Fungal infections in humans have historically received comparatively less attention than those caused by bacteria and viruses. This may, in part, stem from the relative differences in infection prevalence. However, the more widespread use of immunosuppressive therapy, invasive surgery and medical devices in modern medicine has resulted in a more frequent occurrence of human fungal infection. There are a number of fungi that can cause human disease. However, it is arguably a species of the genus Candida that are most often encountered. There are over 150 Candida species that are widely encountered in the environment and in animal hosts, however, only a small number are opportunistic pathogens of humans. Candida albicans is a polymorphic yeast-like fungus and undoubtedly the species most often recovered from human infection. As such, the virulence of C. albicans and its susceptibility to antifungal agents are often investigated. More recently, the prevalence of infections caused by non-C. albicansCandida species have increased and, amongst these, infections caused by Candida glabrata have received attention given its often-higher tolerance to frequently used antifungals exhibited by this species. The papers presented in this Special Issue have focused on aspects relating to host responses to Candida infection, the efficacy of novel therapeutic agents and also treatment regimes. The papers highlight novel findings in their respective areas, whilst also highlighting the need for further research in these key and largely under-researched areas of candidoses.(undefined)info:eu-repo/semantics/publishedVersio

Henriques, Mariana

Williams, David

Pathogens

English

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Pathogenesis and Virulence of Candida albicans and Candida glabrata

Fungal infections in humans have historically received comparatively less attention than those caused by bacteria and viruses. This may, in part, stem from the relative differences in infection prevalence. However, the more widespread use of immunosuppressive therapy, invasive surgery and medical devices in modern medicine has resulted in a more frequent occurrence of human fungal infection. There are a number of fungi that can cause human disease. However, it is arguably a species of the genus Candida that are most often encountered. There are over 150 Candida species that are widely encountered in the environment and in animal hosts, however, only a small number are opportunistic pathogens of humans. Candida albicans is a polymorphic yeast-like fungus and undoubtedly the species most often recovered from human infection. As such, the virulence of C. albicans and its susceptibility to antifungal agents are often investigated. More recently, the prevalence of infections caused by non-C. albicansCandida species have increased and, amongst these, infections caused by Candida glabrata have received attention given its often-higher tolerance to frequently used antifungals exhibited by this species. The papers presented in this Special Issue have focused on aspects relating to host responses to Candida infection, the efficacy of novel therapeutic agents and also treatment regimes. The papers highlight novel findings in their respective areas, whilst also highlighting the need for further research in these key and largely under-researched areas of candidose

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This is a n  Op e n  Acces s  doc u m e n t  dow nloa d e d  fro m  ORCA, Ca r diff U nive r si ty 'sins ti t u tion al r e posi to ry: h t t p s://o rc a .c a r diff.ac.uk/id/e p rin t/13 4 8 6 7/This  is t h e  a u t ho r’s ve r sion  of a  wo rk  t h a t  w as  s u b mi t t e d  to  / a c c e p t e d  forp u blica tion.Cit a tion  for  final p u blish e d  ve r sion:H e n riq u e s,  M a ri a n a  a n d  Willia m s,  David ORCID: h t t p s://o rcid.o rg/00 0 0-0 0 0 2-7 3 5 1-5 1 3 1  2 0 2 0.  Pa t ho g e n e sis  a n d  vi rule nc e  of Ca n did a  albic a n s  a n d  Ca n did agla b r a t a .  Pa tho g e n s  9  (9) , 7 5 2.  1 0.33 9 0/p a t ho g e n s 9 0 9 0 7 5 2  file  P u blish e r s  p a g e:  h t t p://dx.doi.o rg/10.33 9 0/p a t ho g e n s 9 0 9 0 7 5 2< h t t p://dx.doi.o rg/10.33 9 0/p a t hog e n s 9 0 9 0 7 5 2 >Ple a s e  no t e:  Ch a n g e s  m a d e  a s  a  r e s ul t  of p u blishing  p roc e s s e s  s uc h  a s  copy-e di ting,for m a t ting  a n d  p a g e  n u m b e r s  m ay no t  b e  r eflec t e d  in t his  ve r sion.  For  t h ed efini tive  ve r sion  of t his  p u blica tion,  ple a s e  r ef e r  to  t h e  p u blish e d  sou rc e.  Youa r e  a dvise d  to  cons ul t  t h e  p u blish e r’s ve r sion  if you  wish  to  ci t e  t his  p a p er.This ve r sion  is b ein g  m a d e  av ailable  in  a cco r d a n c e  wit h  p u blish e r  policie s.S e e  h t t p://o rc a .cf.ac.uk/policies.h t ml for  u s a g e  policies.  Copyrigh t  a n d  m o r al  r i gh t sfor  p u blica tions  m a d e  available  in ORCA a r e  r e t ain e d  by t h e  copyrig h thold e r s .Editorial Pathogenesis and Virulence of Candida albicans and Candida glabrata Mariana Henriques 1,*, David Williams 2,* 1 Department of Biological Engineering, University of Minho, 4715-338 Braga, Portugal 2 Oral and Biomedical Sciences, School of Dentistry, College of Biomedical and Life Sciences, Cardiff University, Heath Park, Cardiff, CF14 4XY, UK * Correspondence: mcrh@deb.uminho.pt (M.H.); WilliamsDD@cardiff.ac.uk (D.W.) Received: date; Accepted: date; Published: date Abstract: Fungal infections in humans have historically received comparatively less attention than those caused by bacteria and viruses. This may, in part, stem from the relative differences in infection prevalence. However, the more widespread use of immunosuppressive therapy, invasive surgery and medical device use in modern medicine, has resulted in more frequent occurrence of human fungal infection. There are a number of fungi that can cause human disease. However, arguably it is species of the genus Candida that are most often encountered. There are over 150 Candida species that are widely encountered in the environment and in animal hosts, however, only a small number are opportunistic pathogens of humans. Candida albicans is a polymorphic yeast-like fungus and undoubtedly the species most often recovered from human infection. As such, the virulence of C. albicans and its susceptibility to antifungal agents are often investigated. More recently, the prevalence of infections caused by non-C. albicans Candida species have increased and amongst these, infections caused by Candida glabrata have received attention given the often higher tolerance to frequently used antifungals exhibited by this species. The papers presented in this Special Issue have focussed on aspects relating to host responses to Candida infection, the efficacy of novel therapeutic agents and also treatment regimes. The papers highlight novel findings in their respective areas, whilst also highlighting the need for further research in these key and largely under-researched areas of candidoses. Keywords: Candida albicans; Candida glabrata; Candida infection; virulence factors; pathogenicity  Several Candida species are considered to be opportunistic pathogens of humans. Generally these fungal microorganisms colonise mucosal surfaces of the body without causing damage. However, a changing environment can lead to microbial dysbiosis with an accompanying switch in the lifestyle of the Candida from a harmless commensal to an organism that causes disease. The manifestation of infection is frequently mild, and this is especially the case when topical infection occurs. However, in individuals who are severely immunocompromised, systemic infections can develop, and whilst these are relatively uncommon, they are associated with high patient mortality. The prognosis of a candidosis is dependent on numerous factors that relate to the virulence of the microorganism, the host’s response and the susceptibility of the Candida to therapeutic intervention. Compared with bacteria, the levels of our understanding of the virulence, host immune responses and extent of treatment options are limited. This Special Issue collates six papers that cover aspects relating to all of these research areas. Aspects of the host immune response to Candida have been considered by two articles [1, 2] in this Special Issue. The first of these by Braunsdorf et al., [1] is an elegant review of host immunity against C. albicans. The review acknowledges that whilst impaired host immunity has a significant role on the development of candidoses, it is also apparent that strain differences can also effect this process and thus influence whether commensal colonisation by C. albicans progresses to an infection state. Such strain-specific differences can lead to altered regulation at genomic, genetic, and epigenetic levels and this is made more complex by additional environmental factors.  As previously indicated, the most prevalent forms of candidoses are topical infections, and these frequently arise on moist mucosal surfaces as found in the mouth and vagina. One particularly important form of oral candidosis is chronic hyperplastic candidosis (CHC) given its suggested link with malignant cellular transformation. To better understand host immune responses in this infection, Williams et al [2] employed immunohistochemical staining to delineate the inflammatory cell infiltrate mounted by the host in response to hyphal invasion of the epithelium. In CHC, the mean proportion of T-cells (CD3+) in tissues was 15.6%, with the majority found in the lamina propria . B-cells (CD20+) were comparatively in much lower proportions (1.8%). Regarding T-cells, T-helper cells (CD4+) were more prevalent than cytotoxic T-cells (CD8+). The study concluded that a T-helper cell dominated immune response occurred in CHC that was likely driven by the invading Candida and was notably distinct from an inflammatory cell profile encountered in control squamous cell papilloma tissue sections. One of the difficulties in the management of candidoses is the limited number of effective antifungal agents that do not have associated host cell toxicity or at risk of development of resistance.  There is therefore a need for new and alternative antifungal agents that are also active against recalcitrant biofilms of the fungus. Increasingly, natural products such as those derived from plants, are being assessed for their antifungal effects. Such products frequently comprise a complex mixture of compounds that may each have antimicrobial effects on different microbial targets. As such, synergy may be evident with reduced likelihood of resistance development. In this Special Edition, two articles were focused on evaluation of such natural compounds. In the study by Guwca et al., [3] extracts of propolis (EEPs), obtained from Polish apiaries, were evaluated for their antifungal effects against C. albicans, with minimum fungicidal concentrations (MFC) evident between 0.08-1.25% (v/v). Synergistic antifungal effects against C. albicans occurred when EEPs were used in combination treatments with both fluconazole and voriconazole. At subinhibitory concentrations it was evident that the yeast-to-hyphal transformation of C. albicans was inhibited. EEPs were also effective against C. albicans biofilms on polystyrene surfaces at concentrations between 0.04% (v/v) and >1.25% (v/v), as well as C. glabrata and C. krusei biofilms on polyvinyl chloride and silicone catheters.  Similarly, in the study of Serra et al., [4], the anti-C. albicans activity of commercially available essential oils were compared with chlorhexidine and triclosan. Against planktonic C. albicans, all tested essential oils were inhibitory with minimum inhibitory concentrations (MICs) ranging between 0.06% (v/v) to 0.4% (v/v). Of note was that biofilms exhibited elevated resistance to these agents with minimum biofilm eradication concentrations reported at >1.5% (v/v). Importantly, for the essential oils cytotoxicity towards murine fibroblasts was at concentrations lower than the MICs which would be a limitation when developing these new treatments. One potential solution to reducing host cell toxicity from antifungal agents is to develop alternative formulations that retain desired antifungal properties whilst reducing damage to host cells. An excellent example of this is the use of a lipid formulation of amphotericin (AmB) such as AmBisome®, Abelcet® and AmB-L. The latter is a liposomal formulation complexed with DSPG and cholesterol which was investigated along with the deoxycholate (Deox) amphotericin formulation for activity against both C. albicans and C. glabrata in the study by Rodrigues and Henriques [5]. Experiments revealed that C. glabrata was generally more tolerant to the lipid and Deox formulations of AmB. When tested against biofilms the lipid formulation was deemed to have better therapeutic potential than AmB-Deox, as effective concentrations were at 10% of the maximum daily dose. Imbert et al [6], assessed the difficulties in preventing the development of candidemia that is associated with Candida biofilms on vascular catheters. One potential approach is to use very high concentrations of antifungal in antifungal lock therapies to sterilise catheters. This study evaluated existing data in the literature to determine the efficacy of a range of antifungal solutions used for lock therapy. It was concluded that whilst caspofungin, micafungin, anidulafungin and L-AmB were good candidates for lock therapy, they had to be used in combination with systemic therapy.  Author Contributions: D.W.W. and M.H. conceptualised and wrote the manuscript. Both authors have read and agreed to the published version of the manuscript. Funding:  This research received no external funding Acknowledgments: We are grateful to all authors and reviewers that participated in this Special Issue. Conflicts of Interest: The authors declare no conflict of interest. References 1. Braunsdorf, C.; LeibundGut-Landmann, S. Modulation of the Fungal-Host Interaction by the Intra-Species Diversity of C. albicans. Pathogens 2018, 7, 11. 2. Williams, A.; Williams, D.; Rogers, H.; Wei, X.; Lewis, M.; Wozniak, S.; Farnell, D.; Jones, A. Immunohistochemical Expression Patterns of Inflammatory Cells Involved in Chronic Hyperplastic Candidosis. Pathogens 2019, 8, 232. 3. Gucwa, K.; Kusznierewicz, B.; Milewski, S.; Van Dijck, P.; Szweda, P. Antifungal Activity and Synergism with Azoles of Polish Propolis. Pathogens 2018, 7, 56. 4. Serra, E.; Hidalgo-Bastida, L.A.; Verran, J.; Williams, D.; Malic, S. Antifungal Activity of Commercial Essential Oils and Biocides against Candida Albicans. Pathogens 2018, 7, 15. 5. Rodrigues, C.F.; Henriques, M. Liposomal and Deoxycholate Amphotericin B Formulations: Effectiveness against Biofilm Infections of Candida spp.. Pathogens 2017, 6, 62. 6. Imbert, C.; Rammaert, B. What Could Be the Role of Antifungal Lock-Solutions? From Bench to Bedside. Pathogens 2018, 7, 6.  

Pathogenesis and virulence of Candida albicans and Candida glabrata

Universidade do Minho: RepositoriUM

pathogensEditorialPathogenesis and Virulence of Candida albicans andCandida glabrataMariana Henriques 1,* and David Williams 2,*1 Department of Biological Engineering, University of Minho, 4715-338 Braga, Portugal2 Oral and Biomedical Sciences, School of Dentistry, College of Biomedical and Life Sciences,Cardiff University, Heath Park, Cardiff CF14 4XY, UK* Correspondence: mcrh@deb.uminho.pt (M.H.); WilliamsDD@cardiff.ac.uk (D.W.)Received: 2 September 2020; Accepted: 15 September 2020; Published: 16 September 2020 Abstract: Fungal infections in humans have historically received comparatively less attention thanthose caused by bacteria and viruses. This may, in part, stem from the relative differences in infectionprevalence. However, the more widespread use of immunosuppressive therapy, invasive surgeryand medical devices in modern medicine has resulted in a more frequent occurrence of human fungalinfection. There are a number of fungi that can cause human disease. However, it is arguably a speciesof the genus Candida that are most often encountered. There are over 150 Candida species that are widelyencountered in the environment and in animal hosts, however, only a small number are opportunisticpathogens of humans. Candida albicans is a polymorphic yeast-like fungus and undoubtedly thespecies most often recovered from human infection. As such, the virulence of C. albicans and itssusceptibility to antifungal agents are often investigated. More recently, the prevalence of infectionscaused by non-C. albicans Candida species have increased and, amongst these, infections caused byCandida glabrata have received attention given its often-higher tolerance to frequently used antifungalsexhibited by this species. The papers presented in this Special Issue have focused on aspects relatingto host responses to Candida infection, the efficacy of novel therapeutic agents and also treatmentregimes. The papers highlight novel findings in their respective areas, whilst also highlighting theneed for further research in these key and largely under-researched areas of candidoses.Keywords: Candida albicans; Candida glabrata; Candida infection; virulence factors; pathogenicitySeveral Candida species are considered to be opportunistic pathogens in humans. Generally,these fungal microorganisms colonise the mucosal surfaces of the body without causing damage.However, a changing environment can lead to microbial dysbiosis with an accompanying switch in thelifestyle of the Candida from a harmless commensal to an organism that causes disease. The manifestationof infection is frequently mild, and this is especially the case when topical infection occurs. However,in individuals who are severely immunocompromised, systemic infections can develop, and whilstthese are relatively uncommon, they are associated with high patient mortality. The prognosis ofa candidosis is dependent on numerous factors that relate to the virulence of the microorganism,the host’s response and the susceptibility of the Candida to therapeutic intervention. Compared withbacteria, the levels of our understanding of the virulence, host immune responses and extent oftreatment options are limited. This Special Issue collates six papers that cover aspects relating to all ofthese research areas.Aspects of the host immune response to Candida have been considered by two articles [1,2] inthis Special Issue. The first of these, by Braunsdorf et al., [1] is an elegant review of host immunityagainst C. albicans. The review acknowledges that whilst impaired host immunity has a significant rolein the development of candidoses, it is also apparent that strain differences can also affect this processPathogens 2020, 9, 0752; doi:10.3390/pathogens9090752 www.mdpi.com/journal/pathogensPathogens 2020, 9, 0752 2 of 3and thus influence whether commensal colonisation by C. albicans progresses to an infection state.Such strain-specific differences can lead to altered regulation at the genomic, genetic, and epigeneticlevels and this is made more complex by additional environmental factors.As previously indicated, the most prevalent forms of candidoses are topical infections, and thesefrequently arise on moist mucosal surfaces, as found in the mouth and vagina. One particularlyimportant form of oral candidosis is chronic hyperplastic candidosis (CHC) given its suggested linkwith malignant cellular transformation. To better understand host immune responses in this infection,Williams et al. [2] employed immunohistochemical staining to delineate the inflammatory cell infiltratemounted by the host in response to hyphal invasion of the epithelium. In CHC, the mean proportionof T-cells (CD3+) in tissues was 15.6%, with the majority found in the lamina propria. B-cells (CD20+)were, comparatively, present in much lower proportions (1.8%). Regarding T-cells, T-helper cells(CD4+) were more prevalent than cytotoxic T-cells (CD8+). The study concluded that a T-helpercell-dominated immune response occurred in CHC that was likely driven by the invading Candida andwas notably distinct from an inflammatory cell profile encountered in control squamous cell papillomatissue sections.One of the difficulties in the management of candidoses is the limited number of effectiveantifungal agents that do not have an associated host cell toxicity, or risk the development of resistance.There is, therefore, a need for new and alternative antifungal agents that are also active againstrecalcitrant biofilms of the fungus. Increasingly, natural products such as those derived from plants,are being assessed for their antifungal effects. Such products frequently comprise a complex mixtureof compounds that may each have antimicrobial effects on different microbial targets. As such,synergy may be evident with a reduced likelihood of resistance development. In this Special Edition,two articles were focused on the evaluation of such natural compounds. In the study by Guwca et al., [3]extracts of propolis (EEPs), obtained from Polish apiaries, were evaluated for their antifungal effectsagainst C. albicans, with minimum fungicidal concentrations (MFCs) evident between 0.08–1.25%(v/v). Synergistic antifungal effects against C. albicans occurred when EEPs were used in combinationtreatments with both fluconazole and voriconazole. At sub-inhibitory concentrations, it was evidentthat the yeast-to-hyphal transformation of C. albicans was reduced. EEPs were also effective againstC. albicans biofilms on polystyrene surfaces at concentrations between 0.04% (v/v) and >1.25% (v/v),as well as C. glabrata and C. krusei biofilms on polyvinyl chloride and silicone catheters.Similarly, in the study of Serra et al., [4], the anti-C. albicans activity of commercially availableessential oils was compared with chlorhexidine and triclosan. Against planktonic C. albicans, all testedessential oils were inhibitory with minimum inhibitory concentrations (MICs) ranging between 0.06 (v/v)and 0.4% (v/v). Of note, biofilms exhibited an elevated resistance to these agents with minimum biofilmeradication concentrations reported at >1.5% (v/v). Importantly, for the essential oils, cytotoxicitytowards murine fibroblasts was at concentrations lower than the MICs which would be a limitationwhen developing these new treatments.One potential solution to reduce host cell toxicity from antifungal agents is to develop alternativeformulations that retain desired antifungal properties whilst reducing the damage to host cells.An excellent example of this is the use of a lipid formulation of amphotericin (AmB) such as AmBisome®,Abelcet® and AmB-L. The latter is a liposomal formulation complexed with distearylphosphatidylglycerol (DSPG) and cholesterol which was investigated, along with the deoxycholate (Deox)amphotericin formulation, for activity against both C. albicans and C. glabrata in a study by Rodriguesand Henriques [5]. Experiments revealed that C. glabrata was generally more tolerant to the lipid andDeox formulations of AmB. When tested against biofilms, the lipid formulation was deemed to havea better therapeutic potential than AmB-Deox, as effective concentrations were at 10% of the maximumdaily dose.Imbert et al. [6], assessed the difficulties in preventing the development of candidemia that isassociated with Candida biofilms on vascular catheters. One potential approach is to use very highconcentrations of antifungal in antifungal lock therapies to sterilise catheters. This study evaluatedPathogens 2020, 9, 0752 3 of 3existing data in the literature to determine the efficacy of a range of antifungal solutions used for locktherapy. It was concluded that whilst caspofungin, micafungin, anidulafungin and L-AmB were goodcandidates for lock therapy, they had to be used in combination with a systemic therapy.Author Contributions: D.W. and M.H. conceptualised and wrote the manuscript. Both authors have read andagreed to the published version of the manuscript.Funding: This research received no external funding.Acknowledgments: We are grateful to all authors and reviewers that participated in this Special Issue.Conflicts of Interest: The authors declare no conflict of interest.References1. Braunsdorf, C.; LeibundGut-Landmann, S. Modulation of the Fungal-Host Interaction by the Intra-SpeciesDiversity of C. albicans. Pathogens 2018, 7, 11. [CrossRef] [PubMed]2. Williams, A.; Williams, D.; Rogers, H.; Wei, X.; Lewis, M.; Wozniak, S.; Farnell, D.; Jones, A.Immunohistochemical Expression Patterns of Inflammatory Cells Involved in Chronic HyperplasticCandidosis. Pathogens 2019, 8, 232. [CrossRef] [PubMed]3. Gucwa, K.; Kusznierewicz, B.; Milewski, S.; Van Dijck, P.; Szweda, P. Antifungal Activity and Synergismwith Azoles of Polish Propolis. Pathogens 2018, 7, 56. [CrossRef] [PubMed]4. Serra, E.; Hidalgo-Bastida, L.A.; Verran, J.; Williams, D.; Malic, S. Antifungal Activity of Commercial EssentialOils and Biocides against Candida albicans. Pathogens 2018, 7, 15. [CrossRef] [PubMed]5. Rodrigues, C.F.; Henriques, M. Liposomal and Deoxycholate Amphotericin B Formulations: Effectivenessagainst Biofilm Infections of Candida spp. Pathogens 2017, 6, 62. [CrossRef] [PubMed]6. Imbert, C.; Rammaert, B. What Could Be the Role of Antifungal Lock-Solutions? From Bench to Bedside.Pathogens 2018, 7, 6. [CrossRef] [PubMed]© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open accessarticle distributed under the terms and conditions of the Creative Commons Attribution(CC BY) license (http://creativecommons.org/licenses/by/4.0/).

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Pathogenesis and virulence of Candida albicans and Candida glabrata

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