]

This narrowing of activity over evolutionary time suggests that marsupial cathelicidins have specialized toward the specific pathogens each species encounters in its ecological niche. The ancestral broad-spectrum activity, now lost in individual modern peptides, is maintained at the population level through the expansion of cathelicidin gene families.

Amphibian and Fish Cathelicidins

Amphibians and fish occupy a unique position in cathelicidin evolution. Their cathelicidins often serve double duty: defending against environmental pathogens in aquatic or semi-aquatic habitats while also managing the microbial communities on permeable skin surfaces.

Mu et al. (2017) identified the first cathelicidin from tree frogs, demonstrating that it possessed anti-inflammatory activity and could partially neutralize bacterial lipopolysaccharide, functions previously thought to be restricted to mammalian cathelicidins.^[7] Wu et al. (2018) showed that a frog cathelicidin effectively promoted cutaneous wound healing in mice, demonstrating cross-species therapeutic potential.^[8]

Yang et al. (2017) identified the first cathelicidin from the Chinese giant salamander (Andrias davidianus), the world's largest amphibian. This peptide showed broad-spectrum antimicrobial activity and membrane-disrupting properties, adding to the evidence that cathelicidin functions are conserved even across vast evolutionary distances.^[9]

Fish cathelicidins have been characterized in several species. Nunez-Acuna et al. (2018) identified cathelicidin-2 in Atlantic salmon (Salmo salar) as a molecular marker associated with sea lice resistance, connecting cathelicidin function to a major aquaculture parasite problem.^[10] The fact that cathelicidins function against parasites, not just bacteria and fungi, expands the understood scope of this peptide family.

Bat Cathelicidins: Coexisting with Viruses

Bats are extraordinary immunological subjects. They harbor numerous viruses (SARS-like coronaviruses, Ebola-related viruses, rabies) without apparent disease, suggesting an immune system uniquely adapted to tolerate viral cohabitation while still combating bacterial threats.

Lopez et al. (2025) performed genome-wide mining of cathelicidin genes across multiple bat species (order Chiroptera) and characterized their structural and antimicrobial properties. Bat cathelicidins showed potent activity against gram-positive bacteria including MRSA, with minimum inhibitory concentrations as low as 1 microgram/mL, while displaying minimal cytotoxicity to mammalian cells.^[11]

The low cytotoxicity is notable. Many cathelicidins that are potent antimicrobials also damage host cells at therapeutic concentrations, a major barrier to drug development. Bat cathelicidins may have evolved to minimize self-damage as part of the broader immune tolerance that allows bats to coexist with their viral passengers. This makes them particularly attractive as templates for designing new antimicrobial drugs, a concept explored further in the article on antimicrobial peptides as alternatives to antibiotics.

Chicken Cathelicidins: Agricultural and Medical Relevance

Poultry cathelicidins, particularly CATH-2, have attracted attention both for their antimicrobial properties and their potential applications in agricultural disease prevention. Chickens express three cathelicidins (CATH-1, CATH-2, CATH-3, also known as fowlicidins), each with distinct activity profiles.

CATH-2 has been the most extensively studied. Xu et al. (2024) demonstrated that CATH-2 attenuates the inflammatory response to avian pathogenic E. coli, suggesting it functions as an immunomodulator beyond its direct antimicrobial activity. The peptide reduced expression of pro-inflammatory cytokines in chicken macrophages while maintaining bactericidal function.^[3]

The practical relevance extends to the growing crisis of antibiotic resistance in agriculture. Poultry production is one of the largest consumers of antibiotics globally, and cathelicidin-based alternatives could reduce the selective pressure driving resistance. This connects to the broader question of whether antimicrobial peptides can serve as antibiotic alternatives.

What Animal Cathelicidins Teach Drug Designers

The comparative cathelicidin data carries three practical messages for antimicrobial drug development.

First, structural diversity creates a library of mechanisms. Membrane-disrupting peptides (like PMAP-36), intracellular-targeting peptides (like CATH-2), and immunomodulatory peptides (like LL-37) offer different starting points for drug design. Understanding why evolution produced multiple mechanisms, rather than optimizing one, suggests that combinatorial approaches may be more effective than single-peptide therapies. For details on how antimicrobial peptides kill bacteria through pore formation, see the dedicated article.

Second, testing conditions determine which peptides look promising. The Coorens study showed that physiological salt concentrations completely rearranged the ranking of cathelicidins by potency. Peptides developed and tested only under artificial laboratory conditions may fail in the body for reasons that comparative biology could have predicted.

Third, the low toxicity of some animal cathelicidins (particularly from bats) demonstrates that potent antimicrobial activity and safety to host cells are not inherently incompatible. Nature has solved this problem repeatedly. The solutions are encoded in the genomes of species that researchers are only beginning to explore.

The Bottom Line

Cathelicidin antimicrobial peptides have diversified across the animal kingdom into at least 30 mammalian variants with distinct structures, killing mechanisms, and immune-modulatory functions. Head-to-head comparisons reveal that even closely related cathelicidins from different species use fundamentally different strategies against the same bacteria. Marsupial, bat, amphibian, and fish cathelicidins expand the known functional repertoire beyond what human LL-37 alone could teach us, offering diverse templates for antimicrobial drug design.

Frequently Asked Questions

How many cathelicidins do humans have?

Humans have exactly one cathelicidin, encoded by the CAMP gene. The active form is LL-37, a 37-amino-acid peptide. This contrasts with pigs (11 cathelicidins), cattle (7+), and many other mammals that maintain expanded cathelicidin gene families. The reason humans retained only one cathelicidin while other species expanded their repertoire is not fully understood.

What is the difference between LL-37 and other cathelicidins?

LL-37 is the human cathelicidin with both antimicrobial and immunomodulatory functions. Comparative studies show it kills bacteria differently than porcine PMAP-36 (which destroys membranes more aggressively) or chicken CATH-2 (which targets intracellular processes). LL-37 is the strongest inhibitor of LPS-induced inflammation despite weaker direct LPS binding than some animal cathelicidins.

Do animals have stronger antimicrobial peptides than humans?

Some animal cathelicidins show greater potency against specific pathogens than human LL-37. Tasmanian devil cathelicidins outperformed LL-37 against certain gram-negative bacteria, and bat cathelicidins killed MRSA at concentrations as low as 1 microgram/mL. Potency depends on the pathogen and testing conditions; no single peptide is universally strongest.

Can animal cathelicidins be used as drugs?

Animal cathelicidins serve as templates for drug design rather than direct therapeutic agents. Bat cathelicidins are particularly interesting because they combine strong antimicrobial activity with low toxicity to mammalian cells. Several research groups are using the structural features of animal cathelicidins to engineer synthetic peptides optimized for human therapeutic use.

Why do some animals have many cathelicidins and humans have one?

The expansion of cathelicidin gene families in species like pigs and cattle may relate to the diversity of pathogen challenges they face, particularly at large mucosal surfaces. Humans may compensate for having one cathelicidin through other antimicrobial peptide families (defensins, histatins) and a more developed adaptive immune system. Evolutionary pressures shaped different solutions in different lineages.

What are marsupial cathelicidins used for?

Marsupial cathelicidins protect immunologically immature newborns from infection during pouch development. Research on Tasmanian devil cathelicidins found antimicrobial activity against multiple bacterial species. A 2025 study showed ancestral marsupial cathelicidins had broader activity than modern variants, suggesting evolutionary specialization toward niche-specific pathogens over time.