Pathogenesis

Dermatophytes exhibit a broad armamentarium of enzymes (keratinolytic proteases, lipases etc.)

that act as virulence factors to allow adherence and invasion of skin, hair, and nails, and also to
utilize keratin as a source of nutrients for survival. The initial steps in dermatophyte infections
are adherence to keratin followed by invasion and growth of mycelial elements. As a
consequence of keratin degradation and subsequent release of proinflammatory mediators, the
host develops an inflammatory response of varying degree. The classic ringworm, or annular
morphology of tinea corporis results from an inflammatory host response against a spreading
dermatophyte followed by a reduction or clearance of fungal elements from within the plaque,
and in many cases by spontaneous resolution of the infection.
Adherence
Dermatophytes overcome several lines of host defense before hyphae begin to thrive in
keratinized tissues. The first step is successful adherence of arthroconidia, asexual spores formed
by fragmentation of hyphae, to the surface of keratinized tissues.
12
Early nonspecific lines of host
defense include fungistatic fatty acids in sebum as well competing bacterial colonization.
13,14

Several recent studies have focused on the molecular steps involved in arthroconidial adherence
to keratinized surfaces. Dermatophytes have been shown make selective use of their proteolytic
armamentarium during adherence and invasion.
15,16
The basis for this highly concerted attack
may be explained partially by specific upregulation of multiple genes induced by contact with
keratin, as has been shown by differential gene expression analysis in T. rubrum.
17
Following
several hours of successful adherence, the spores begin to germinate in preparation for the next
step in the infective chain of events, invasion.
Invasion
Trauma and maceration facilitate penetration of dermatophytes through the skin. Invasion of
germinating fungal elements is further accomplished through secretion of specific proteases,
lipases and ceramidases, the digestive products of which also serve as fungal nutrients.
18

Interestingly mannans, which are components of the fungal cell wall, show inhibitory effects on
keratinocyte proliferation and cell-mediated immunity.
19,20

Host Response
Dermatophytes encounter a range of host responses from several lines of nonspecific
mechanisms including fungistatic fatty acids, increased epidermal proliferation, and secretion of
inflammatory mediators to cell mediated-immunity. In the line of defense mechanisms,
keratinocytes represent the first frontier of living cells to encounter invading fungal elements.
The key position of keratinocytes is reflected by their complex response to invasion including
proliferation to increase shedding as well as secretion of antimicrobial peptides including human
defensin-2
21
as well as proinflammatory cytokines (IFN-, TNF, IL-1, 8, 16, and 17) that
further activate the immune system. Once deeper layers of epidermis are involved, new
nonspecific defenses such as competition for iron by unsaturated transferrin emerge. The degree
of host inflammatory reaction depends on the host's immune status as well as the natural habitat
of the dermatophyte species involved. Interestingly, anthropophilic dermatophytes induce
secretion of a limited cytokine profile from keratinocytes in vitro compared to zoophilic
species.
22,23
This difference may reflect the augmented inflammatory response generally
observed with zoophilic species.
The next level of defense is cell-mediated immunity resulting in a specific delayed type
hypersensitivity response against invading fungi. The inflammatory response associated with this
hypersensitivity is associated with clinical resolution, while defective cell-mediated immunity
may result in chronic or recurrent dermatophytoses. The Th2 response does not appear to be
protective, since patients with elevated fungal antigen antibody titers are observed to have
widespread dermatophyte infections.
24
A possible role for the Th17 response to dermatophyte
infections is suggested by the recent discovery of binding of hyphal elements to Dectin-2, a C-
type lectin pattern recognition receptor on dendritic cells, critical for inducing Th17
responses.
25,26
However, the relative importance of the Th17 immune response to
dermatophytosis remains to be elucidated.
Genetics
Despite epidemiological observations suggesting a genetic predisposition to fungal infections,
molecular insight confirming this hypothesis has been lacking. Recently, however, two families
with increased susceptibility to fungal infections and mutations in the C-type lectin fungal
pattern recognition pathway have been described. In addition, mutations in CARD9, an adaptor
molecule downstream of Dectin-1 and Dectin-2, which result in failure of Th17 activation, were
associated with susceptibility to chronic mucocutaneous candidiasis along with chronic
dermatophyte infections.
27