This article was downloaded by: [University of Calgary] On: 24 March 2015, At: 16:06 Publisher: Taylor & Francis Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Virulence Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/kvir20
Candida parapsilosis: An emerging pathogen developing its own identity Joseph M. Bliss
a
a
Department of Pediatrics, Women & Infants Hospital of Rhode Island, Warren Alpert, Medical School of Brown University Accepted author version posted online: 10 Feb 2015.
Click for updates To cite this article: Joseph M. Bliss (2015): Candida parapsilosis: An emerging pathogen developing its own identity, Virulence To link to this article: http://dx.doi.org/10.1080/21505594.2015.1008897
Disclaimer: This is a version of an unedited manuscript that has been accepted for publication. As a service to authors and researchers we are providing this version of the accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proof will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to this version also.
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Candida parapsilosis: An emerging pathogen developing its own identity Joseph M. Bliss Department of Pediatrics, Women & Infants Hospital of Rhode Island, Warren Alpert, Medical School of Brown University
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Email: [email protected]
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Keywords
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pt
ed
M
an
us
phagocytosis
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Downloaded by [University of Calgary] at 16:06 24 March 2015
Candida parapsilosis, candidiasis, virulence, host-defense, macrophage, neutrophil,
1
Candida species account for a sizeable proportion of healthcare-associated infections with an increasing frequency over the last decade. 1-3 Historically, C. albicans was the most frequent cause of these infections, accounting for 70-80% of isolates from infected patients. 4 Accordingly, studies involving virulence attributes of C. albicans and
ip t
its interactions with the host have dominated the Candida literature. However, infections
cr
caused by non-albicans species are increasing in frequency, and in many centers,
us
as the leading cause of invasive candidiasis. 1, 5 As the clinical importance of the nonalbicans species has garnered attention, so have efforts to understand their biology.
an
Importantly, these studies continue to identify important differences among non-albicans species and C. albicans, challenging the notion that lessons learned from study of C.
M
albicans will be broadly applicable to other pathogenic Candida.
ed
Recent epidemiologic surveys of invasive candidiasis have identified C. parapsilosis as the third most commonly isolated species, albeit with wide variation
pt
among centers, geographic region, and patient characteristics. 1, 5 Notably, C. parapsilosis has a significantly higher prevalence in neonates than other at risk
ce
populations, suggesting a unique susceptibility of neonates to infection with this species. 6-8 In this issue, Grózer et al. compare C. parapsilosis to C. albicans in regard to its ability to produce prostaglandins from arachidonic acid and interrogate the role of
Ac
Downloaded by [University of Calgary] at 16:06 24 March 2015
these species (C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei) have emerged
OLE2 in the process. 9 C. albicans produces prostaglandins, which are biologically active in mammalian cells and have immunomodulatory effects that may contribute to fungal virulence. 10 The authors in the current study detected a variety of prostaglandin compounds produced by both C. albicans and C. parapsilosis when the yeast were
2
cultured in the presence of arachidonic acid, with PGE2 and PGD2 at the highest concentrations for both species. However, disruption of the putative 9-desaturase gene, OLE2, which in C. albicans significantly decreases PGE2 production, 11 had no effect on PGE2 synthesis in C. parapsilosis. The OLE2-deficient strain did show
ip t
alterations in fatty acid composition, however, suggesting a role in fatty acid
cr
biosynthesis. Finally, a role for OLE2 in virulence was suggested by the finding that the
us
macrophages with somewhat higher efficiency than wild-type C. parapsilosis. These findings add to existing literature supporting a role for fatty acid biosynthesis pathways
an
in the virulence attributes of pathogenic fungi including Cryptococcus neoformans, 12 C. albicans, 13 and C. parapsilosis.14, 15 Despite the similarities, however, this study
M
highlights important differences between the species that may have relevance to unique
ed
attributes of these host-pathogen interactions.
As studies similar to these continue to gain momentum, host interactions unique
pt
to C. parapsilosis relative to C. albicans are increasingly being recognized. Studies from this same group have highlighted some key differences in both innate and adaptive
ce
immune responses to these related pathogens. Human macrophages undergo phagocytosis of C. parapsilosis with higher efficiency than C. albicans or C. glabrata, and murine J774.1 macrophages show faster migration toward C. parapsilosis. 16 The
Ac
Downloaded by [University of Calgary] at 16:06 24 March 2015
OLE2-deficient strain underwent phagocytosis and killing by human monocyte-derived
organism is also able to survive and undergo replication within the macrophage. Investigation of the transcriptional response of murine macrophages to C. parapsilosis
by microarray also demonstrated significant differences in the transcriptome following exposure compared to that of C. albicans. 17 T-cell responses to C. parapsilosis and C.
3
albicans are also quite unique. Whereas C. albicans induces a Th1-biased response, C. parapsilosis induces more of a Th2-type response characterized by higher amounts of IL-10 and less IFN-γ upon coincubation with human peripheral blood mononuclear cells (PBMCs). Additionally, coincubation of PBMCs with C. parapsilosis results in less
ip t
Th17 differentiation that C. albicans, accompanied by lower production of IL-17 and IL-
cr
22. 18
us
the innate immune system interact with these related species. Neutrophils have long been recognized to be key elements contributing to anti-fungal host defense. Like
an
macrophages, human neutrophils also undergo phagocytosis of C. parapsilosis yeast with much higher efficiency than C. albicans yeast, resulting in increased toxicity to the
M
former. 19 The process is markedly faster in neutrophils than macrophages. In kinetic assays, phagocytosis rates had reached a plateau within 5-10 minutes of incubation, 20
ed
whereas with macrophages phagocytosis was noted to continue beyond 3 hours. 16
pt
Neutrophils undergoing phagocytosis of each species likewise demonstrated differing morphology in scanning electron microscopic images, suggesting that different
ce
phagocytic pathways may be invoked by each species. 20 These studies also suggested a role for the S-type lectin, galectin-3, in the process of neutrophil phagocytosis. Indeed, galectin-3 deficient mice infected with C. albicans or C.
Ac
Downloaded by [University of Calgary] at 16:06 24 March 2015
Other groups have documented additional key differences in how components of
parapsilosis showed increased disease susceptibility relative to wild-type mice, although the manifestations of disease differed between the two species. 21 Host innate immune cells respond to pathogens by recognition of pathogen-
associated molecular patterns (PAMPs) through pattern recognition receptors (PRRs).
4
In the case of pathogenic fungi, PAMPs are largely comprised of cell wall components. “Mannan” refers to the collection of mannose polymers, covalently associated with protein, that make up the outermost layer of the fungal cell wall. Mannan is the major antigenic determinant of Candida species, and basic structural differences in the
ip t
composition of mannan between C. albicans and C. parapsilosis have been previously
cr
defined. 22, 23 Interactions between Candida mannan and various host PRRs are well
us
to C. albicans have been noted that are likely attributable to unique PAMPs. For example, C. albicans is bound and internalized by dendritic cells (DC) through binding
an
of N-linked mannan to DC-SIGN whereas C. parapsilosis interacts weakly. 25, 26 In contrast, C. parapsilosis induces a “fungipod” by DC through binding to mannose
M
receptor while C. albicans has a weaker effect. 27 Our understanding of how variability
ed
in cell surface makeup among species impacts host defense mechanisms is in its infancy and is an area ripe for investigation.
pt
Investigation of similarities and differences in pathogenesis among the various species of Candida was facilitated by whole genome sequencing of C. parapsilosis and
ce
5 other Candida species in 2009. 28 Methods for efficient gene disruption initially developed in C. albicans 29 have now been applied successfully to C. parapsilosis allowing efficient construction of targeted gene deletions. 30 Careful phenotypic
Ac
Downloaded by [University of Calgary] at 16:06 24 March 2015
described. 24 In some cases, differences in cellular response to C. parapsilosis relative
analyses of deletion mutants in relevant gene families have begun to highlight key similarities and differences between C. parapsilosis and C. albicans that will be
instrumental in defining the molecular aspects of their virulence. The emergence of non-albicans species as increasingly important pathogens in
5
invasive candidiasis is well documented in the literature and has captured the attention of the research community. Comparisons of virulence attributes and host-response to these species have begun to reveal both similarities as well as important differences in comparison to the wealth of information available from study of C. albicans. Differences
ip t
among species likely underlie important differences in pathogenesis, host immune
cr
mechanisms, and clinical manifestations, and continued efforts in this area are
us
Funding
The author was funded by Grant Number P20GM103537 from the National Institute of
an
General Medical Sciences (NIGMS), a component of the National Institutes of Health (NIH), and by funds from the Oh Zopfi Professorship for Pediatrics and Perinatal
ce
pt
ed
M
Research from Brown University and Women & Infants Hospital of Rhode Island.
Ac
Downloaded by [University of Calgary] at 16:06 24 March 2015
necessary to optimize prevention and therapeutic strategies.
6
References 1. Pfaller M, Neofytos D, Diekema D, Azie N, Meier-Kriesche HU, Quan SP, Horn D. Epidemiology and outcomes of candidemia in 3648 patients: data from the Prospective Antifungal Therapy (PATH Alliance(R)) registry, 2004-2008. Diagn Microbiol Infect Dis
ip t
2012; 74:323-31.
cr
2. Chen PY, Chuang YC, Wang JT, Sheng WH, Yu CJ, Chu CC, Hsueh PR, Chang SC,
us
candidemia at a teaching hospital in Northern Taiwan, in 2002 and 2010. J Microbiol Immunol Infect 2014; 47:95-103.
an
3. Arendrup MC, Bruun B, Christensen JJ, Fuursted K, Johansen HK, Kjaeldgaard P, Knudsen JD, Kristensen L, Moller J, Nielsen L, et al. National surveillance of fungemia
M
in Denmark (2004 to 2009). J Clin Microbiol 2011; 49:325-34.
ed
4. Beck-Sague C, Jarvis WR. Secular trends in the epidemiology of nosocomial fungal infections in the United States, 1980-1990. National Nosocomial Infections Surveillance
pt
System. J Infect Dis 1993; 167:1247-51.
5. Guinea J. Global trends in the distribution of Candida species causing candidemia.
ce
Clin Microbiol Infect 2014; 20 Suppl 6:5-10. 6. van Asbeck EC, Clemons KV, Stevens DA. Candida parapsilosis: a review of its epidemiology, pathogenesis, clinical aspects, typing and antimicrobial susceptibility. Crit
Ac
Downloaded by [University of Calgary] at 16:06 24 March 2015
Chen YC. Comparison of epidemiology and treatment outcome of patients with
Rev Microbiol 2009; 35:283-309. 7. Neu N, Malik M, Lunding A, Whittier S, Alba L, Kubin C, Saiman L. Epidemiology of candidemia at a Children's hospital, 2002 to 2006. Pediatr Infect Dis J 2009; 28:806-9. 8. Pammi M, Holland L, Butler G, Gacser A, Bliss JM. Candida parapsilosis is a
7
significant neonatal pathogen: a systematic review and meta-analysis. Pediatr Infect Dis J 2013; 32:e206-16. 9. Grozer Z, Toth A, Toth R, Kecskemeti A, Vagvolgyi C, Nosanchuk JD, Szekeres A,
acid and OLE2 is not required for their synthesis. Virulence 2015.
ip t
Gacser A. Candida parapsilosis produces prostaglandins from exogenous arachidonic
cr
10. Noverr MC, Phare SM, Toews GB, Coffey MJ, Huffnagle GB. Pathogenic yeasts
us
prostaglandins. Infect Immun 2001; 69:2957-63.
11. Erb-Downward JR, Noverr MC. Characterization of prostaglandin E2 production by
an
Candida albicans. Infect Immun 2007; 75:3498-505.
12. Chayakulkeeree M, Rude TH, Toffaletti DL, Perfect JR. Fatty acid synthesis is
M
essential for survival of Cryptococcus neoformans and a potential fungicidal target.
ed
Antimicrob Agents Chemother 2007; 51:3537-45. 13. Xu D, Sillaots S, Davison J, Hu W, Jiang B, Kauffman S, Martel N, Ocampo P, Oh
pt
C, Trosok S, et al. Chemical genetic profiling and characterization of small-molecule compounds that affect the biosynthesis of unsaturated fatty acids in Candida albicans. J
ce
Biol Chem 2009; 284:19754-64.
14. Nguyen LN, Gacser A, Nosanchuk JD. The stearoyl-coenzyme A desaturase 1 is essential for virulence and membrane stress in Candida parapsilosis through
Ac
Downloaded by [University of Calgary] at 16:06 24 March 2015
Cryptococcus neoformans and Candida albicans produce immunomodulatory
unsaturated fatty acid production. Infect Immun 2011; 79:136-45. 15. Nguyen LN, Trofa D, Nosanchuk JD. Fatty acid synthase impacts the pathobiology of Candida parapsilosis in vitro and during mammalian infection. PLoS One 2009; 4:e8421.
8
16. Toth R, Toth A, Papp C, Jankovics F, Vagvolgyi C, Alonso MF, Bain JM, Erwig LP, Gacser A. Kinetic studies of Candida parapsilosis phagocytosis by macrophages and detection of intracellular survival mechanisms. Front Microbiol 2014; 5:633. 17. Nemeth T, Toth A, Hamari Z, Falus A, Eder K, Vagvolgyi C, Guimaraes AJ,
ip t
Nosanchuk JD, Gacser A. Transcriptome profile of the murine macrophage cell
cr
response to Candida parapsilosis. Fungal Genet Biol 2014; 65:48-56.
us
Candida albicans and Candida parapsilosis induce different T-cell responses in human peripheral blood mononuclear cells. J Infect Dis 2013; 208:690-8.
an
19. Linden JR, Maccani MA, Laforce-Nesbitt SS, Bliss JM. High efficiency opsoninindependent phagocytosis of Candida parapsilosis by human neutrophils. Med Mycol
M
2010; 48:355-64.
ed
20. Linden JR, Kunkel D, Laforce-Nesbitt SS, Bliss JM. The role of galectin-3 in phagocytosis of Candida albicans and Candida parapsilosis by human neutrophils. Cell
pt
Microbiol 2013; 15:1127-42.
21. Linden JR, De Paepe ME, Laforce-Nesbitt SS, Bliss JM. Galectin-3 plays an
ce
important role in protection against disseminated candidiasis. Med Mycol 2013; 51:64151.
22. Goins TL, Cutler JE. Relative abundance of oligosaccharides in Candida species as
Ac
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18. Toth A, Csonka K, Jacobs C, Vagvolgyi C, Nosanchuk JD, Netea MG, Gacser A.
determined by fluorophore-assisted carbohydrate electrophoresis. J Clin Microbiol 2000; 38:2862-9.
23. Shibata N, Ikuta K, Imai T, Satoh Y, Satoh R, Suzuki A, Kojima C, Kobayashi H, Hisamichi K, Suzuki S. Existence of branched side chains in the cell wall mannan of
9
pathogenic yeast, Candida albicans. Structure-antigenicity relationship between the cell wall mannans of Candida albicans and Candida parapsilosis. J Biol Chem 1995; 270:1113-22.
with phagocytic cells. Med Microbiol Immunol 2013; 202:183-95.
ip t
24. Miramon P, Kasper L, Hube B. Thriving within the host: Candida spp. interactions
cr
25. Cambi A, Gijzen K, de Vries JM, Torensma R, Joosten B, Adema GJ, Netea MG,
us
uptake receptor for Candida albicans on dendritic cells. Eur J Immunol 2003; 33:532-8. 26. Cambi A, Netea MG, Mora-Montes HM, Gow NA, Hato SV, Lowman DW, Kullberg
an
BJ, Torensma R, Williams DL, Figdor CG. Dendritic cell interaction with Candida albicans critically depends on N-linked mannan. J Biol Chem 2008; 283:20590-9.
M
27. Neumann AK, Jacobson K. A novel pseudopodial component of the dendritic cell
ed
anti-fungal response: the fungipod. PLoS Pathog 2010; 6:e1000760. 28. Butler G, Rasmussen MD, Lin MF, Santos MA, Sakthikumar S, Munro CA, Rheinbay
pt
E, Grabherr M, Forche A, Reedy JL, et al. Evolution of pathogenicity and sexual reproduction in eight Candida genomes. Nature 2009; 459:657-62.
ce
29. Noble SM, Johnson AD. Strains and strategies for large-scale gene deletion studies of the diploid human fungal pathogen Candida albicans. Eukaryot Cell 2005; 4:298-309. 30. Holland LM, Schroder MS, Turner SA, Taff H, Andes D, Grozer Z, Gacser A, Ames
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Kullberg BJ, Romani L, Figdor CG. The C-type lectin DC-SIGN (CD209) is an antigen-
L, Haynes K, Higgins DG, et al. Comparative phenotypic analysis of the major fungal pathogens Candida parapsilosis and Candida albicans. PLoS Pathog 2014;
10:e1004365.
10
Virulence Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/kvir20
Candida parapsilosis: An emerging pathogen developing its own identity Joseph M. Bliss
a
a
Department of Pediatrics, Women & Infants Hospital of Rhode Island, Warren Alpert, Medical School of Brown University Accepted author version posted online: 10 Feb 2015.
Click for updates To cite this article: Joseph M. Bliss (2015): Candida parapsilosis: An emerging pathogen developing its own identity, Virulence To link to this article: http://dx.doi.org/10.1080/21505594.2015.1008897
Disclaimer: This is a version of an unedited manuscript that has been accepted for publication. As a service to authors and researchers we are providing this version of the accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proof will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to this version also.
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Candida parapsilosis: An emerging pathogen developing its own identity Joseph M. Bliss Department of Pediatrics, Women & Infants Hospital of Rhode Island, Warren Alpert, Medical School of Brown University
ip t
Email: [email protected]
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Keywords
ce
pt
ed
M
an
us
phagocytosis
Ac
Downloaded by [University of Calgary] at 16:06 24 March 2015
Candida parapsilosis, candidiasis, virulence, host-defense, macrophage, neutrophil,
1
Candida species account for a sizeable proportion of healthcare-associated infections with an increasing frequency over the last decade. 1-3 Historically, C. albicans was the most frequent cause of these infections, accounting for 70-80% of isolates from infected patients. 4 Accordingly, studies involving virulence attributes of C. albicans and
ip t
its interactions with the host have dominated the Candida literature. However, infections
cr
caused by non-albicans species are increasing in frequency, and in many centers,
us
as the leading cause of invasive candidiasis. 1, 5 As the clinical importance of the nonalbicans species has garnered attention, so have efforts to understand their biology.
an
Importantly, these studies continue to identify important differences among non-albicans species and C. albicans, challenging the notion that lessons learned from study of C.
M
albicans will be broadly applicable to other pathogenic Candida.
ed
Recent epidemiologic surveys of invasive candidiasis have identified C. parapsilosis as the third most commonly isolated species, albeit with wide variation
pt
among centers, geographic region, and patient characteristics. 1, 5 Notably, C. parapsilosis has a significantly higher prevalence in neonates than other at risk
ce
populations, suggesting a unique susceptibility of neonates to infection with this species. 6-8 In this issue, Grózer et al. compare C. parapsilosis to C. albicans in regard to its ability to produce prostaglandins from arachidonic acid and interrogate the role of
Ac
Downloaded by [University of Calgary] at 16:06 24 March 2015
these species (C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei) have emerged
OLE2 in the process. 9 C. albicans produces prostaglandins, which are biologically active in mammalian cells and have immunomodulatory effects that may contribute to fungal virulence. 10 The authors in the current study detected a variety of prostaglandin compounds produced by both C. albicans and C. parapsilosis when the yeast were
2
cultured in the presence of arachidonic acid, with PGE2 and PGD2 at the highest concentrations for both species. However, disruption of the putative 9-desaturase gene, OLE2, which in C. albicans significantly decreases PGE2 production, 11 had no effect on PGE2 synthesis in C. parapsilosis. The OLE2-deficient strain did show
ip t
alterations in fatty acid composition, however, suggesting a role in fatty acid
cr
biosynthesis. Finally, a role for OLE2 in virulence was suggested by the finding that the
us
macrophages with somewhat higher efficiency than wild-type C. parapsilosis. These findings add to existing literature supporting a role for fatty acid biosynthesis pathways
an
in the virulence attributes of pathogenic fungi including Cryptococcus neoformans, 12 C. albicans, 13 and C. parapsilosis.14, 15 Despite the similarities, however, this study
M
highlights important differences between the species that may have relevance to unique
ed
attributes of these host-pathogen interactions.
As studies similar to these continue to gain momentum, host interactions unique
pt
to C. parapsilosis relative to C. albicans are increasingly being recognized. Studies from this same group have highlighted some key differences in both innate and adaptive
ce
immune responses to these related pathogens. Human macrophages undergo phagocytosis of C. parapsilosis with higher efficiency than C. albicans or C. glabrata, and murine J774.1 macrophages show faster migration toward C. parapsilosis. 16 The
Ac
Downloaded by [University of Calgary] at 16:06 24 March 2015
OLE2-deficient strain underwent phagocytosis and killing by human monocyte-derived
organism is also able to survive and undergo replication within the macrophage. Investigation of the transcriptional response of murine macrophages to C. parapsilosis
by microarray also demonstrated significant differences in the transcriptome following exposure compared to that of C. albicans. 17 T-cell responses to C. parapsilosis and C.
3
albicans are also quite unique. Whereas C. albicans induces a Th1-biased response, C. parapsilosis induces more of a Th2-type response characterized by higher amounts of IL-10 and less IFN-γ upon coincubation with human peripheral blood mononuclear cells (PBMCs). Additionally, coincubation of PBMCs with C. parapsilosis results in less
ip t
Th17 differentiation that C. albicans, accompanied by lower production of IL-17 and IL-
cr
22. 18
us
the innate immune system interact with these related species. Neutrophils have long been recognized to be key elements contributing to anti-fungal host defense. Like
an
macrophages, human neutrophils also undergo phagocytosis of C. parapsilosis yeast with much higher efficiency than C. albicans yeast, resulting in increased toxicity to the
M
former. 19 The process is markedly faster in neutrophils than macrophages. In kinetic assays, phagocytosis rates had reached a plateau within 5-10 minutes of incubation, 20
ed
whereas with macrophages phagocytosis was noted to continue beyond 3 hours. 16
pt
Neutrophils undergoing phagocytosis of each species likewise demonstrated differing morphology in scanning electron microscopic images, suggesting that different
ce
phagocytic pathways may be invoked by each species. 20 These studies also suggested a role for the S-type lectin, galectin-3, in the process of neutrophil phagocytosis. Indeed, galectin-3 deficient mice infected with C. albicans or C.
Ac
Downloaded by [University of Calgary] at 16:06 24 March 2015
Other groups have documented additional key differences in how components of
parapsilosis showed increased disease susceptibility relative to wild-type mice, although the manifestations of disease differed between the two species. 21 Host innate immune cells respond to pathogens by recognition of pathogen-
associated molecular patterns (PAMPs) through pattern recognition receptors (PRRs).
4
In the case of pathogenic fungi, PAMPs are largely comprised of cell wall components. “Mannan” refers to the collection of mannose polymers, covalently associated with protein, that make up the outermost layer of the fungal cell wall. Mannan is the major antigenic determinant of Candida species, and basic structural differences in the
ip t
composition of mannan between C. albicans and C. parapsilosis have been previously
cr
defined. 22, 23 Interactions between Candida mannan and various host PRRs are well
us
to C. albicans have been noted that are likely attributable to unique PAMPs. For example, C. albicans is bound and internalized by dendritic cells (DC) through binding
an
of N-linked mannan to DC-SIGN whereas C. parapsilosis interacts weakly. 25, 26 In contrast, C. parapsilosis induces a “fungipod” by DC through binding to mannose
M
receptor while C. albicans has a weaker effect. 27 Our understanding of how variability
ed
in cell surface makeup among species impacts host defense mechanisms is in its infancy and is an area ripe for investigation.
pt
Investigation of similarities and differences in pathogenesis among the various species of Candida was facilitated by whole genome sequencing of C. parapsilosis and
ce
5 other Candida species in 2009. 28 Methods for efficient gene disruption initially developed in C. albicans 29 have now been applied successfully to C. parapsilosis allowing efficient construction of targeted gene deletions. 30 Careful phenotypic
Ac
Downloaded by [University of Calgary] at 16:06 24 March 2015
described. 24 In some cases, differences in cellular response to C. parapsilosis relative
analyses of deletion mutants in relevant gene families have begun to highlight key similarities and differences between C. parapsilosis and C. albicans that will be
instrumental in defining the molecular aspects of their virulence. The emergence of non-albicans species as increasingly important pathogens in
5
invasive candidiasis is well documented in the literature and has captured the attention of the research community. Comparisons of virulence attributes and host-response to these species have begun to reveal both similarities as well as important differences in comparison to the wealth of information available from study of C. albicans. Differences
ip t
among species likely underlie important differences in pathogenesis, host immune
cr
mechanisms, and clinical manifestations, and continued efforts in this area are
us
Funding
The author was funded by Grant Number P20GM103537 from the National Institute of
an
General Medical Sciences (NIGMS), a component of the National Institutes of Health (NIH), and by funds from the Oh Zopfi Professorship for Pediatrics and Perinatal
ce
pt
ed
M
Research from Brown University and Women & Infants Hospital of Rhode Island.
Ac
Downloaded by [University of Calgary] at 16:06 24 March 2015
necessary to optimize prevention and therapeutic strategies.
6
References 1. Pfaller M, Neofytos D, Diekema D, Azie N, Meier-Kriesche HU, Quan SP, Horn D. Epidemiology and outcomes of candidemia in 3648 patients: data from the Prospective Antifungal Therapy (PATH Alliance(R)) registry, 2004-2008. Diagn Microbiol Infect Dis
ip t
2012; 74:323-31.
cr
2. Chen PY, Chuang YC, Wang JT, Sheng WH, Yu CJ, Chu CC, Hsueh PR, Chang SC,
us
candidemia at a teaching hospital in Northern Taiwan, in 2002 and 2010. J Microbiol Immunol Infect 2014; 47:95-103.
an
3. Arendrup MC, Bruun B, Christensen JJ, Fuursted K, Johansen HK, Kjaeldgaard P, Knudsen JD, Kristensen L, Moller J, Nielsen L, et al. National surveillance of fungemia
M
in Denmark (2004 to 2009). J Clin Microbiol 2011; 49:325-34.
ed
4. Beck-Sague C, Jarvis WR. Secular trends in the epidemiology of nosocomial fungal infections in the United States, 1980-1990. National Nosocomial Infections Surveillance
pt
System. J Infect Dis 1993; 167:1247-51.
5. Guinea J. Global trends in the distribution of Candida species causing candidemia.
ce
Clin Microbiol Infect 2014; 20 Suppl 6:5-10. 6. van Asbeck EC, Clemons KV, Stevens DA. Candida parapsilosis: a review of its epidemiology, pathogenesis, clinical aspects, typing and antimicrobial susceptibility. Crit
Ac
Downloaded by [University of Calgary] at 16:06 24 March 2015
Chen YC. Comparison of epidemiology and treatment outcome of patients with
Rev Microbiol 2009; 35:283-309. 7. Neu N, Malik M, Lunding A, Whittier S, Alba L, Kubin C, Saiman L. Epidemiology of candidemia at a Children's hospital, 2002 to 2006. Pediatr Infect Dis J 2009; 28:806-9. 8. Pammi M, Holland L, Butler G, Gacser A, Bliss JM. Candida parapsilosis is a
7
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