Date Published: March 30, 2016
Publisher: Public Library of Science
Author(s): Swetha Tati, Peter Davidow, Andrew McCall, Elizabeth Hwang-Wong, Isolde G. Rojas, Brendan Cormack, Mira Edgerton, Mairi C Noverr.
Pathogenic mechanisms of Candida glabrata in oral candidiasis, especially because of its inability to form hyphae, are understudied. Since both Candida albicans and C. glabrata are frequently co-isolated in oropharyngeal candidiasis (OPC), we examined their co-adhesion in vitro and observed adhesion of C. glabrata only to C. albicans hyphae microscopically. Mice were infected sublingually with C. albicans or C. glabrata individually, or with both species concurrently, to study their ability to cause OPC. Infection with C. glabrata alone resulted in negligible infection of tongues; however, colonization by C. glabrata was increased by co-infection or a pre-established infection with C. albicans. Furthermore, C. glabrata required C. albicans for colonization of tongues, since decreasing C. albicans burden with fluconazole also reduced C. glabrata. C. albicans hyphal wall adhesins Als1 and Als3 were important for in vitro adhesion of C. glabrata and to establish OPC. C. glabrata cell wall protein coding genes EPA8, EPA19, AWP2, AWP7, and CAGL0F00181 were implicated in mediating adhesion to C. albicans hyphae and remarkably, their expression was induced by incubation with germinated C. albicans. Thus, we found a near essential requirement for the presence of C. albicans for both initial colonization and establishment of OPC infection by C. glabrata.
Oropharyngeal candidiasis (OPC) is an opportunistic mucosal infection caused by Candida species [1,2]. Candida albicans and Candida glabrata are the first and second major etiological agents of OPC, respectively . Although other Candida species, including C. parapsilosis, C. tropicalis, and C. krusei, may be isolated as the sole species from oral infection sites, single species infection by C. glabrata alone is rare [4,5]. C. glabrata is most frequently co-isolated along with C. albicans in mixed species oral infections [4,6,7]. Oral infections involving C. glabrata have increased by 17% over the past several years , and are particularly common in cancer patients, denture-wearers, or following prolonged use of broad spectrum antibiotics, steriods or following head and neck radiation therapy . These infections were often associated with multiple Candida species [3,4]. Oral infections with mixed C. albicans and C. glabrata were found to be more severe and difficult to treat  since many C. glabrata strains are innately resistant to azole antifungal agents used in treating mucosal infections. Prophylactic use of azole antifungal drugs has been implicated as a major cause for the increase in non-C. albicans fungemia . Fungemia caused by C. glabrata has high mortality especially in adult patients in intensive care units , and although fluconazole prophylaxis has reduced the incidence of invasive candidiasis in high-risk neonates and immunosuppressed patients, there has been little effect on the overall incidence of C. glabrata candidiasis. Given the frequency of C. glabrata and C. albicans co-infection, it is imperative to understand the mechanisms deployed by C. glabrata in co- infections with C. albicans.
Although clinical studies have shown that C. albicans and C. glabrata are common partners co-isolated from oral infections, C. glabrata alone rarely causes oral infection. This work identifies for the first time that C. glabrata adherence to C. albicans hyphae is the basis for this partnership and that it is mediated by specific adhesins on both species. Previous in vitro studies found that C. glabrata alone was unable to colonize or invade reconstituted human vaginal epithelium (RHVE)  or reconstituted human oral epithelium (RHOE) . Mixed infections using both C. glabrata and C. albicans increased tissue damage in RHOE  and were permissive for infection in RHVE  and in vivo in tongues of immunosuppressed mice , although others found no difference in host damage or inflammation in co-infected human oral epithelial . These and our own studies are in agreement that C. glabrata alone is non-invasive in respect to oral-esophageal mucosal epithelium, in contrast to its ability to penetrate gastric epithelium . The basis for this difference in tissue tropism is unknown, although it is possible that differences in the gut environment induces differential expression of C. glabrata adhesins.