Editing Candida albicans (section)

==Role in disease==
{{Main|Candidiasis}}
''Candida'' is found worldwide but most commonly compromises immunocompromised individuals diagnosed with serious diseases such as HIV and cancer. ''Candida'' are ranked as one of the most common groups of organisms that cause [[hospital-acquired infection]]s. Especially high-risk individuals are patients that have recently undergone surgery, a transplant or are in the Intensive Care Units (ICU),<ref name=":0">{{cite web |url=https://microbewiki.kenyon.edu/index.php/Candida_albicans |title=Candida Albicans |vauthors=Brosnahan M |date=July 22, 2013 |website=MicrobeWiki |publisher=Kenyon College |access-date=October 24, 2016 |archive-date=November 18, 2023 |archive-url=https://web.archive.org/web/20231118161321/https://microbewiki.kenyon.edu/index.php/Candida_albicans |url-status=live }}</ref> ''C. albicans'' infections is the top source of fungal infections in critically ill or otherwise immunocompromised patients.<ref>{{cite journal | vauthors = Sydnor ER, Perl TM | title = Hospital epidemiology and infection control in acute-care settings | journal = Clinical Microbiology Reviews | volume = 24 | issue = 1 | pages = 141–173 | date = January 2011 | pmid = 21233510 | pmc = 3021207 | doi = 10.1128/CMR.00027-10 }}</ref> These patients predominantly develop oropharyngeal or thrush candidiasis, which can lead to malnutrition and interfere with the absorption of medication.<ref>{{cite journal | vauthors = Sardi JC, Scorzoni L, Bernardi T, Fusco-Almeida AM, Mendes Giannini MJ | title = Candida species: current epidemiology, pathogenicity, biofilm formation, natural antifungal products and new therapeutic options | journal = Journal of Medical Microbiology | volume = 62 | issue = Pt 1 | pages = 10–24 | date = January 2013 | pmid = 23180477 | doi = 10.1099/jmm.0.045054-0 | doi-access = free }}</ref> Methods of transmission include mother to infant through childbirth, people-to-people acquired infections that most commonly occur in hospital settings where immunocompromised patients acquire the yeast from healthcare workers and has a 40% incident rate.{{citation needed|date=November 2020}} People can become infected after having sex with a woman that has an existing vaginal yeast infection.<ref name=":0"/> Parts of the body that are commonly infected include the skin, genitals, throat, mouth, and blood.<ref>Tortora, Funke, Case. Microbiology, An Introduction 10th Edition. Pearson Benjamin Cummings. 2004, 2007, 2010.</ref> Distinguishing features of vaginal infection include discharge, and dry and red appearance of vaginal mucosa or skin. ''Candida'' continues to be the fourth most commonly isolated organism in bloodstream infections.<ref>{{cite web |url=http://www.medscape.org/viewarticle/462510 |title=Epidemiology, Management, and Prevention of Invasive Candidiasis |vauthors=Vazquez J |date=2016-04-16 |website=Medscape.org |publisher=Medscape |access-date=2016-04-16 |archive-date=2014-03-08 |archive-url=https://web.archive.org/web/20140308025902/http://www.medscape.org/viewarticle/462510 |url-status=live }}</ref> Healthy people usually do not suffer (severely) from superficial infections caused by a local alteration in cellular immunity as seen by asthma patients that use oral corticosteroids.{{Citation needed|date=January 2021}}

===Superficial and local infections===

It commonly occurs as a [[mycosis|superficial infection]] on mucous membranes in the [[oral candidiasis|mouth]] or vagina. Once in their lives around 75% of women will suffer from [[vaginal yeast infection|vulvovaginal candidiasis (VVC)]] and about 90% of these infections are caused by ''C. albicans''.{{citation needed|date=February 2021}} It may also affect a [[candidiasis#Classification|number of other regions]]. For example, higher [[prevalence]] of [[colonisation (biology)|colonization]] of ''C. albicans'' was reported in young individuals with [[tongue piercing]], in comparison to unpierced matched individuals,<ref name="Candida">{{cite journal | vauthors = Zadik Y, Burnstein S, Derazne E, Sandler V, Ianculovici C, Halperin T | title = Colonization of Candida: prevalence among tongue-pierced and non-pierced immunocompetent adults | journal = Oral Diseases | volume = 16 | issue = 2 | pages = 172–175 | date = March 2010 | pmid = 19732353 | doi = 10.1111/j.1601-0825.2009.01618.x | doi-access = free }}</ref> but not in healthy young individuals who use intraoral orthodontic acrylic appliances.<ref name="ORTHO">{{cite journal | vauthors = Yitschaky O, Katorza A, Zini A, Yitschaky M, Zadik Y | title = Acrylic orthodontic retainer is not a risk factor for focal Candida colonization in young healthy patients: a pilot study | journal =  Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology| volume = 121 | issue = 1 | pages = 39–42 | date = January 2016 | pmid = 26679358 | doi = 10.1016/j.oooo.2015.10.001 }}</ref> To infect host tissue, the usual [[unicellular organism|unicellular]] yeast-like form of ''C. albicans'' reacts to environmental cues and switches into an invasive, multicellular filamentous form, a phenomenon called [[Dimorphic fungus|dimorphism]].<ref name=Sherris>{{cite book |veditors=Ryan KJ, Ray CG |title=Sherris Medical Microbiology |edition=4th |publisher=McGraw Hill |year=2004 |isbn=978-0-8385-8529-0}}</ref> In addition, an overgrowth infection is considered a superinfection, the term usually applied when an infection becomes opportunistic and very [[Antimicrobial resistance|resistant]] to [[antifungal]]s. It then becomes suppressible by antibiotics{{clarify|date=July 2020 |reason=please clarify antifungal vs antibiotic vs antibacterial, and "then becomes suppressible" vs need another method of treatment}}{{Citation needed|reason=this info not present in the existing citations|date=July 2020}}. The infection is prolonged when the original sensitive strain is replaced by the antifungal-resistant strain.<ref>{{cite book |title=Microbiology: an Introduction |url=https://archive.org/details/microbiologyintr00tort_505 |url-access=limited | vauthors = Tortora GJ |publisher=Pearson Benjamin Cummings |year=2010 |location=San Francisco, CA |pages=[https://archive.org/details/microbiologyintr00tort_505/page/n791 759]}}</ref>

Candidiasis is known to cause gastrointestinal (GI) symptoms particularly in immunocompromised patients or those receiving steroids (e.g. to treat [[asthma]]) or antibiotics. Recently, there is an emerging literature that an overgrowth of fungus in the small intestine of non-immunocompromised subjects may cause unexplained GI symptoms. Small intestinal fungal overgrowth (SIFO) is characterized by the presence of an excessive number of fungal organisms in the small intestine associated with gastrointestinal symptoms. The most common symptoms observed in these patients were belching, bloating, indigestion, nausea, diarrhea, and gas. The underlying mechanism(s) that predisposes to SIFO is unclear. Further studies are needed; both to confirm these observations and to examine the clinical relevance of fungal overgrowth.<ref name="SIFO"/><ref name="pmid24789109">{{cite journal | vauthors = Martins N, Ferreira IC, Barros L, Silva S, Henriques M | title = Candidiasis: predisposing factors, prevention, diagnosis and alternative treatment | journal = Mycopathologia | volume = 177 | issue = 5–6 | pages = 223–240 | date = June 2014 | pmid = 24789109 | doi = 10.1007/s11046-014-9749-1 | hdl-access = free | quote = Candida species and other microorganisms are involved in this complicated fungal infection, but Candida albicans continues to be the most prevalent. In the past two decades, it has been observed that abnormal overgrowth in the gastrointestinal, urinary and respiratory tracts, not only in immunocompromised patients, but also related to nosocomial infections and even in healthy individuals. There is a wide variety of causal factors that contribute to yeast infection which means that candidiasis is a good example of a multifactorial syndrome. | s2cid = 795450 | hdl = 10198/10147 }}</ref><ref name="pmid25385227">{{cite journal | vauthors = Mukherjee PK, Sendid B, Hoarau G, Colombel JF, Poulain D, Ghannoum MA | title = Mycobiota in gastrointestinal diseases | journal = Nature Reviews. Gastroenterology & Hepatology | volume = 12 | issue = 2 | pages = 77–87 | date = February 2015 | pmid = 25385227 | doi = 10.1038/nrgastro.2014.188 | s2cid = 5370536 }}</ref>

===Systemic infections===

Systemic fungal infections ([[fungemia]]s) including those by ''C. albicans'' have emerged as important causes of [[morbidity]] and [[death|mortality]] in [[immunodeficiency|immunocompromised]] patients (e.g., [[HIV/AIDS|AIDS]], cancer [[chemotherapy]], organ or [[bone marrow]] transplantation). ''C. albicans'' often forms biofilms inside the body. Such ''C. albicans'' [[biofilm]]s may form on the surface of implantable medical devices or organs. In these biofilms it is often found together with ''[[Staphylococcus aureus]]''.<ref name="Kumamoto2002"/><ref name="Donlan2001"/><ref>{{cite journal | vauthors = Peters BM, Jabra-Rizk MA, Scheper MA, Leid JG, Costerton JW, Shirtliff ME | title = Microbial interactions and differential protein expression in Staphylococcus aureus -Candida albicans dual-species biofilms | journal = FEMS Immunology and Medical Microbiology | volume = 59 | issue = 3 | pages = 493–503 | date = August 2010 | pmid = 20608978 | pmc = 2936118 | doi = 10.1111/j.1574-695X.2010.00710.x }}</ref><ref>{{cite journal | vauthors = Saygin D, Tabib T, Bittar HE, Valenzi E, Sembrat J, Chan SY, Rojas M, Lafyatis R | display-authors = 6 | title = Transcriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension | journal = Pulmonary Circulation | volume = 10 | issue = 1 | pages = 30–39 | year = 2013 | pmid = 32166015 | doi = 10.1893/0005-3155-84.1.30 | pmc = 7052475 | s2cid = 96930404 }}</ref> Such multispecies infections lead to higher mortalities.<ref>{{cite journal | vauthors = Zago CE, Silva S, Sanitá PV, Barbugli PA, Dias CM, Lordello VB, Vergani CE | title = Dynamics of biofilm formation and the interaction between Candida albicans and methicillin-susceptible (MSSA) and -resistant Staphylococcus aureus (MRSA) | journal = PLOS ONE | volume = 10 | issue = 4 | pages = e0123206 | year = 2015 | pmid = 25875834 | pmc = 4395328 | doi = 10.1371/journal.pone.0123206 | doi-access = free | bibcode = 2015PLoSO..1023206Z }}</ref> In addition [[nosocomial infection|hospital-acquired infections]] by ''C. albicans'' have become a cause of major health concerns.<ref name=Calderone/><ref>{{cite book |title=Mibrobiology:an Introduction | vauthors = Tortora GJ |publisher=Pearson Benjamin Cummings |year=2010 |location=San Francisco, CA |pages=758}}</ref> Especially once candida cells are introduced in the bloodstream a high mortality, up to 40–60% can occur.<ref name=Calderone>{{cite book |veditors=Calderone A, Clancy CJ |title=Candida and Candidiasis |edition=2nd |publisher=ASM Press |year=2012 |isbn=978-1-55581-539-4}}</ref><ref>{{cite journal | vauthors = Weinberger M, Leibovici L, Perez S, Samra Z, Ostfeld I, Levi I, Bash E, Turner D, Goldschmied-Reouven A, Regev-Yochay G, Pitlik SD, Keller N | display-authors = 6 | title = Characteristics of candidaemia with Candida-albicans compared with non-albicans Candida species and predictors of mortality | journal = The Journal of Hospital Infection | volume = 61 | issue = 2 | pages = 146–154 | date = October 2005 | pmid = 16009456 | doi = 10.1016/j.jhin.2005.02.009 }}</ref>

Although ''Candida albicans'' is the most common cause of [[fungemia|candidemia]], there has been a decrease in the incidence and an increased isolation of non-albicans species of ''Candida'' in recent years.<ref>{{cite journal | vauthors = Yapar N | title = Epidemiology and risk factors for invasive candidiasis | journal = Therapeutics and Clinical Risk Management | volume = 10 | pages = 95–105 | date = 2016-04-16 | pmid = 24611015 | pmc = 3928396 | doi = 10.2147/TCRM.S40160 | doi-access = free }}</ref> Preventive measures include maintaining a good oral hygiene, keeping a healthy lifestyle including good nutrition, the careful use of antibiotics, treatment of infected areas and keeping skin dry and clean, free from open wounds.<ref>"Fungal Diseases." Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 12 June 2015, www.cdc.gov/fungal/diseases/candidiasis/invasive/diagnosis.html.</ref><ref>{{cite web|url=http://www.microbiologybook.org/mycology/mycology-3.htm|title=Yeasts|website=www.microbiologybook.org|access-date=27 March 2018|archive-date=14 March 2018|archive-url=https://web.archive.org/web/20180314095810/http://www.microbiologybook.org/mycology/mycology-3.htm|url-status=live}}</ref>

===Role of ''C. albicans'' in Crohn's disease===
The link between ''C. albicans'' and [[Crohn's disease]] has been investigated in a large cohort. This study demonstrated that members of families with multiple cases of Crohn's disease were more likely to be colonized by ''C. albicans'' than members of control families.<ref>{{cite journal | vauthors = Poulain D, Sendid B, Standaert-Vitse A, Fradin C, Jouault T, Jawhara S, Colombel JF | title = Yeasts: neglected pathogens | journal = Digestive Diseases | volume = 27 | issue = Suppl 1 | pages = 104–110 | date = 2009 | pmid = 20203505 | doi = 10.1159/000268129 | s2cid = 9014160 }}</ref> Experimental studies show that chemically induced colitis promotes ''C. albicans'' colonization. In turn, ''C. albicans'' colonization generates anti-''Saccharomyces cerevisiae'' antibodies (ASCA), increases inflammation, histological scores and pro-inflammatory cytokine expression.<ref>{{cite journal | vauthors = Jawhara S, Poulain D | title = Saccharomyces boulardii decreases inflammation and intestinal colonization by Candida albicans in a mouse model of chemically-induced colitis | journal = Medical Mycology | volume = 45 | issue = 8 | pages = 691–700 | date = December 2007 | pmid = 17885943 | doi = 10.1080/13693780701523013 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Jawhara S, Thuru X, Standaert-Vitse A, Jouault T, Mordon S, Sendid B, Desreumaux P, Poulain D | display-authors = 6 | title = Colonization of mice by Candida albicans is promoted by chemically induced colitis and augments inflammatory responses through galectin-3 | journal = The Journal of Infectious Diseases | volume = 197 | issue = 7 | pages = 972–980 | date = April 2008 | pmid = 18419533 | doi = 10.1086/528990 | doi-access = free }}</ref>

===Diagnosis===
A United States study in 2022 showed that most cases of candidiasis are treated [[empiric therapy|empirically]] (without culture, pending culture or by symptoms in cases where culture did not show candida), thus not knowing whether the subtype is ''Candida albicans'' or any other candida species.<ref name="pmid36505943">{{cite journal| author=Eguiguren L, Lee BR, Newland JG, Kronman MP, Hersh AL, Gerber JS | display-authors=etal| title=Characteristics of antifungal utilization for hospitalized children in the United States. | journal=Antimicrob Steward Healthc Epidemiol | year= 2022 | volume= 2 | issue= 1 | pages= e190 | pmid=36505943 | doi=10.1017/ash.2022.338 | pmc=9726632 }}</ref> For subtyping of candidiasis, a [[fungal culture]] can be performed, followed by a [[germ tube]] test in which a sample of fungal spores are suspended in animal [[blood serum|serum]] and examined by [[microscopy]] for the detection of any germ tubes.<ref name=doctorfungus>Chapter  IV. Germ Tube Test in [http://www.doctorfungus.org/thelabor/sec12.pdf YEAST IDENTIFICATION] {{Webarchive|url=https://web.archive.org/web/20110927045233/http://www.doctorfungus.org/thelabor/sec12.pdf |date=2011-09-27 }} document at doctorfungus.org. Retrieved July 2011</ref> Colonies of white or cream color on fungal culture having a positive germ tube test is strongly indicative of ''Candida albicans''.<ref name=doctorfungus/>
<gallery>
File:Candida albicans PHIL 3192 lores.jpg|[[Agar plate]] culture of ''C. albicans''
File:C albicans germ tubes.jpg|Germ tubes of ''Candida albicans''
File:Candida Gram stain.jpg|[[Gram stain]] of ''Candida albicans'' from a vaginal swab; the small oval [[chlamydospore]]s are 2–4&nbsp;[[micrometre|μm]] in diameter 
File:CHROMAgar with N glabratus, P kudriavzevii, Candida albicans and Candida tropicalis, annotated.jpg|Chromogenic agar can help in indicating main species of ''Candida'' versus similar fungi. (CHROMAgar shown)
File:Mycology algorithm.png|Algorithm for the diagnosis of ''Candida albicans'' versus differential diagnoses
</gallery>

===Treatment===
There are relatively few drugs that can successfully treat Candidiasis.<ref name="Sellama">{{cite journal | vauthors = Sellam A, Whiteway M | title = Recent advances on ''Candida albicans'' biology and virulence | journal = F1000Research | volume = 5 | pages = 2582 | date = 2016 | pmid = 27853524 | pmc = 5089126 | doi = 10.12688/f1000research.9617.1 | doi-access = free }}</ref><ref>{{cite journal | vauthors =  | title = Stop neglecting fungi | journal = Nature Microbiology | volume = 2 | issue = 8 | pages = 17120 | date = July 2017 | pmid = 28741610 | doi = 10.1038/nmicrobiol.2017.120 | doi-access = free }}</ref> Treatment commonly includes:<ref>{{cite journal | vauthors = Rambach G, Oberhauser H, Speth C, Lass-Flörl C | title = Susceptibility of Candida species and various moulds to antimycotic drugs: use of epidemiological cutoff values according to EUCAST and CLSI in an 8-year survey | journal = Medical Mycology | volume = 49 | issue = 8 | pages = 856–863 | date = November 2011 | pmid = 21619497 | doi = 10.3109/13693786.2011.583943 | doi-access = free }}</ref>
* [[amphotericin B]], [[echinocandin]], or [[fluconazole]] for systemic infections
* [[nystatin]] for oral and esophageal infections
* [[clotrimazole]] for skin and genital yeast infections<ref>{{cite book | vauthors =  Tortora GJ, Funke BR, Case CL  |title= Microbiology an Introduction |year=2002 |url=https://archive.org/details/microbiologyintr00gera |url-access=limited |publisher=Pearson Benjamin Cummings |location=San Francisco, CA. |pages=[https://archive.org/details/microbiologyintr00gera/page/759 759] |edition=10th}}</ref>
Similarly to antibiotic resistance, resistance to many anti-fungals is becoming a problem. New anti-fungals have to be developed to cope with this problem since only a limited number of anti-fungals are available.<ref name="Sellama"/><ref>{{cite web|url=https://www.cdc.gov/fungal/antifungal-resistance.html|title=Antifungal Resistance – Fungal Diseases – CDC|date=26 June 2017|website=www.cdc.gov|access-date=27 March 2018|archive-date=19 May 2017|archive-url=https://web.archive.org/web/20170519094753/https://www.cdc.gov/fungal/antifungal-resistance.html|url-status=live}}</ref> A general problem is that in contrast to bacteria, fungi are often overlooked as a potential health problem.<ref>{{cite journal | vauthors =  | title = Stop neglecting fungi | journal = Nature Microbiology | volume = 2 | issue = 8 | pages = 17120 | date = July 2017 | pmid = 28741610 | doi = 10.1038/nmicrobiol.2017.120 | doi-access = free | department = Editorial }}</ref>

===Economic implications===
Given the fact that candidiasis is the fourth- (to third-) most frequent hospital acquired infection worldwide it leads to immense financial implications. Approximately 60,000 cases of systemic candidiasis each year in the USA alone lead up to a cost to be between $2–4 billion.<ref>{{cite book| vauthors = Uppuluri P, Khan A, Edwards JE | veditors = Prasad R |title=Candida albicans: Cellular and Molecular Biology|date=2017|publisher=Springer International Publishing AG|location=Switzerland|isbn=978-3-319-50408-7|page=6|chapter=Current Trends in Candidiasis}}</ref> The total costs for candidiasis are among the highest compared to other fungal infections due to the high prevalence.<ref>{{cite journal | vauthors = Wilson LS, Reyes CM, Stolpman M, Speckman J, Allen K, Beney J | title = The direct cost and incidence of systemic fungal infections | journal = Value in Health | volume = 5 | issue = 1 | pages = 26–34 | year = 2002 | pmid = 11873380 | doi = 10.1046/j.1524-4733.2002.51108.x | doi-access = free }}</ref> The immense costs are partly explained by a longer stay in the intensive care unit or hospital in general. An extended stay for up to 21 more days compared to non-infected patients is not uncommon.<ref>{{cite journal | vauthors = Rentz AM, Halpern MT, Bowden R | title = The impact of candidemia on length of hospital stay, outcome, and overall cost of illness | journal = Clinical Infectious Diseases | volume = 27 | issue = 4 | pages = 781–788 | date = October 1998 | pmid = 9798034 | doi = 10.1086/514955 | doi-access = free }}</ref>

=== Role of GSDMD in C.albicans infection ===
Gasdermin D (GSDMD) is a protein that in humans is encoded by the GSDMD gene and is a known target of the inflammasome and acts as an effector molecule of programmed cell death known as pyroptosis. This protein determines cell lysis to prevent pathogen replication and results in the release of the inflammatory cytokine interleukin-1β (IL-1β) into the extracellular space to recruit and activate immune cells at the site of infection. Inflammasome activation due to C.albicans infection triggers the release of a [[cytokine storm]] necessary to fight the pathogen. Excessive release of these pro-inflammatory mediators has been shown to exaggerate systemic inflammation leading to vascular injury and damage to vital organs. Unfortunately, Candida albicans therapy is often ineffective despite the availability of many antifungal drugs, mainly because of resistance phenomena. During conventional pyroptosis controlled by the inflammasome-GSDMD axis is hijacked by C. albicans to facilitate escape from macrophages through unfolding of hyphae and candidalysin, a fungal toxin released from hyphae. It has been shown<ref>{{cite journal |last1=Ding |first1=Xionghui |last2=Kambara |first2=Hiroto |last3=Guo |first3=Rongxia |last4=Kanneganti |first4=Apurva |last5=Acosta-Zaldívar |first5=Maikel |last6=Li |first6=Jiajia |last7=Liu |first7=Fei |last8=Bei |first8=Ting |last9=Qi |first9=Wanjun |last10=Xie |first10=Xuemei |last11=Han |first11=Wenli |last12=Liu |first12=Ningning |last13=Zhang |first13=Cunling |last14=Zhang |first14=Xiaoyu |last15=Yu |first15=Hongbo |date=2021-11-18 |title=Inflammasome-mediated GSDMD activation facilitates escape of Candida albicans from macrophages |journal=Nature Communications |volume=12 |issue=1 |pages=6699 |doi=10.1038/s41467-021-27034-9 |issn=2041-1723 |pmc=8602704 |pmid=34795266|bibcode=2021NatCo..12.6699D }}</ref> that disruption of GSDMD in macrophages infected with Candida albicans reduces the fungal load. In addition, the presence of hyphae and candidalysin are key factors in the activation of GSDMD and the release of Candida from macrophages. Also using Candida-infected mice, inhibition of GSDMD has been shown to paradoxically improve prognosis and survival, indicating that this protein may be a potential therapeutic target in C. albicans-induced sepsis.{{citation needed|date=March 2023}}