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Candida-Host Interactions in HIV Disease: Relationships in Oropharyngeal Candidiasis

P.L. Fidel, Jr.

Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA 70112-1393, USA; pfidel{at}lsuhsc.edu

	Abstract

TOP Abstract Introduction Host Defense against OPC Conclusions References

 
Oropharyngeal candidiasis (OPC) caused by the commensal organism, Candida albicans, is the most common oral infection in HIV disease. Although cell-mediated immunity (CMI) by Th1-type CD4⁺ T-cells is considered the predominant host defense mechanism against OPC, other systemic or local immune mechanisms are critical when blood CD4⁺ T-cells are reduced below a protective threshold. For example, the Th cytokine profile in saliva may influence resistance or susceptibility to OPC. In OPC lesions, CD8⁺ T-cells become accumulated at the lamina propria-epithelium interface, suggesting some role for CD8⁺ T-cells against OPC. However, the absence of CD8⁺ T-cells close to Candida at the outer epithelium indicates that susceptibility to OPC involves a dysfunction in the CD8⁺ T-cells or in the micro-environment. Further evaluation of the buccal mucosa lesion showed that CD8 T-cell-associated cytokine and chemokine mRNA is increased compared with buccal mucosa from lesion-negative matched controls. The majority of CD8⁺ T-cells present possess the ß T-cell receptor and several homing receptors (i.e., ₄ß₇, ₄ß₁, _eß₇). While several adhesion molecules are similar in OPC⁺ vs. OPC^– persons, E-cadherin is reduced in the tissue of OPC⁺ persons. These results support evidence for a role for CD8⁺ T-cells against OPC, but suggest that a putative dysfunction in mucosal T-cell trafficking may be associated with susceptibility to infection. Similar levels of Candida-specific antibodies in persons with and without OPC confirmed a limited role for humoral immunity. Finally, oral epithelial cells inhibit the growth of Candida in vitro in a static rather than a cidal manner. Clinically, oral epithelial cell anti-Candida activity is reduced in HIV⁺ persons with OPC, compared with controls. The mechanism of action includes a strict requirement for cell contact by an acid-labile moiety on intact, but not necessarily live, epithelial cells, with no role for soluble factors. Taken together, host defense against OPC involves several levels of activity. The status and efficiency of local host defenses when blood CD4⁺ T-cells are not available appear to play a role in protection against or susceptibility to OPC.

KEY WORDS: Candida albicans • epithelial cells • T-cells • mucosal immunity • cytokines

	Introduction

TOP Abstract Introduction Host Defense against OPC Conclusions References

 
Oropharyngeal candidiasis (OPC) is an opportunistic fungal infection that can involve the hard and soft palates, tongue, buccal mucosa, and floor of the mouth. It presents as reddened patches (erythematous) or white curd-like lesions (pseudomembranous) (thrush). OPC is defined as superficial candidiasis with shallow levels of tissue invasion. As a result, chewing and swallowing can be difficult. Infections can be acute or recurrent, and are common in immunocompromised patients, especially those infected with the human immunodeficiency virus (HIV) (reviewed in Fidel, 2002). In fact, OPC is often one of the first clinical signs of underlying HIV infection and will occur in 50 to 95% of all HIV⁺ persons at some time during their progression to full-blown AIDS (Rabeneck et al., 1993). OPC is also a common manifestation of chronic mucocutaneous candidiasis, and also occurs in patients with lymphoma, those undergoing steroid therapy, and in transplant recipients (Odds, 1988; Calderone, 2002). Although OPC will occur under several immunocompromising conditions, it appears to be much more common in HIV^-infected persons than under any other condition. The use of highly active antiretroviral therapy (HAART) in those with HIV has reduced the incidence of OPC (Palella et al., 1998). This is postulated to be due both to increased immune responsiveness as well as to direct action on the organism (Cassone et al., 1999; Gruber et al., 1999; Calderone and Fonzi, 2001).

OPC is caused primarily by C. albicans, a ubiquitous dimorphic fungal organism that is part of the normal microflora of the gastrointestinal and reproductive tracts of healthy individuals. As asymptomatic carriers, the approximate rate of oral yeast carriage in HIV-negative persons is 50–60%, with C. albicans present in 85% of isolates recovered (Glick and Siegel, 1999). In HIV-positive individuals, the asymptomatic colonization rate is higher, approaching 76% (Leigh et al., 1998; Wozniak et al., 2002). Colonization with C. albicans is assumed to be responsible for acquired immune responsiveness. Anti-Candida antibodies, circulating IgG and mucosal IgA and IgG, can be detected in most healthy individuals (Witkin et al., 1988, 1989; Regulez et al., 1994; Wozniak et al., 2002). Moreover, greater than 80% of healthy persons have positive cutaneous skin test reactivity to Candida antigen, and peripheral blood lymphocytes from over 90% of healthy individuals proliferate in vitro to Candida antigen (Kirkpatrick et al., 1971; Mathur et al., 1977; Odds, 1988; Fidel et al., 1993). It is presumed that these acquired host responses, in conjunction with innate resistance (i.e., polymorphonuclear leukocytes and macrophages), play a significant role in restricting C. albicans to mucosal surfaces in an asymptomatic commensal state. Under immunocompromised conditions, however, C. albicans can convert into an opportunistic pathogen with significant morbidity. The following will briefly review published data regarding host defenses present in persons with and without OPC relative to T-cells, cytokines, and epithelial cells, and follow with new data presented at the 5th World Workshop on Oral Health and Disease in AIDS, that together provide potential explanations for both resistance and susceptibility to OPC.

	Host Defense against OPC

TOP Abstract Introduction Host Defense against OPC Conclusions References

 
Previously Reported Data
In general, analysis of most data to date suggests that CD4⁺ Th1-type cells are critical for host defense against OPC. Clinically, OPC is most common in HIV⁺ persons when CD4⁺ cell numbers drop below 200 cells/µL (Rabeneck et al., 1993; Nielsen et al., 1994; Schuman et al., 1998; Greenspan et al., 2000). In vitro immune analyses of peripheral blood mononuclear cells (PBMC) show that cells from most individuals respond to Candida antigens with Th1-type cytokines. Thus, it is generally considered that susceptibility to OPC is enhanced under reduced CD4⁺ T-cells, due to either a lack of protective Th1-type responses and/or a shift to susceptible Th2-type responses (Romani et al., 1996). Some early studies in HIV⁺ individuals showed a strong association between OPC and reduced Th1-type cytokine responses (Quinti et al., 1991). However, a study evaluating PBMC reactivity in HIV^– and HIV⁺ persons, with or without symptomatic OPC and stratified by CD4⁺ T-cell numbers, showed little to no appreciable differences in Candida-specific proliferation or cytokine production between the two groups (Leigh et al., 2001). In another study, no demonstrable deficiencies in clonal responses of PBMC from such patients to a variety of antigenic peptides were shown (Kunkl et al., 1998). Together, these results suggest the Candida-specific T-cells themselves were not becoming defective with immunosuppression, but that a threshold number of CD4⁺ T-cells was required to protect the oral cavity against infection by this commensal organism. Below this threshold number of cells, local immune mechanisms must function exclusively. The prevalence of OPC may then depend on the status of the local immune mechanisms. Indeed, some individuals with < 200 CD4 cells/µL never have OPC, while others have recurrent episodes of OPC.

Several aspects of local immunity have now been evaluated clinically. In support of the Th1/Th2 dichotomy concept, it was recently reported that HIV^– individuals had Th1/Th0 cytokines in their saliva, whereas HIV⁺ individuals had primarily Th2-type cytokines, which was more profound in those patients with OPC (Leigh et al., 1998). Interestingly, the Th2-type profile was the result of reduced Th1-type cytokines rather than increased Th2-type cytokines. Lymphocytes have also been examined in the OPC lesions, and both CD4⁺ and CD8⁺ cells have been identified (Romagnoli et al., 1997). Other investigators have suggested that only CD8⁺ cells were present. Data from our laboratory support the latter observation, and, in fact, we have shown an accumulation of CD8⁺ T-cells at a considerable distance from Candida, located superficially at the outer epithelium (Myers et al., 2003). This cellular accumulation is not seen in OPC^– persons. This may suggest a role for CD8⁺ T-cells against infection, with a potential problem in cell trafficking or the micro-environment, promoting susceptibility to OPC. In support of the presence of CD8⁺ T-cells, mRNA for several CD8 cell-associated cytokines (IL-2 and IL-15) and chemokines (IP-10, RANTES, and MCP-1) were found to be increased in persons with OPC compared with HIV⁺ persons with asymptomatic Candida colonization (Lilly et al., 2004). Interestingly, a murine AIDS model (MAIDS) showed a rate of 30% recurrent OPC in inoculated mice, with a predominance of CD8⁺ T-cells recruited into the tissues (Deslauriers et al., 1997).

Studies with experimental models support a role for a combination of T-cells and innate cells against OPC. Both CD4⁺ and CD8⁺ T-cells were shown to be recruited, along with macrophages, into the mucosal tissue, and intra-epithelial CD4⁺ T-cells persisted after resolution of the infection (Allen et al., 1994; Chakir et al., 1994). Moreover, there was a time-dependent recruitment of /TCR⁺ cells that correlated with the resolution of the disease (Chakir et al., 1994; Elahi et al., 2000). Analysis of cytokines showed a role for both Th1- and Th2-type cytokines in resistance to infection, depending on the strain of mice used (Elahi et al., 2000). A recent study examined cytokines in oral tissues from infected mice and found increases in IL-6, IFN-, and TNF- in mice recovering from oral infection (Farah et al., 2002). Interestingly, no IL-2, IL-4, or IL-10 was detected during infection (Farah et al., 2002). As with other forms of mucosal candidiasis, however, little is known concerning the specific roles of mucosal vs. systemic T-cells in protection against infection. In a recent study where in vivo cellular depletions were used to create immunocompromised mice, CD4⁺ T-cells, polymorphonuclear leukocytes (PMNL), and macrophages all appeared to be important in resistance to disease (Farah et al., 2001).

Humoral immunity, in contrast, does not appear to play a role in protection against or susceptibility to OPC. Early studies of Candida-specific antibodies in saliva of HIV⁺ persons with or without OPC yielded similar or elevated levels of IgA or IgG, although, in one study, a reduced affinity of Candida-specific IgA antibodies was shown in AIDS patients (Coogan et al., 1994). There is no evidence to date, however, that a deficiency in Candida-specific antibodies is present in HIV⁺ persons that could account for the increased prevalence of OPC (Wray et al., 1990; Millon et al., 2001). A recent comprehensive analysis of Candida-specific IgA and IgG in saliva of a large number of HIV^– and HIV⁺ persons, stratified by OPC status as well as by CD4⁺ T-cell numbers, which included subclass analysis, supports the earlier findings (Wozniak et al., 2002).

Other anti-OPC mechanisms involve innate cellular defenses. Polymorphonuclear leukocytes (PMNL) appear to play a role, since neutropenic patients are susceptible to OPC (Anaissie and Bodey, 1990). However, in-depth studies with PMNL in the oral cavity have not been conducted. Epithelial cells represent another cell type with potential innate function. Oral epithelial cells have been shown to inhibit up to 80% of the growth of Candida species in vitro by a static mechanism via cell contact, with no role for soluble factors (Steele et al., 1999, 2000; Nomanbhoy et al., 2002). Analysis of the initial data suggested that the inhibition occurred through a putative carbohydrate moiety (Steele et al., 2001), although analysis of the most recent data has cast some doubt on the role for carbohydrate. Analysis of oral epithelial cells in HIV⁺ persons showed significantly reduced activity in cells from patients with OPC compared with that from patients without OPC, providing support for epithelial cells as an innate protective mechanism that, when under reduced activity, contributes to the susceptibility to infection (Steele et al., 2000). Additionally, epithelial cells produce both cytokines and chemokines in response to Candida, which may contribute to the innate and/or adaptive immune response (Rouabhia et al., 2002; Schaller et al., 2002; Steele and Fidel, 2002; Dongari-Bagtzoglou et al., 2003a,b).

Based on these data, it appears that several lines of defense may be important for protection against OPC, many of which do not become evident until CD4⁺ cells are reduced below the protective threshold. Accordingly, we propose that there are both primary and secondary host defenses that protect against OPC. The primary host defenses are the CD4⁺ T-cells that are maintained by a threshold number and recruited into the oral mucosa when necessary. Th1-type cytokines in saliva may also contribute to protection. Secondary host defenses include the CD8⁺ T-cells and other innate cells, such as PMNL, macrophages, and epithelial cells. The origin of the CD8⁺ T-cells, as well as the mechanism of action, is currently unknown. Since standard cytotoxic T-cell activity by CD8⁺ T-cells is not active against fungal organisms, it is speculated that it may be a non-HLA-restricted growth inhibition activity that has been described for murine cells (Beno and Mathews, 1992; Beno et al., 1995) and in humans against HIV (Stranford et al., 1999; Mackewicz et al., 2000). A diagram depicting this hypothesis is illustrated in the Fig. In HIV⁺ persons with < 200 CD4 cells/µL and OPC^–, it is postulated that, although the CD4⁺ T-cells are below the protective threshold, epithelial cells have activity against Candida to hold it ’in check’, and CD8⁺ T-cells are able to migrate to the outer epithelium to aid in protection. In contrast, in persons with OPC, the CD8⁺ T-cells or the micro-environment is dysfunctional, together with reduced levels of epithelial cell anti-Candida activity, resulting in susceptibility to OPC.

View larger version (35K): [in this window] [in a new window]   Fig. - Proposed immune function of the oral mucosa in HIV+ individuals with and without OPC and < 200 CD4 cells/µL. (lefthand diagram) The protective mechanisms associated with the HIV+ OPC– individual colonized with Candida albicans when the primary defense of CD4+ T-cells is below the protective threshold (200 cells/µL). The secondary defense consists of CD8+ T-cells migrating to the outer epithelium and functional oral epithelial cell anti-Candida activity that, together, keep Candida in check and prevent Candida infection. Th1 cytokines in saliva may also act in protection against infection, along with cytokines in tissue. (righthand diagram) The condition of OPC. In this scenario, where CD4+ T-cells are below the protective threshold, CD8+ T-cells are inhibited from migrating to Candida for effector function, and the epithelial cells possess reduced capacity to inhibit Candida, resulting in increased susceptibility to infection. Reduced Th1 cytokines in saliva may also contribute to the susceptibility. The presence of CD8+ T-cells in the tissue is supported by the presence of CD8+ T-cell-associated cytokines and chemokines. Reproduced with permission from Leigh et al., 2004.

With regard to epithelial cells, while a putative carbohydrate was implicated in the anti-Candida activity by sensitivity to periodic acid treatment, several attempts to identify the carbohydrate by enzyme inhibitors have been unsuccessful (Steele et al., 2001; Nomanbhoy et al., 2002). Indeed, analysis of the latest data on this subject provides substantial evidence that challenges a role for carbohydrates. First, neutralized supernatants from periodic acid-treated oral epithelial cells containing the putative carbohydrate could not compete with fresh epithelial cells for inhibition of Candida. Second, the abrogation of anti-Candida activity by periodic acid did not depend on the amount of carbohydrate released that, at times, did not show any release over buffer-treated cells (Yano et al., 2005). Together, these results suggested that the epithelial cell antifungal activity was potentially acid-labile, rather than via an effector carbohydrate. In fact, this was confirmed by additional studies showing abrogation of anti-Candida activity by treatment of epithelial cells with several other acids that release little to no carbohydrate from the cells (Yano et al., 2005).

In yet other studies with the epithelial cells, we revisited the interesting observation that the antifungal activity was partially resistant to fixation (Steele et al., 2001). Recognizing that fixation has permanent effects on cells, effectively killing them, we found it interesting that the antifungal activity remained fairly intact, despite the high viability by standard trypan blue exclusion following fixation. In fact, viability by trypan blue averaged 75% in fixed or unfixed cells, whereas viability assessed by propidium iodide and fluorescein diacetate (PI/FDA) was 16% for fixed cells and 75% for unfixed cells. Thus, it appeared that antifungal activity was dependent on intact epithelial cells impermeable to trypan blue, but was not dependent on live epithelial cells. This was further supported by experiments evaluating viability by trypan blue, PI/FDA, and antifungal activity in freshly fixed and unfixed epithelial cells, compared with those held in culture for 4 days prior to co-culture with Candida, where viability by trypan blue was reduced to < 25%. In each case, antifungal activity directly correlated to trypan blue viability (Yano et al., 2005). Analysis of these latest data, taken together, suggests that antifungal activity is static and dependent on cell contact by intact, but not necessarily live, epithelial cells through an acid-labile mechanism.

	Conclusions

TOP Abstract Introduction Host Defense against OPC Conclusions References

 
If one accepts the overall concept that protection against OPC involves both primary and secondary host defense mechanisms, indeed the most critical host defense against OPC involves CD4⁺ T-cells. This point is not being debated in this review, but becomes insignificant in persons who progress further and further to AIDS. What is critical, however, to the patients with significant progression to AIDS is the secondary host defenses. These include cytokines in saliva that can promote protection (Th1-type or pro-inflammatory), the epithelial cell anti-Candida activity, and tissue-associated CD8⁺ T-cells with the appropriate homing receptors and adhesion molecules that allow them to maximize their presence. The mechanism of epithelial cell activity is becoming clearer. Future studies are planned to identify the effector moiety and further our understanding of the static mechanism. The non-inflammatory mechanism is appealing as a means to protect commensalism, and the fact that the cells do not need to be alive is appealing to explain how fully differentiated cells at the outer epithelium, although they have the most contact with Candida, are also the cells in the least healthy state. This also suggests that the growth-inhibitory signal(s) occurring following contact with Candida may be derived from Candida, and not the epithelial cells, as part of a sophisticated symbiosis where Candida sacrifices growth for protection against killing by some other means (immune evasion). In contrast, the mechanism of the putative CD8⁺ T-cell activity has not been investigated and is under complete speculation at this time. Standard CTL activity would not be predicted. Rather, a non-Major Histocompatibility Complex-restricted activity is postulated, similar to that reported for murine CD8⁺ T-cells cultured with IL-2 (Beno and Mathews, 1992; Beno et al., 1995) and that described against HIV (Stranford et al., 1999; Mackewicz et al., 2000). Interestingly, IL-2 mRNA has been shown to be present in the tissue of persons without OPC and increased in cases of OPC. Thus, if the CD8⁺ cells were present, they may be effective against OPC, despite other factors that promote OPC. Nonetheless, based on these latest data, it would appear that the tissue-associated CD8⁺ T-cells are not dysfunctional and could be effective if they are able to migrate to the outer epithelium, where the organism is located. Rather, the dysfunction may lie with the micro-environment and, specifically, the E-cadherin adhesion molecule that promotes the migration of T-cells through mucosal tissues. If indeed the CD8⁺ T-cells play a role in protection against OPC, but are inhibited from migration through the tissue, the protective capacity of the cells would be lost, representing a factor in the susceptibility to infection. If so, this would serve as a major breakthrough in our understanding of the pathogenesis of OPC. The main question then becomes whether the reduced E-cadherin is transient or permanent, and whether co-factors such as HAART, HIV viral load, intravenous drug use, and other factors play a role. Longitudinal studies are planned to address these issues. It is anticipated that, as the mechanisms are uncovered and co-factors identified, immunotherapeutic strategies can be developed to eliminate these susceptibility factors and significantly reduce OPC in vulnerable populations such as HIV⁺ persons.

	Acknowledgments

 
This work was supported by Public Health Service grant DE-12178 from the National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.

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