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 19th 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).
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False color image of Trichophyton
growing on human skin cells |
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.
