New Research Shines Light on Historical Skin Blight

by KS

“Ringworm” is a common infection that has plagued humans for centuries. It lives on the skin of humans and our domesticated animals, causing a distinctive oozy, red, ring-shaped sore (1). This infection has an interesting history that starts in the early 1800s, though disease was present in human populations well before that. The 1800s brought great societal changes for the inhabitants of Western Europe where the industrial revolution was in full force. Many people left behind their small village agricultural lifestyle in search of prosperity in the growing cities. This was great for development but it had one massive unintended consequence: disease. One disease that became a public nuisance during this time was ringworm. People originally thought that the ringworm infection was caused by a worm that you could contract via everything from having bad hygiene to associating with the poor (2). The late 19^th century saw a shift in the perception of the disease. Instead of being seen as a fact of life, it was starting to be seen as a highly contagious pathogen. In fact, many immigrants were turned away at Ellis Island due to this infection (2). A breakthrough was finally made during this time period that identified the causative agent of ringworm infection as a fungus, Trichophyton rubrum that is neither a worm nor associated with the poor (3).

False color image of Trichophyton growing
on human skin cells    

Trichophyton is part of a group of fungal pathogens called dermatophytes, which live and feed on the skin of humans and mammals. These eukaryotic microbes have a very specialized way in which they go about eating human skin; they feed on keratin, the main protein component of skin and hair. Feeding on keratin is a very interesting survival strategy because keratin is a rigid protein that is very hard breakdown and extract nutrients from (4). On the other hand, it is one of the most abundant proteins on the planet, so the ability to feed on it is a clear advantage for Trichophyton. This raises an interesting question for researchers, what allows Trichophyton to use keratin as a food source and is this ability the reason it so readily infects humans?

Recently researchers have aimed to explore the infectiousness of Trichophyton by looking at virulence factors (5). Virulence factors are proteins or molecules that are produced by the pathogen that help it to infect the host. Virulence factors play an important role in Trichophyton infection because the fungus must adhere to your skin and start breaking down keratin, a process that is likely mediated by proteins or molecules that the fungus secretes. A group of researchers decided to explore in the role that virulence factors play in Trichophyton’s ability to adhere to and devour human skin cells by looking at what genes were overexpressed during growth on keratin. This experiment was done ex vivo, outside of actual host infection but with attempts made to recreate some of the natural environment. Trichophyton cells were grown on either keratin or glucose and their gene expression was evaluated at several time points (5). The authors used a really interesting method called subtractive suppression that uses messenger RNA levels to look at how much a gene is being transcribed and comparing that with library DNA measurements to identify only genes that differing in expression. Using this method they found 238 genes that appeared to be overexpressed in Trichophyton grown on keratin. They investigated further 28 of these genes and found that several of them encoded virulence factors that help Trichophyton infect skin cells. The most significant virulence factors they found were subtilisins, which are proteins that digest and breakdown other proteins (5). Some of the subtilisins that are overexpressed are specific for keratin. This data shows Trichophyton has genes that encode keratin specific subtilisins which give a glimpse into how they are able to breakdown and feed on keratin.

Another group of researchers took a different approach in hopes of answering the same question, what makes Trichophyton so infectious? Martinez et al conducted a full genome comparison between different Trichophyton species, T. rubrum, T.tonsurans, T. equinum, and the non-dermatophyte species Microsporum canis and Microsporum gypseum (6). They sequenced the complete genomes of each species and then compared the genome composition and gene between the Trichophyton species as well as the non-dermatophyte fungi. They found some interesting and significant results. The data shows Trichophyton species do in fact have unique genes that are not found in other pathogenic fungi and may give them the ability to live and fed on human skin. A group of unique genes in Trichophyton encode for distinct proteases that are not found in other fungi. These proteases are very similar to the subtilisins identified in the other paper, as they are used by cells to breakdown proteins. Similarly these proteases where shown to be specific for keratin (6). These results further support idea that Trichophyton has unique genes that produce proteins that allow the parasite to effectively break down keratin. However, the breakdown of keratin is not the only thing that enables the fungi to survive. This research also discovered some genes that do not code for virulence factors but are unique to the Trichophyton genus (6). Genes encoding novel kinases were common to only the Trichophyton fungi. Interestingly, they discovered many non-functional pseudokinases that, instead of turning on signaling pathways and activating proteins like normal kinases, they actually interfere with those processes due to competition. This may seem like something that wouldn’t be helpful to a pathogen but here it actually gives them a nontraditional way of regulating signaling and gene expression. This extra method for controlling cell processes may contribute to their ability to switch their metabolism to keratin digestion. Thus, this paper identified genes that are unique to Trichophyton that play an important role in keratin breakdown and cell process regulation, allowing Trichophyton to effectively infect and feed on human skin cells.

            Recent research has shed new light on an old and irritating pathogen, the causative agent of ringworm that definitely isn’t a worm; Trichophyton. The information gained from the papers above show that this pathogen’s genome does contain unique genes that encode novel proteases and pseudokinases that seem to function during infection of human skin cell. These proteins allow Trichophyton to disassemble the tough structure of keratin and then use cellular metabolic pathways to digest it, allowing this fungal pathogen to survive in the challenging environment that is the human skin. In the end, new research has shown that novel genes and proteins that enable Trichophyton to breakdown and digest keratin are part of what make Trichophyton such a prolific human pathogen.

1. Degreef, H. (2008). Clinical forms of dermatophytosis (ringworm infection).Mycopathologia, 166(5-6), 257-265.

2. Unna, P. G. (1896). The Histopathology of the Diseases of the Skin. WF Clay.

3. Morris, M., & Henderson, G. C. (1883). The Cultivation and Life‐History of the Ringworm Fungus (Trichophyton tonsurans). Journal of the Royal Microscopical Society, 3(3), 329-337.

4. Tombolato, L., Novitskaya, E. E., Chen, P. Y., Sheppard, F. A., & McKittrick, J. (2010). Microstructure, elastic properties and deformation mechanisms of horn keratin. Acta biomaterialia,6(2), 319-330.

5. Maranhão, F. C., Paião, F. G., & Martinez-Rossi, N. M. (2007). Isolation of transcripts over-expressed in human pathogen Trichophyton rubrum during growth in keratin. Microbial pathogenesis, 43(4), 166-172.

6. Martinez, D. A., Oliver, B. G., Gräser, Y., Goldberg, J. M., Li, W., Martinez-Rossi, N. M., ... & White, T. C. (2012). Comparative genome analysis of Trichophyton rubrum and related dermatophytes reveals candidate genes involved in infection. MBio, 3(5), e00259-12.