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Sensing and signaling pathways in Candida albicans

"A good article that looks at the sensing and signaling pathways found in Candida albicans that play a role in its ability undergo transformation from yeast to hyphal form and back, and how this affects in pathogenicity. Talks about the ability of candida to “rapidly acquireresistance to antifungal drugs” and how this adaptability, enables it to survive in many different environments of the body, under many different conditions. In spite of acknowledging that Candida has an amazingly quick ability to develop antifungal resistance, this article talks about developing new drug targets around the different sensing and signaling pathways. Unfortunately, this is something that is repeated in research article after research article, where finding a new drug target is the main purpose of the research, despite the fact that it adapts to every drug and develops antifungal resistant strains, that leave people even more vulnerable when following the medical models. " - Dr. Jeffrey McCombs, DC

Environmental Sensing and Signal Transduction Pathways Regulating Morphopathogenic Determinants of Candida albicans

Subhrajit Biswas, Patrick Van Dijck, and Asis Datta

SUMMARY
Candida albicans is an opportunistic fungal pathogen that is found in the normal gastrointestinal flora of most healthy humans. However, under certain environmental conditions, it can become a life-threatening pathogen. The shift from commensal organism to pathogen is often correlated with the capacity to undergo morphogenesis. Indeed, under certain conditions, including growth at ambient temperature, the presence of serum or N-acetylglucosamine, neutral pH, and nutrient starvation, C. albicans can undergo reversible transitions from the yeast form to the mycelial form. This morphological plasticity reflects the interplay of various signal transduction pathways, either stimulating or repressing hyphal formation. In this review, we provide an overview of the different sensing and signaling pathways involved in the morphogenesis and pathogenesis of C. albicans. Where appropriate, we compare the analogous pathways/genes in Saccharomyces cerevisiae in an attempt to highlight the evolution of the different components of the two organisms. The downstream components of these pathways, some of which may be interesting antifungal targets, are also discussed.

INTRODUCTION

Opportunistic fungal pathogens, such as Candida albicans, are found in the normal gastrointestinal flora and the oral mucosa of most healthy humans. However, in immunocompromised patients, bloodstream infections often cause death, despite the use of antifungal therapies (152). The underlying molecular mechanisms for survival inside the human body and adaptation to various environments are probably distinct but overlapping. Dietary factors, such as an excess of or deficiency in certain nutrients, may alter the endogenous microbial flora. Mechanical factors, such as trauma or occlusive injury, can also alter the microenvironment, deplete the system of "friendly bacteria," and enable the pathogenic fungus to take over. Immunocompromised or immunosuppressed persons, including AIDS patients, neonates, and transplant recipients, are also particularly susceptible to fungal infections. The most common systemic fungal infection is candidiasis, which accounts for well over half of these invasive mycoses. A single species, C. albicans, causes the majority of these infections. Its success stems in part from its capacity to live as a benign commensal in a variety of body locations, most notably the oral cavity, genitalia, and gastrointestinal tract (272). C. albicans expresses various traits critical for existence on mucosal surfaces, where a constant but dynamic interplay occurs between innate and acquired host defense mechanisms. The pathogenic Candida species also establish well-developed biofilms, which occur easily on various implants and are resistant to antifungal agents (76). The nature of disease resulting from tissue invasion by this organism is complex and depends on a variety of physical and physiological conditions in the host and on specific C. albicans traits. The capacity of C. albicans to rapidly acquire resistance to antifungal drugs, such as amphotericin B, flucytosine, and a series of azoles, means that continued development of new antifungals remains an important focus for clinicians and pharmaceutical companies. An important feature of C. albicans, relevant to its pathogenesis, is its ability to switch between different morphological forms. C. albicans can grow in a single-celled, budding yeast form (blastospore) or in a filamentous form (including both pseudohyphae and true hyphae) (31). A crucial component of this versatility is the ability to survive as a commensal in several anatomically distinct sites, each with its own specific set of environmental pressures. Thus, C. albicans must be able to adapt its growth to a range of physiological extremes. To achieve adaptability, the fungus has evolved sophisticated mechanisms of sensing and responding to environmental cues by activating developmental switches that result in coordinated changes in cell physiology, morphology, and adherence. Progress in understanding many aspects of the biology of C. albicans has been hindered by the inability to carry out simple, large-scale genetic screens because of the diploid nature of this organism. A major breakthrough in assessing the contribution of specific genes to morphogenesis and virulence occurred with the development of transformation protocols and methods of deleting both alleles of a gene sequentially. Also, whole-genome microarray analysis has now become an important tool for probing signal transduction pathways during morphogenesis in C. albicans (102). Additional interest in the molecular mechanisms of C. albicans morphopathogenic determinants originated from the necessity of identifying new drug targets due to increased drug resistance in clinical isolates. There is hope that recently developed techniques of manipulating C. albicans and the sequencing of its whole genome will lead to a thorough understanding of its virulence and biology, thus offering the possibility of a knowledge-based approach to the development of novel antifungal agents. A major strategy for determining virulence genes as molecular targets for antifungal drugs and vaccines is to identify a specific biochemical or structural target unique to C. albicans (or to fungi in general) in an attempt to specifically and selectively disrupt them and determine their effects on virulence. In this review, we focus on recent advances in the environmental sensing and signal transduction pathways that mediate the morphogenesis and pathogenesis of C. albicans. Where possible, we compare the pathways of C. albicans with the analogous pathways/genes in Saccharomyces cerevisiae.

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http://mmbr.asm.org/cgi/content/full/71/2/348?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=hypha&searchid=1&FIRSTINDEX=150&resource>





Keywords: Environmental Sensing and Signal Transduction Pathways Regulating Morphopathogenic Determinants of Candida albicans Sending signalling drjefftop adapatation antifungal resistance

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