Microbiology in its broadest sense is a branch of science that deals with microorganisms. Although several scientists contributed to this field, the credit goes to Antonie van Leeuwenhoek whose work in the late 1600’s observing microscopic organisms is regarded as the first to accurately describe protozoa, fungi, and bacteria. The origin of diseases at the time was still debated and Leeuwenhoek did not make the connection between these microorganisms he was observing and various disease states which occurred. At that point in time the world held beliefs rooted in the Miasma theory. The Miasma theory postulated that disease happened from suspended particles of decaying matter which produced a putrid smell, akin to a noxious gas. It wasn’t until the work of Louis Pastuer and Robert Koch that the scientific proof of a new theory, Germ theory. Contrary to Miasma theory, the Germ theory stated that many diseases are caused by the presence and actions of certain micro-organisms within the body. This brings us to a fascinating fungi whose presence was first mentioned by The Father of Western Medicine, Hippocrates, around 400 B.C. In his work “Of the Epidemics, Hippocrates first described what we know today as oral candidiasis, or thrush; however, the idea of microbial pathogens needed much longer to catch up. It wasn’t until the mid-1800’s that the identity of the fungal pathogen was discovered, and even then it was over a hundred years before the current Latin binomial was fully accepted, Candida albicans. This paper will detail C. albicans from its humble origin and existence within us, to the various infections it causes and how modern science is reacting to it.
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The etymology of the name C. albicans lies in the Latin language with the word candidus meaning white, and albico meaning becoming white. The genus Candida was first described by the mycologist Christine Marie Berkhout in her doctoral thesis for the University of Utrecht in the Netherlands in 1923[i]. Berkhout was technically not the one to identify the micro-organism per say, she instead reassigned it to the Candida genus from its original Monilia. This change was due to her observations of the funguses ability to infect humans where the prior genus contains fungi that commonly grow in plants. Although it has been less than one hundred years since the classification of this fungus, it has long been a part of the human microbiome. The majority of this genus contains species which are harmless to humans and quite natural to our flora in a relationship defined as commensalism in about 70% of humans[ii]; however, a simple disruption of the immune system can trigger them to become opportunistic pathogens resulting in a wide range of disease states. As the most common cause of fungal infections, Candida as a genus spans about one hundred and fifty species of interest including medically important ones such as C. parapsilosis, C. tropicalis and C. dubliniensis. As large as this genus is, a number around 20 are known to cause diseases in humans and C. albicans is the most significant of these pathogenic species although some of its related species have been making noise in the scientific community.
C. albicans is a curious “fungus” when it comes to morphology because it exhibits something called phenotypic switching which is an, “in vitro reversible phenomenon defined as the spontaneous emergence of colonies with altered colony morphology at a rates higher than somatic mutation rates”, as well as a transition between two states of shape so to speak where it fluctuates from bud to hypha.[iii] Many resources will categorize C. albicans as a dimorphic fungus which would mean it only has two distinct forms it occurs in; however, it is truly pleomorphic where the shape and size is altered in response to environmental conditions. The switching occurs from “yeast” cells to hyphae which are a filamentous growth pattern. This occurrence can be seen distinctly when you grow C. albicans in a standard yeast laboratory medium which is likely composed of bacterial peptones, yeast extract, and glucose. The culturing media can be done also in solid agar such as blood or potato dextrose, as well as broths. In these types of mediums C. albicans will grow as an egg shaped “yeast”. However, when you start to manipulate variables such as temperature, pH, nutrient availability, or other environmental factors the ovoid shape transitions to the filamentous shape referred to as hyphae.[iv] For many human fungal pathogens morphology can be associated with virulence. This is a common occurrence in the Candida genus, but may not be required for the species Albicans which we are discussing. In other species the morphology is known to be a factor in colonization and dissemination to tissues of the host, as well as indicative of virulence factors such as adhesion and biofilm formation. In general, it seems that the yeast shape is able to travel easily through the bloodstream while the hyphae or pseudo hyphae are more directly responsible for the actual virulence of the micro-organism. Hyphae formation has been studied in C. albicans to encourage virulence by invading epithelial cells either growing between them or fully penetrating them. This morphological structure can also reach endothelial cells, and lyse immune factors such as macrophages and neutrophils.
The phenotypic switching that occurs in C. albicans is not limited to the physical morphology, and three other systems have been identified. These systems are high frequency switching, white to opaque switching and white-GUT switching.[v] The high frequency system is where spontaneous development of phenotypes occurs regardless of environmental conditions. The white to opaque switching is a non DNA related phenotypic inheritance that differentiates two growth phases, the first being the white form which is identified by smooth round cells in white colonies, while the second form is a flat rod like gray color which is referred to as opaque since there is another phenotypic gray form. As stated before this difference is a factor in virulence though it may not be necessary. What this is necessary for is the ability of C. albicans to reproduce as the opaque form is highly more favorable than the white type. Bringing more complexity to the mating issue was the longstanding belief that C. albicans was a diploid organism meaning it could reproduce asexually by themselves as they have two sets of chromosomes; however, new studies are showing that sometimes the yeast is haploid, meaning it only has one set of chromosomes and needs a partner to reproduce sexually. The last type of switch is the White-GUT switch where the cells adapt to survive in the digestive tract due to environmental factors. While morphology plays a key role in C. albicans and its virulence, perhaps the most important virulence factor of this organism is its ability to produce a biofilm.
Biofilm formation in micro-organisms is where microbial cells adhere to each other on a surface within a self-produced matrix of extracellular polymeric substances such as proteins, polysaccharides, and small molecules.[vi] The main function of this biofilm as a virulence factor is to provide protection of the micro-organism from host defenses as well as medicine such as antibiotics. In C. albicans, the biofilm is produced in distinct steps starting with the adherence where the cells are present in the “yeast” form, then moving to colonization, proliferation, maturation and finally dispersion. The mechanisms responsible for this formation lie within quorum sensing, adhesive interactions, and the previously discussed ability to transition between morphological shapes.
C. albicans is the role model in molecular biology for the study of pathogenic fungi and its genome was sequenced almost 15 years ago in 2004. The pathogenicity of the micro-organism is due to the several factors listed above. However, to understand this fungus fully, we need to look at its existence within our own bodies. C. albicans is part of our normal flora and exists mainly in the gastrointestinal tract but can also be found in warm moist mucosal membranes including those of the mouth, rectum, vagina, and even the skin. Most of the time, this fungus lives in harmony with its human counterparts however a disruption in the immune system can cause this micro-organism to turn into an opportunistic pathogen. This disruption can cause Candida overgrowth and several factors can lead to it such as immunocompromised patients, a diet high in sugar and refined carbs, alcohol consumption, antibiotics, diabetes, and even stress. A broad term for the overgrowth of Candida is called candidiasis and can occur all over the body. Symptoms associated with this overgrowth are dependent on the system of the body being infected which I will go into detail about a few major occurrences.
First, let’s look at when Candida overgrowth occurs in the mouth. This was first described by Hippocrates as Thrush or Oral Candidiasis. While other Candida species can be the culprit of this infection, the most common culprit is our species of interest, Albicans. The most common occurrence of this infection happens in infants and toddlers as their immune systems are not fully developed at the time. Symptomology includes white bumps which form on the inner cheeks and tongue, pain or bleeding from these protrusions, difficulty swallowing, and a bad taste in the mouth. In infants in particular, common manifestations are confirmed by fussiness, irritability, and difficulty feeding which can also be considered normal; therefore, a biopsy may be taken for culture. Infants are not the only demographic at risk as any immune compromised patient can develop an overgrowth of this typically harmless fungi. Treatment for thrush is dependent on the person and is mainly to prevent further growth and spread of the organism. Several antifungals such as fluconazole, and clovtrimazole are used but in treatment resistant patients such as immunocompromised HIV persons, Itraconazole is used or in the most severe cases Amphotericin B is used.[vii]
Similarly, to the mouth this Candida overgrowth commonly occurs in the vagina. When an overgrowth of C. albicans occurs in the vagina it is referred to as a yeast infection which are so common they affect up to 75% of women at some point in their lifetime. The flora of the vagina is carefully balanced between beneficial bacteria and some yeast cells; however, when this equilibrium is disturbed the yeast cells can proliferate and cause candidiasis. Yeast infection symptomology is rather universal and includes vaginal itching, swelling, and redness while also causing burning or pain during urination or sex. Discharge is also a common manifestation of a yeast infection and is characteristically similar to cottage cheese. Although not considered a sexually transmitted infection, you can pass this infection through sexual contact. Factors contributing to a yeast infection include the weakened immune system as well as pregnancy, hormonal imbalance, stress and antibiotics. The reason why antibiotics are one of the major causes of yeast infections is due to their ability to decrease the Lactobacillus bacteria which keep the Candida in check. Diagnosing a vaginal yeast infection is fairly simple with a pelvic exam by an OBGYN. If a diagnosis cannot be made from visual markers sometimes cells are collected to be examined by a lab, and more often are collected from recurring infections. Yeast infections range in their severity and treatment. Usually a common infection will be remedied by a one to three-day regimen of an anti-fungal which can be purchased over the counter. These medications are azoles which have anti-fungal activity.[viii] Severity of infections range from those which lead to sores or tears in the vagina, to recurring infections. Special consideration needs to be made for those who are pregnant, HIV-positive, or a weak immune system due to medication. Again antifungals are prescribed but for a much longer period of time such as two weeks or even a long term prescription lasting six weeks or even more long term. Natural remedies can also remediate a yeast infection and include coconut oil, tea tree essential oil, or even yogurt. Yeast infection occurrence can be mitigated by a well-balanced diet including eating foods with probiotics that support normal flora, wearing moisture wicking natural fibers, and replacing feminine products frequently. Avoidance of tight clothing which does not allow the vagina to “breathe”, as well as avoiding being in moist clothing for extended periods can help to prevent yeast infections. Other common products to avoid include those that interfere with vaginal pH including douching as well as scented female products such as pads and tampons. Overall the vagina is a miraculous sexual organ that has a unique ability to “clean” itself given the opportunity.
Other infections due to Candida albicans are more invasive than the mouth, throat, and vagina and are broadly called Candidemia because the fungus enters the bloodstream where it can be widely disseminated to organs including the eyes, kidney, liver and brain. The prevalence of this form of Candida infection is in about 40% of the bloodstream infections in the hospital.[ix] The risk factors associated with this are similar to the other Candida infections previously mentioned but the main factor involves being hospitalized especially in the ICU and having a catheter or other medical device. To diagnose Candidemia a healthcare professional will take a blood sample and look for Candida specifically or try to detect antigens. Sometimes prophylactic treatments are employed by giving antifungals ahead of time if you are at risk, but this does not work for all cases. If prophylactic treatment is not employed and an infection occurs the treatment options are again the anti-fungals with particular ones being used depending on the severity of the infection.
With all of this information present one may be wondering just how important this micro-organism is to us humans, after all we live with it every second of the day. As the most prevalent fungal species of the human microbiota, Candida can become a concern when the delicate balance is disturbed. Research over the last thirty years has vastly improved our understanding of this fungus with help from genome sequencing as well as advanced microscopy. However, with the antifungals that currently exist for treatment, the variability of Candida albicans discussed in phenotypic differences has led to anti-fungal resistant forms of the yeast. Where the common treatment of infections relied on “azoles”, multi drug resistant infections rely on Amphotericin B which can have toxic effects in humans that have compromised immune systems already.
Anti-fungal resistance is a threat similar to antibiotic resistant microbes. While some species of fungi tend to be naturally resistant, those like C. albicans have developed a resistance overtime likely due to improper anti-fungal use where doses are too low or courses are not followed for the full amount of time. Recent studies have shown that mutations affecting uptake of flucytosine or its intracellular conversion are responsible for the drug resistance as well as mutations in the gene ERG11, and two flux pumps.[x] It has even been indicated that antibacterials may be contributing to anti-fungal resistance. This happens because antibacterial drugs can reduce the amount of bacteria in the gut, throwing off the balance of “good” microbes and creating an environment in which Candida can thrive. In fighting this resistance like any other it is imperative to properly and appropriately use antibiotics and antifungals.
Candida is a unique fungal pathogen that is easily grown in standard yeast media in the laboratory setting. Although the genetics of C. albicans are complex, we now have the availability of the complete genome sequence to assist in studying the organism. From the genome perspective scientists apply “reverse genetics” to study the genus. The genome sequencing has turned out about 6107 genes but the functions are not crystal clear and are mainly comparable to another bug S. cerevisiae which exists as a model microbe for the study of eukaryotic organisms.[xi] This poses a unique problem though because 13% of the total genes of Candida are not homologous to S. cerevisiae[xii]. In understanding these unique 13% of genes it is possible to fully understand the virulence of C. albicans and how to properly develop new treatment options. Currently the scientific community has been investigating natural products to develop new anti-fungal treatments for those who are becoming resistant to current conventional therapies. The main challenge I believe with Candida is going to be the biofilm formation which is perhaps its most lethal virulence factor. If we can discover natural products which disrupt this formation it is possible to then target with new anti-fungal treatments.
In conclusion research on C. albicans is always going to be relevant to human health because of its close relationship to the human microbiome from the time it was first written about in 400 BC by Hippocrates. The fungus is responsible for around 400,000 deaths annually which I believe can significantly increase or decrease depending on the research that evolves within the next ten years.[xiii] Major discoveries about the fungus include the morphological transformation it undergoes sometimes due to environmental cues and otherwise due to genetic information which we have just scratched the surface on. Disease states originating from this pathogenic fungus range from the gastrointestinal tract, to the genitourinary tract, and almost anywhere in between. The diseases I highlighted including thrush, and yeast infections are going to be more common than Candidemia in which the fungus can reach the blood stream; however, they are also far less dangerous and easily treated. Due to its opportunistic nature, Candida overgrowth poses a serious threat, and with its ability to transform its shape to easier penetrate the body and move into the blood, we need to be vigilant about researching the functions of the genes which have been sequenced thus far. Aside from its opportunistic nature being a threat, we need to be cautious of the resistance of this fungus to current treatments available. The Center for Disease Control has an Emerging Infections program where they track trends in antifungal resistance by surveilling bloodstream isolates of the fungus. Concurrently doing genetic sequencing scientists are trying to develop new laboratory tests that will help us understand the mutations that are associated with this resistance.[xiv] Plants are by far one of the richest sources of bioactive secondary metabolites which come in a wide variety of compounds including tannins, terpenoids, and alkaloids. So far research in vitro has shown some of these compounds to have anti-fungal properties. I believe the future of developing these new treatments lies in plant or even fungi compounds which already exist and may be used as a precursor to develop new medicines. With all of the information on one of the more well-known fungal pathogens out there, it was impossible to fit every detail of Candida albicans into this paper. Several other virulence factors have been discovered as well as more in depth information about the genetic profile of the fungus which I truthfully do not comprehend. There is a wealth of research papers should one decide to dig farther into this fungus but for now this brief introduction and overview should suffice.
[i] Knoke M, Bernhardt H. The first description of an oesophageal candidosis. Mycises. 2006;49 (4):283-7
[ii] Kabir MA, Hussain MA, Ahmad Z. Candida albicans: A Model Organism for Studying Fungal Pathogens. ISRN Microbiology. 2012:2012:1-15
[iii] Jain N, Hasan F, Fries BC. Phenotypic Switching in Fungi. Curr Fungal Infect Rep. 2008;2(3):180-188.
[iv] Mayer, F. L., Wilson, D., & Hube, B. (2013). Candida albicans pathogenicity mechanisms. Virulence, 4(2), 119-28.
[v] Ruchel R. Candida and Candidiasis. International Journal of Medical Microbiology. 2002;292:246.
[vi] Fanning S, Mitchell AP. Fungal biofilms. PLoS Pathog. 2012;8(4):e1002585.
[vii] CDC.gov Candida infections of the mouth, throat, and esophagus
[viii] Sardi JCO, Scorzoni L, Bernardi T, Fusco-Almeida AM, Mendes Giannini MJS. Candida species: Current epidemiology, pathogenicity, biofilm formation, natural antifungal products and new therapeutic options. Journal of Medical Microbiology. 2013;62:10-24.
[ix] American Thoracic Society- Candida Infection of the Bloodstream- Candidemia
[x] Morschhäuser J. Regulation of multidrug resistance in pathogenic fungi. Fungal Genetics and Biology. 2010;47:94-106
[xi] Jones T, Federspiel NA, Chibana H, et al. The diploid genome sequence of Candida albicans. Proc Natl Acad Sci U S A. 2004;101(19):7329-34.
[xii] Kabir MA, Hussain MA, Ahmad Z. Candida albicans: A Model Organism for Studying Fungal Pathogens. ISRN Microbiology. 2012:2012:1-15
[xiii] Pfaller MA, Diekema DJ. Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev. 2007;20(1):133-63.
[xiv] CDC.gov “Fungal Diseases: Anti-fungal Resistance”
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