Chapter 9 Oral fungal infections
Candida species are fungi that are frequently encountered in the mouth of healthy individuals and as such can be considered to be normal residents of the oral microflora. The actual incidence of oral candidal carriage is estimated to be between 35 and 55% of healthy individuals, depending on the population group studied. Other fungi, such as Saccharomyces spp., Geotrichum spp. and Cryptococcus spp. are also encountered (Table 9.1), but their occurrences are rare and these are not generally implicated with oral infection. While Candida species are normally harmless commensals, when conditions in the mouth alter to one that favours proliferation of Candida, a shift to a pathogenic state can occur. As such, Candida infection is invariably an opportunistic one dependent upon some form of underlying host predisposition. Infection with Candida is described in the literature as a candidosis (candidoses, pl) or candidiasis (candidiases, pl). Both terms are widely used, although candidosis is often preferred due to its consistent use of the ‘osis’ stem with the terminology for other fungal infections. The term Candida originates from the Latin word candid, meaning white.
|Candida species||Other fungal species (rare)|
|Candida albicans||Paracoccidioides brasiliensis|
|Candida glabrata||Aspergillus spp.|
|Candida tropicalis||Cryptococcus neoformans|
|Candida krusei||Histoplasma capsulatum|
|Candida lusitaniae||Mucor spp.|
|Candida dubliniensis||Saccharomyces spp.|
|Candida kefyr||Geotrichum spp.|
|Candida guilliermondii||Rhizopus spp.|
The genus Candida contains over 200 different species that are ubiquitously distributed. However, only a few of these have been implicated in human infection. The most prevalent Candida species recovered from the human mouth, in both commensal state and cases of oral candidosis, is Candida albicans. It is estimated that this species accounts for over 80% of all oral yeast isolates. In terms of oral prevalence, C. albicans is followed by C. glabrata, C. krusei, C. tropicalis, C. guilliermondii,C. kefyr and C. parapsilosis. In more recent years there has been a greater recognition of the importance of the non-albicans Candida species in human disease. Candida glabrata and C. krusei are species that have received attention due to their enhanced resistance to certain antifungal agents. Candida dubliniensis is a recently identified pathogenic species, first described in 1995 when it was co-isolated with C. albicans from cases of oral candidosis in HIV-infected individuals.
The transition of Candida from a harmless commensal to a pathogenic organism is complex and may relate to subtle environmental changes that lead to the expression of a range of virulence factors (Table 9.2). It is likely that it is the combined effect of both host and candidal factors that ultimately contribute to the development of oral candidosis.
|Adherence||Promotes retention in the mouth|
|Evasion of host defences||Promotes retention in the mouth|
|Invasion and destruction of host tissue||Enhances pathogenicity|
One of the key virulence factors of Candida spp. is the ability to adhere to host surfaces. In the oral cavity, this allows the organism to avoid removal through the effects of salivary flow and swallowing. Adherence can be to oral epithelial tissue or to biomaterials of prosthetic devices such as dentures, that have been introduced into the mouth. Attachment to such oral surfaces can be specific or non-specific, the latter involving electrostatic or hydrophobic interactions, together with the simple physical entrapment of the microorganism at specific locations in the mouth.
The cell surface molecules on Candida that are involved in its specific adherence are described as adhesins (Ch. 4). The host cell component that these adhesins interact with, are referred to as receptors. A wide range of adhesins have been identified for C. albicans and include mannoproteins, fibrillar adhesins that bind to fucosyl receptors and proteins that bind to complement receptors on host cells. Candidal adherence is a complex and multifactorial process, dependent on both host and candidal characteristics.
Candida have the ability to grow in several morphological states including budding yeast cells, pseudohyphae (elongated chains of yeast cells), and also true filamentous hyphae (Fig. 9.1). Pseudohyphae and hyphae are distinguishable as the former contains constrictions at the septa of the filaments. Once attached to host surfaces the ability of Candida and in particular C. albicans to switch from its yeast morphology to a filamentous form may promote penetration of the epithelium and increase resistance of cells to phagocytosis by host immune cells.
Candida glabrata is notable for its inability to form filaments while other non-albicans Candida species can develop pseudohyphae. True hyphal development is an attribute reserved for C. albicans and the closely related C. dubliniensis. A number of genes have been shown to positively control hyphal production in C. albicans including HGC1 which encodes for a cytoplasmic protein (hyphae-specific G1 cyclin) without which the hyphal morphology will not occur. Studies examining mutants of C. albicans unable to express HGC1 show that non-filamentous strains are less virulent.
The candidal phenomenon of high frequency switching is related to cell morphology and reflected in vitro as reversible changes in colony morphology induced by exposure to various environmental stimuli. Switching has multiple effects on the Candida cells and is associated with altered gene expression which affects surface antigenicity, adhesiveness, drug susceptibility, and resistance to phagocytosis by polymorphonuclear leukocytes. A high switching mode is a strain-dependent trait and can clearly influence strain virulence.
Destruction of host tissues by Candida may be facilitated by the release of hydrolytic enzymes into the local environment and secreted aspartyl proteinases (SAPs) and phospholipases are the enzymes most frequently implicated with C. albicans.
At present, 10 different genes have been identified that encode for candidal SAPs. Expression of these genes can be induced under different conditions and three (SAP4, SAP5 and SAP6) appear to be expressed during hyphal development. All SAPs exhibit a number of common characteristics including an activity restricted to a largely acidic environment and inhibition by pepstatin A (a hexa-peptide originally isolated from Actinomycete species). The exact role of these enzymes in virulence remains unclear, however their ability to degrade host extracellular matrix proteins would be an obvious pathogenic factor as would the destruction of host proteins involved in defence against infection.
In addition to SAPs, enzymes categorized as phospholipases (PLs) are often considered to be factors in Candida pathogenicity. Phospholipases are enzymes that hydrolyse phospholipids into fatty acids. Four classes of phospholipases (A, B, C, and D) have been defined depending upon the type of ester bond cleaved. The production of all classes of phospholipase has been described for Candida species and their production could contribute to host cell membrane damage which could promote cell lysis or expose receptors to facilitate adherence.
Several Candida species are recognized as important opportunistic pathogens of humans and the ability to cause disease is dependent upon the delicate balance that exists between the host defence processes and the expression of virulence factors by the infecting Candida. No single predominant virulence factor for Candida is recognized although there are a number of factors that have been implicated in promoting the infection process. These include attributes involved in the adhesion of Candida to oral surfaces (e.g. relative cell surface hydrophobicity and the presence of specific adhesin molecules), the ability to resist host immune defence mechanisms (e.g. high frequency phenotypic switching and morphological transition) and the release of hydrolytic enzymes (e.g. secreted aspartyl proteinases and phospholipases) that can induce damage to host cells.
Candidosis is a ‘disease of the diseased’ which highlights the importance of host-related factors on the development of oral candidosis. This is most clearly exemplified by the high incidence of oral candidosis in Human Immunodeficiency Virus (HIV)-positive individuals and Acquired Immunodeficiency Syndrome (AIDS) sufferers. However, transition from healthy oral carriage to a diseased state can be triggered by less extreme changes within the oral environment and numerous other factors have been implicated (Table 9.3).
|Suggested host factor|
|Local host factors|
|Systemic host factors|
Fig. 9.2 Clinically distinct forms of oral candidosis (A) pseudomembranous candidosis (thrush), (B) acute erythematous candidosis, (C) chronic hyperplastic candidosis, (D) chronic erythematous candidosis, and (E) chronic mucocutaneous candid/>