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Title: Self-Regulation of Candida albicans Population Size during GI Colonization}
Article:
Abstract:
Interactions between colonizing commensal microorganisms and their hosts play important roles in health and disease. The opportunistic fungal pathogen Candida albicans is a common component of human intestinal flora. To gain insight into C. albicans colonization, genes expressed by fungi grown within a host were studied. The EFH1 gene, encoding a putative transcription factor, was highly expressed during growth of C. albicans in the intestinal tract. Counterintuitively, an efh1 null mutant exhibited increased colonization of the murine intestinal tract, a model of commensal colonization, whereas an EFH1 overexpressing strain exhibited reduced colonization of the intestinal tract and of the oral cavity of athymic mice, the latter situation modeling human mucosal candidiasis. When inoculated into the bloodstream of mice, both efh1 null and EFH1 overexpressing strains caused lethal infections. In contrast, other mutants are attenuated in virulence following intravenous inoculation but exhibited normal levels of intestinal colonization. Finally, although expression of several genes is dependent on transcription factor Efg1p during laboratory growth, Efg1p-independent expression of these genes was observed during growth within the murine intestinal tract. These results show that expression of EFH1 regulated the level of colonizing fungi, favoring commensalism as opposed to candidiasis. Also, different genes are required in different host niches and the pathway( s) that regulates gene expression during host colonization can differ from well-characterized pathways used during laboratory growth.
Introduction:
The opportunistic fungal pathogen Candida albicans colonizes its host long before disease arises. In humans, C. albicans colonization of the oral cavity is detected in most infants by the age of one month[1]. The majority of adults are detectably colonized in the intestinal tract by C. albicans[2]. Colonization is believed to persist for long periods of time[2], and in this situation, C. albicans is primarily nonpathogenic. However, if the host becomes immunocompromised, disease caused by dissemination of commensal organisms from the intestinal tract can occur. For example, disseminated candidiasis occurs in neutropenic patients, and Candida spp are among the most common organisms isolated from the blood of hospitalized patients[3]. In AIDS patients, oropharyngeal candidiasis( OPC) is a common opportunistic infection[4]. Despite the importance of commensal organisms as the source of infection, little is known about C. albicans factors that influence intestinal colonization. A growing body of literature indicates that the interplay between commensal organisms and the host GI tract is characterized by reciprocal regulatory interactions. In addition to a role in nutrition, normal flora are required for proper development of the intestinal capillary network as well as Peyer's patches and other components of the intestinal immune system[5]. Normal flora stimulate host toll-like receptors, and these interactions are important for regulation of the inflammatory response. In the absence of toll-like receptors, dysregulation of the inflammatory response with concomitant damage to the GI tract occurs[6]. Thus, the flora make important contributions to the health of the host. The host also influences its flora. Bulk movement of material through the GI tract regulates populations of commensal organisms[7], and host secretions and immune effectors play key roles in regulating colonization and determining the composition of the flora[8]. Therefore, reciprocal interactions between the commensal flora and the host maintain the balance between overexuberant inflammation and uncontrolled growth of microorganisms. To gain insight into the activities of C. albicans that are important for host colonization or disease, studies of C. albicans gene expression during interaction with a host or host cells have been pursued. Microarray studies analyzing interactions between C. albicans and cultured immune cells have detected dramatic changes in C. albicans metabolism and stress responses[9–11]. For example, genes encoding enzymes of the glyoxylate cycle are highly expressed in phagocytosed fungal cells, and isocitrate lyase is important for systemic virulence[9]. A study of antigens expressed during oral infection revealed that components of a MAP kinase signal transduction pathway were expressed[12]. In addition, the Not5 protein is expressed during oral infection and is required for systemic virulence. Recent analysis of C. albicans cells invading host parenchymal tissue revealed changes in expression of numerous genes, demonstrating that invading cells experience metabolic changes and initiate responses to stresses such as iron limitation[13]. The goals of this study were to identify C. albicans genes that were expressed during growth within a host and to compare the genetic requirements for infection and intestinal colonization. Therefore, genes expressed in C. albicans cells associated with oral infection or in cells growing in the intestinal tract were identified, and the ability of mutants lacking some of the genes to colonize the murine intestinal tract or to produce disease was characterized. Mutants lacking the EFH1 gene, encoding a putative transcription factor[14], colonized the intestinal tract at higher levels than wild-type( WT) organisms. Strains engineered to overexpress EFH1 exhibited reduced levels of intestinal colonization and reduced colonization of the oral cavity of immunodeficient( athymic) mice. Therefore, EFH1 is important for determining the population size of C. albicans during colonization. Despite its importance during intestinal colonization, EFH1 did not affect virulence in the disseminated infection model or cellular physiology under laboratory conditions. In contrast, RBT1, encoding a putative cell wall protein, and RBT4, encoding a possible secreted protein, are required for normal virulence in the disseminated infection model[15] but are not required for normal intestinal colonization, despite their high expression during growth in the intestinal tract. Therefore, genes that influence commensal colonization can be distinct from genes that are required for virulence.
Discussion:
In this communication, several genes that were relatively highly expressed during growth within a host( host-growth genes) were characterized. The host-growth genes differ in their importance for intestinal colonization and systemic virulence demonstrating that different factors control host-pathogen interactions in different sites. The genes RBT1 and RBT4 are required for C. albicans to cause lethal infection following intravenous inoculation and for invasive infection of the cornea[15]. However, these genes are not required for colonization of the intestinal tract. In contrast, the C. albicans EFH1 gene regulates intestinal colonization but not systemic infection. Thus, some genes are required in one niche but not in another. Intestinal colonization is an essential stage in the life cycle of C. albicans because the organism is not thought to have an environmental reservoir. Therefore, optimal intestinal colonization is crucial for survival of the organism, and it is not surprising that the organism possesses genes that regulate colonization in this niche. EFH1 was relatively highly expressed by C. albicans cells growing in the mammalian intestinal tract, but paradoxically, expression of EFH1 was associated with lower colonization. Ectopic overexpression of EFH1 resulted in very poor colonization; this latter finding probably reflects a true difference in colonization, because for in vitro–grown EFH1 overexpressing cells, the ratio of DNA content( determined by qPCR) to CFUs( measured by plating) was less than 2-fold less than the ratio obtained for WT C. albicans( unpublished data). In this niche, therefore, expression of EFH1 had a negative effect on population size. Expression of Efh1p may affect the interactions between colonizing C. albicans and the cells of the intestinal tract, resulting in changes such as altered adherence or altered signaling to the immune system. By reducing colonization, expression of EFH1 may also reduce the likelihood of C. albicans infection, favoring commensal colonization as opposed to candidiasis. The effects of Efh1p on colonization are reversible, because expression of EFH1 was regulated during growth within the host( lower expression in cells recovered from OPC lesions than in cells recovered from the intestinal tract). Therefore, the negative effects of Efh1p that reduce colonization are inactivated during oral infection. Since forced expression of EFH1 reduced colonization of the oral cavity in an immunodeficient host, repression of EFH1 expression during active infection may be an important step in the progression from benign colonizer to active invader on mucosal surfaces. Since EFH1 encodes a putative transcription factor, its effects on colonization are probably indirect. Most likely, deletion of EFH1 alters the expression of other genes, some of which directly influence colonization. Under laboratory conditions, EFH1 did not strongly affect the expression of the collection of genes studied in this report( unpublished data). However, in previous studies, a laboratory-grown EFH1 overexpressing strain was shown to have altered expression of several cell surface proteins[14], which may play roles in colonization. The genes studied here were relatively poorly expressed in laboratory-grown log phase cells but showed expression in laboratory-grown post-exponential phase cells, suggesting that during growth within a host, C. albicans cells express some features of post-exponential phase cells. Numerous bacterial genes that play important roles governing host-pathogen interactions are expressed in post-exponential phase. For example, expression of virulence factors by organisms such as Bacillus anthracis[37], Staphylococcus aureus[38], Helicobacter pylori[39], Legionella pneumophila[40], or Salmonella[41] occurs in post-exponential phase. Therefore, expression of post-exponential phase genes during host interaction is a common theme for many bacterial pathogens and for the fungus C. albicans. In the laboratory, expression of ECE1, RBT1, and RBT4 is linked to hyphal morphogenesis. However, in cells growing within the intestinal tract, expression of these genes does not depend on Efg1p and most likely occurs in yeast cells. ECE1, RBT1, and RBT4 were also found to be expressed in efh1 null mutants recovered from the cecum of mice( unpublished data). Therefore, the pathway( s) responsible for the expression of these genes during growth within the host is uncharacterized. Since the genes show relatively high expression during post-exponential phase in the laboratory, there may be a post-exponential phase regulator( s) that is responsible for their expression in the host. Several regulators required for normal viability in post-exponential phase have been recently described[42]. Deeper understanding of the biology of post-exponential phase cells may reveal C. albicans activities that are important for colonization and disease. During colonization, the population size of a microorganism reflects a balance between external forces that limit the population, such as the effects of the host immune system, and intrinsic factors, such as the ability of the organism to increase in number. The ability of commensal C. albicans to regulate its own population size through reversible expression of a negative regulator of colonization adds another layer of regulation to the interactions that take place between host and colonizer. The combined effects of these regulatory interactions maintain the balance between healthy colonization and disease.
Although the fungus Candida albicans commonly colonizes the human gastrointestinal tract as a commensal , the organism is also an opportunistic pathogen , responsible for a wide range of infections in immunocompromised persons . While numerous studies of infection have been conducted , few studies have analyzed the commensal state . The studies described here analyze C . albicans cells colonizing the intestinal tract of immunocompetent mice in the absence of disease , a model for commensalism . Results showed that expression of the putative transcription factor Efh1p by cells colonizing the intestinal tract was relatively high , but paradoxically , expression of Efh1p was associated with lower colonization . Efh1p had no detectable effect on the ability of C . albicans to cause lethal disseminated infection in mice . In contrast , Rbt1p and Rbt4p , two proteins of poorly defined function required for normal disseminated infection , were not required for intestinal colonization . These results argue that the commensal state is distinct from the pathogenic state and that different factors are important in different states . Also , the regulation of expression of genes RBT1 , RBT4 , and ECE1 during intestinal colonization differed from their well-characterized regulation during laboratory growth . Further studies of commensal colonization are needed to understand this important stage of C . albicans biology .