ABSTRACTTo understand differences in host-Candida albicansinteractions that occur during colonization of healthy or compromised hosts, production of phenotypic variants and colonization of healthy or immunodeficient mice byC. albicanswere studied. We showed that activity of the transcription factor Efg1p exhibited cell-to-cell variability and identified Efg1p as a major regulator of colonization. InC. albicanspopulations colonizing the murine gastrointestinal tract, average expression ofEFG1differed depending on the immune status of the host. We propose that cellular heterogeneity in Efg1p activity allows theC. albicanscolonizing population to differ depending on the immune status of the host, because selective pressure from a healthy host alters the composition of the population. These data are the first demonstration that differences in host immune status are associated with differences in gene expression in colonizingC. albicanscells. Altered gene expression in organisms colonizing immunocompromised hosts may begin the transition ofC. albicansfrom a commensal to a pathogen.IMPORTANCEIn healthy people, the fungusCandida albicanscolonizes the gastrointestinal tract and other sites without producing obvious pathology. In an immunocompromised patient, the organism can cause serious disease. The demonstration that the expression and activity of theC. albicanstranscription factor Efg1p differs during colonization of healthy or immunocompromised mice shows that the organism adjusts its physiology when colonizing different hosts. Further, the effects of a healthy host on a heterogeneousC. albicanspopulation containing cells with different levels of Efg1p activity show that selective pressure in the host can change the makeup of the population, allowing the population to respond to host immune status. The ability to sense host status may be key to the ability ofC. albicansto colonize as a harmless commensal in some hosts but become a deadly pathogen in others.

Although the fungus Candida albicans is a commensal colonizer of humans, the organism is also an important opportunistic pathogen. Most infections caused by C. albicans arise from organisms that were previously colonizing the host as commensals, and therefore successful establishment of colonization is a prerequisite for pathogenicity.

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cAlthough gastrointestinal colonization by the opportunistic fungal pathogen Candida albicans is generally benign, severe systemic infections are thought to arise due to escape of commensal C. albicans from the gastrointestinal (GI) tract. The C. albicans transcription factor Efg1p is a major regulator of GI colonization, hyphal morphogenesis, and virulence. The goals of this study were to identify the Efg1p regulon during GI tract colonization and to compare C. albicans gene expression during colonization of different organs of the GI tract. Our results identified significant differences in gene expression between cells colonizing the cecum and ileum. During colonization, efg1؊ null mutant cells expressed higher levels of genes involved in lipid catabolism, carnitine biosynthesis, and carnitine utilization than did colonizing wild-type (WT) cells. In addition, during laboratory growth, efg1؊ null mutant cells grew to a higher density than WT cells. The efg1 ؊ null mutant grew in depleted medium, while WT cells could grow only if the depleted medium was supplemented with carnitine, a compound that promotes the metabolism of fatty acids. Altered gene expression and altered growth capability support the ability of efg1 ؊ cells to hypercolonize naïve mice. Also, Efg1p was shown to be important for transcriptional responses to the stresses present in the cecum environment. For example, during colonization, SOD5, encoding a superoxide dismutase, was highly upregulated in an Efg1p-dependent manner. Ectopic expression of SOD5 in an efg1 ؊ null mutant increased the fitness of the efg1 ؊ null mutant cells during colonization. These data show that EFG1 is an important regulator of GI colonization.

Adaptive evolution progresses as a series of steps toward a multidimensional phenotypic optimum, and organismal or environmental complexity determines the number of phenotypic dimensions, or traits, under selection. Populations evolving in complex environments may experience costs of complexity such that improvement in one or more traits is impeded by selection on others. We compared the fitness effects of the first fixed mutations for populations of single-stranded DNA bacteriophage evolving under simple selection for growth rate to those of populations evolving under more complex selection for growth rate as well as capsid stability. We detected a cost of complexity manifested as a smaller growth rate improvement for mutations fixed under complex conditions. We found that, despite imposing a cost for growth rate improvement, strong complex selection resulted in the greatest overall fitness improvement, even for single mutations. Under weaker secondary selective pressures, tradeoffs between growth rate and stability were pervasive, but strong selection on the secondary trait resulted largely in mutations beneficial to both traits. Strength of selection therefore determined the nature of pleiotropy governing observed trait evolution, and strong positive selection forced populations to find mutations that improved multiple traits, thereby overriding costs incurred as a result of a more complex selective environment. The costs of complexity, however, remained substantial when considering the effects on a single trait in the context of selection on multiple traits.