What is the pathophysiology of cutaneous candidiasis?

Updated: Jan 17, 2020
  • Author: Richard Harold "Hal" Flowers, IV, MD; Chief Editor: Dirk M Elston, MD  more...
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Candida is a versatile fungus that can exist commensally in many locations of the human body. Several different adaptive mechanisms help Candida survive in such diverse anatomical areas. The ability of C albicans to adjust to the different pH environments found in regions such as the bloodstream, at a neutral pH, versus the vagina, which has a more acidic pH, is explained by the differential expression of pH-regulated genes. In acidic environments, C albicans expresses PHR2, while in environments of pH 5.5 or higher, PHR1 is expressed to a greater extent. [2]

Another critical virulence factor is the ability of Candida to adhere to the host tissue. The protein Hwp1 is vital for C albicans to form attachments to host tissue, as is CaMnt1p, a mannosyl transferase. [3, 4] The ability of yeast forms to adhere to the underlying epithelium is an important step in the production of hyphae and tissue penetration.

In a broader view, a 2013 review of pathologic mechanisms of C albicans cited (1) the secretion of hydrolases, (2) molecules that mediate adhesion with concomitant invasion into host cells, (3) the yeast-to-hypha transition, (4) biofilm formation, (5) contact sensing and thigmotropism, (6) phenotypic switching, and (7) a variety of fitness attributes. [5] Candida species also produce proteases, which contribute to pathogenicity.

In a more narrow lens, additional research has elucidated the effect of Candida on keratinocytes. Within the epidermis, C albicans phospholipomannan triggers an inflammatory response through Toll-like receptor (TLR)–2. [6] Additionally, C albicans aborts the expression of interferon-gamma–inducible protein-10 in human keratinocytes. [7] Once C albicans invades the keratinocytes, the host cells express host defense proteins and secrete chemokines and cytokines. [4, 8] Melanocytes also play a role in the innate immune system; these cells detect C albicans through TLR4 and begin producing antimicrobial products and melanin, which can sequester and, in some cases, kill, the fungi. Langerhans cells detect C albicans via Dectin-1 and initiate a Th17 response via interleukin (IL)–6. [8] Furthermore, CD103+ dermal Langerhans cells, upon interaction with TLR-2, enhance Th1 production in secondary lymphoid organs. [8]

Observing the effects of deficiency in key regulatory molecules has helped elucidate host defense against Candida. For example, IL-17 is essential to combat C albicans infections. [9, 10, 11] Thus, phenotypes that knock out IL-17 are more susceptible to C albicans and drugs such as secukinumab, an IL-17 blocker used for psoriasis, can increase the incidence of candidal infections. Relatedly, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)—secondary to mutations in the autoimmune regulator (AIRE) gene—predispose to mucocutaneous Candida infection. In patients with this disease, autoantibodies to IL-17A can be linked to mucocutaneous candidiasis severity. [12]

STAT1 gain-of-function mutations, as well as STAT3 loss-of-function mutations (which cause the autosomal dominant hyper-IgE syndrome), are both associated with mucocutaneous candidiasis. [13, 14] Mucocutaneous Candida infections can be the presenting sign of IL-12 receptor β1 deficiency. [15] Additionally, Candida is a catalase-positive fungi; therefore, patients with chronic granulomatous disease (CGD), which is due to a mutation in the NADPH oxidase complex involved in respiratory burst, are at increased risk for Candida infection. [16] In those with CGD, Candida is the most common cause of meningitis, fungemia, and lymphadenitis. [17]

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