Candida albicans (Pathogenesis)

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University of Oklahoma Study Abroad Microbiology in Arezzo, Italy[1]

Scanning electron microscope image of Candida albicans yeast cell. From: Science Photo Library [2]

Etiology/Bacteriology

Taxonomy

Domain = Eukaryota
Phylum = Ascomycota
Class = Saccharomycetes
Order = Saccharomycetales
Family = Saccharomycetaceae
Genus = Candida
species = albicans

NCBI: Taxonomy Genome: Candida albicans

Description

Candida albicans is an opportunistic fungal pathogen that is responsible for candidiasis in human hosts. C. albicans grow in several different morphological forms, ranging from unicellular budding yeast to true hyphae with parallel-side wall [1]. Typically, C. albicanslive as harmless commensals in the gastrointestinal and genitourinary tract and are found in over 70% of the population. Overgrowth of these organisms, however, will lead to disease, and it usually occurs in immunocompromised individuals, such as HIV-infected victims, transplant recipients, chemotherapy patients, and low birth-weight babies [2]. There are three major forms of disease: oropharyngeal candidiasis, vulvovaginal candidiasis, and invasive candidiasis. Over 75% of women will suffer from a C. albicans infection, usually vulvovaginal candidiasis, in their lifetimes, and 40-50% of them will have additional occurrences(s). Interestingly, C. albicans are the 4th leading cause for nosocomial infections in patients’ bloodstreams. This could result in an extremely life-threatening, systemic infection in hospital patients with a mortality rate of 30% [3]. For oropharyngeal candidiasis, infection occurs in the mouth or throat, and is identified by white plaque growth on oral mucous membranes. Vulvovaginal candidiasis or a “yeast infection” is the overgrowth of C. albicans in the vagina, and results in rash, itchiness, and discharge from the genital region. Lastly, invasive candidiasis occurs when the fungal pathogen enters the bloodstream and can easily spread to organs throughout the body. Invasive candidiasis is best identified when antibiotics fail to cure a patient’s fever [4]. C. albicans infections are usually treatable with fluconazole, while severe infections require amphotericin B.

Pathogenesis

Transmission

Candida albicans is usually transmitted from mother to infant through childbirth, and remains as part of a normal human’s microflora. The overgrowth of C. albicans leads to symptoms of disease, and it occurs when there are imbalances – for example, changes in the normal acidity of the vagina. C. albicans infections very rarely spread through sexual intercourse. The typical reservoir for C. albicans is in the normal human microflora, and is not found in animal vectors [5]. People-to-people acquired infections mostly happen in hospital settings where immunocompromised patients acquire the yeast from healthcare workers; studies show about a 40% incident rate [6].

Infectious dose, incubation, colonization

There is no exact known infectious dose of Candida albicans. This is mostly due to the fact that a C. albicans infection stems from the commensal population of C. albicans in the human microflora. Candidiasis is caused by the abnormal growth in C. albicans, which is usually due to an imbalance in the environment. Usually, this imbalance occurs in a woman’s vagina – this infection less likely to occur for men. Several events can spark an imbalance. For example, antibiotic use can decrease the amount of lactobacillus bacteria, which decreases the amount of acidic products and the pH of the vagina. Other events are pregnancy, uncontrolled diabetes, impaired immune system, and irritation of the vagina. C. albicans are able to take advantage of the conditions and outcompete the normal microflora, resulting in candidiasis or a yeast infection [7].

Epidemiology

United States

In the United States, oropharyngeal colonization by Candida albicans can be found in almost 30-55% of young adults. Also, the presence of C. albicans is detected in about 40-65% of normal fecal samples [8]. Overall, C. albicans infections remain as the top source of fungal infections in immunocompromised people. For example, in HIV compromised patients, over 90% will develop a case of oropharyngeal candidiasis [9]. On the other hand, about 75% of women experience vulvovaginal candidiasis, and about 40-50% will experience more than one episode.

In addition, candidemia is the fourth most common bloodstream infection in the United States. Almost 6.9 out of every 1000 intensive care unit patients are suffer from candidemia [10].

Worldwide

Rates for candidiasis and candidemia are similar throughout the world [8].

Virulence factors

Polymorphism

Different Morphologies:
A: Budding Yeast
B: Pseudohyphae
C: Hyphae
From: uvm.edu [3]

Candida albicans is a polymorphic fungus that can grow in several different forms, primarily yeast, pseudohyphae, and hyphae. For its pathogenicity, its ovoid-shaped budding yeast and parallel-walled true hyphae forms are the most important. The hyphae form is more prevalent for an infection, while the yeast form is believed to be important in the spread of C. albicans. The role of pseudohyphae is not very well understood, other than being an intermediate form between yeast and hyphae [1]. Several factors can cause a change in morphology, such as pH differences, temperature changes, carbon dioxide levels, starvation, and quorum-sensing molecules (farnesol, tyrosol, and dodecanol) [11].

Adhesins

Candida albicans have special sets of glycosylphosphatidylinositol (GPI)-linked cell surface glycoproteins that allow it to adhere to the surfaces of microorganisms. These glycoproteins are encoded by 8 sets of agglutinin-like sequence (ALS) genes, ranging from Als1-7 and Als9. For adhesion, the Als3 gene appears to the most important as it is upregulated during an infection of oral and vaginal epithelial cells. Also, it helps with biofilm formation by helping with adhesion to each other [12].

Invasins

Along with adhesion, Als3 proteins can function as invasins that help with the invasion of C. albicans into host epithelial and endothelial cells. Another important invasin gene is Ssa1, which normally codes for heat-shock proteins. Basically, these specialized proteins on the pathogen’s surface mediate binding to host ligands, such as E-cadherin on epithelial cells and N-cadherin on endothelial cells, and it induces host cells to engulf the fungal pathogen. Another method of invasion is the active penetration of C. albicans into host cells by an unknown mechanism involving hyphae [13].

Biofilm formation

Candida albicans have the ability to form biofilms on living and non-living surfaces, such as mucosal membranes and catheters, respectively. After the adherence of yeast cells to the surface, there is development of hyphae cells in the upper part of the biofilm. Eventually, this leads to a more resistant, mature biofilm and the dispersion of yeast cells – both contributing to the pathogen’s virulence. In the process of biofilm formation, Bcr1, Tec1 and Efg1 function as important transcriptional factors [14]. Recent studies show that biofilms protect C. albicans colonization from neutrophil attack and deter the formation of reactive oxygen species [15].

Secreted hydrolases

Candida albicans secrete 3 main classes of hydrolases: proteases, phospholipases and lipases. It is proposed that these hydrolases help facilitate the pathogen’s active penetration into host cells and the uptake of extracellular nutrients from the environment. There are about 10 known secreted aspartic proteases (Sap1-10), and their exact contribution to pathogenicity is controversial. For phospholipases, there are 4 major classes (A, B, C, and D), and all 5 members of the B class are involved with the disruption of a host cell surface. Thirdly, lipases are consisted of 10 members (LIP1-10), and studies show that there is decreased virulence in their absent [16].

Metabolic adaption

Candida albicans are usually found in the gastrointestinal microbiome of healthy individuals, and in this environment, nutrient levels are relatively high. However, during niche changes in the course of an infection, available nutrient levels will also change. Consequently, the fungus can quickly undergo metabolic adaption, such as their glycolysis, gluconeogenesis, and starvation responses [17]. For example, in the case of candidemia, C. albicans infect the bloodstream, which is typically rich in glucose. Nevertheless, it might be phagocytosed into a macrophage or neutrophil, where it’s surrounded by ROS, RNS, and AMPs. In response, C. albicans quickly switch from its glycolysis to starvation response with the activation of the glyoxylate cycle. Due to this flexibility, C. albicans can infect almost every organ in a human host through the bloodstream, providing candidemia’s higher mortality rate.

Clinical features

There are 3 major type of infections caused by Candida albicans: oropharyngeal candidiasis, vulvovaginal (genital) candidiasis, and invasive candidiasis (candidemia).

Symptoms

Oropharyngeal candidiasis

Oropharyngeal Candidiasis: Thrush From: uvm.edu [4]

Oropharyngeal candidiasis is an infection in the mouth and throat area. Usually, it is characterized by the formation of white patches on top of the tongue and throughout the mouth, which is also known as “thrush”. Thrush can be removed with a blade or a cotton-tipped swab, but the underlying tissue will be irritable and show a distinct redness. This infected area will cause soreness and difficultly during eating [18].

Vulvovaginal (genital) candidiasis

Vulvovaginal candidiasis is the infection of the genital region, typically the vaginal walls, in women. The vaginal yeast infection causes itchiness and a burning-sensation in the vagina and surrounding tissues. Also, a white discharge – described with an appearance similar to white cottage cheese – is typically present. Genital candidiasis is much more prevalent in women, but men can also contract it. Although it is not considered an STD, men are usually infected after sex with a woman having a vaginal yeast infection. Symptoms involved rash, irritation on the head and surrounding skin of the penis [18].

Invasive candidiasis (candidemia)

Invasive candidiasis (or candidemia) is the infection of C. albicans into the bloodstream. This leads to its invasion of organs throughout the body, such as the kidney, liver, brain, and many more. Patients began to suffer from fevers, chills, fatigue, muscles aches, and abdominal pains. Typically, patients with compromised immune systems are only at risk, while healthy people are susceptible to oral/genital candidiasis. Compromised immune systems can be caused by chemotherapy, transplantation, broad-spectrum antibiotics, and much more [19].

Mortality

Most patients can recover from oral and genital candidiasis after a treatment with antifungal such as fluconazole. On the other hand, candidemia is much more life-threatening infection. In one study, the mortality rate for patients with candidemia was about 34% [20]. Shockingly, this figure almost doubled when treatment is delayed; i.e., the mortality rate was 78% when therapy was delayed for more than 48 hours [21].

References

1. Sudbery P, Gow N, Berman J. 2004. The distinct morphogenic states of Candida albicans. Trends in Microbiology. 12(7):317-24.

2. Kabir MA, Hussain MA, Ahmad Z. 2012. Candida albicans: A Model Organism for Studying Fungal Pathogens. ISRN Microbiology. 2012: 538694.

3. Pfaller MA, Diekema DJ. 2007. Epidemiology of Invasive Candidiasis: a Persistent Public Health Problem. Virulence. (2): 119–128.

4. Centers for Disease Control and Prevention. Candidiasis. [<http://www.cdc.gov/fungal/diseases/candidiasis/index.html/>].

5. Public Health Agency of Canada. Candida albicans - Material Safety Data Sheets. [<http://www.phac-aspc.gc.ca/lab-bio/res/psds-ftss/msds30e-eng.php>].

6. Fanelloa S, Boucharab JP, Jousseta N, Delbosa V, LeFlohicc AM. 2001. Nosocomial Candida albicans acquisition in a geriatric unit: epidemiology and evidence for person-to-person transmission. Journal of Hospital Infection. 47(1):46-52.

7. Mayo Clinic. Diseases and Conditions: Yeast infection (vaginal). [<http://www.mayoclinic.org/diseases-conditions/yeast-infection/basics/definition/con-20035129>].

8. Hidalgo JA, Vazquez JA, Bronze MS. 2014. Candidiasis: Frequency. [<http://emedicine.medscape.com/article/213853-overview#aw2aab6b2b3aa>].

9. de Repentigny L, Lewandowski D, Jolicoeur P. 2004. Immunopathogenesis of oropharyngeal candidiasis in human immunodeficiency virus infection. Clinical Microbiology Review. 17(4):729-59.

10. Mikulska M, Bono VD, Ratto S, Viscoli C. 2012. Occurrence, Presentation and Treatment of Candidemia. Expert Review of Clinical Immunology. 8(8):755-765.

11. Mayer FL, Wilson D, Hube B. 2013. Candida albicans pathogenicity mechanisms. Virulence. 4(2): 119–128.

12. Murciano C, Moyes DL, Runglall M, Tobouti P, Islam A, Hoyer LL, Naglik JR. 2012. Evaluation of the Role of Candida albicans Agglutinin-Like Sequence (Als) Proteins in Human Oral Epithelial Cell Interactions. PLoS One. 7(3): e33362.

13. Wächtler B, Wilson D, Haedicke K, Dalle F, Hube B. 2011. From Attachment to Damage: Defined Genes of Candida albicansMediate Adhesion, Invasion and Damage during Interaction with Oral Epithelial Cells. PLoS One. 6(2): e17046.

14. Fanning S, Mitchell AP. 2012. Fungal Biofilms. PLoS Pathog. 8(4): e1002585.

15. Xie Z, Thompson A, Sobue T, Kashleva H, Xu H, Vasilakos J, Dongari-Bagtzoglou A. 2012. Candida albicans biofilms do not trigger reactive oxygen species and evade neutrophil killing. The Journal of Infectious Diseases. 206(12):1936-45.

16. Wächtler B, Citiulo F, Jablonowski N, Förster S, Dalle F, Schaller M. 2012. Candida albicans-epithelial interactions: dissecting the roles of active penetration, induced endocytosis and host factors on the infection process. PLoS One. 7:e36952.

17. Brock M. 2009. Fungal metabolism in host niches. Current Opinion in Microbiology. 12(4):371-6.

18. eMedicineHealth. Candidiasis Yeast Infection Symptoms and Signs. [<http://www.emedicinehealth.com/candidiasis_yeast_infection/page3_em.htm#candidiasis_yeast_infection_symptoms_and_signs>].

19. American Thoracic Society. Candida Infection of the Bloodstream – Candidemia. [<http://patients.thoracic.org/information-series/en/resources/candidemia.pdf>].

20. Nguyen MH, Peacock JE Jr, Tanner DC, Morris AJ, Nguyen ML, Snydman DR, Wagener MM, Yu VL. 1995. Therapeutic approaches in patients with candidemia. Evaluation in a multicenter, prospective, observational study. Archives of Internal Medicine. 155(22):2429-35.

21. Blot SI, Vandewoude KH, Hoste EA, Colardyn FA. 2002. Effects of nosocomial candidemia on outcomes of critically ill patients. American Journal of Medicine. 113(6):480-5.

Created by Johnson Ong, a student of Tyrrell Conway at the University of Oklahoma.