Candidalysin drives epithelial signaling, neutrophil recruitment, and immunopathology at the vaginal mucosa

Infection and Immunity

Volumn 86, Issue 2, 2018, Pages

  Richardson, Jonathan P ^a   Willems, Hubertine M E ^b   Moyes, David L ^a   Shoaie, Saeed ^a   Barker, Katherine S ^b   Tan, Shir Lynn ^a   Palmer, Glen E ^b   Hube, Bernhard ^c,d   Naglik, Julian R ^a   Peters, Brian M ^b  

^a KING'S COLLEGE LONDON   (United Kingdom)

^b UNIVERSITY OF TENNESSEE HEALTH SCIENCE CENTER   (United States)

^c HANS KNÖLL INSTITUTE   (Germany)

^d FRIEDRICH SCHILLER UNIVERSITY JENA   (Germany)

Author keywords

Candida; Candidalysin; Epithelial cells; Immunopathogenesis; Mucosal immunity; Mucosal pathogens; Mycology; Vaginitis; Vulvovaginal

Indexed keywords

CALGRANULIN A; CANDIDALYSIN; CXCL1 CHEMOKINE; CXCL2 CHEMOKINE; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; INTERLEUKIN 1ALPHA; INTERLEUKIN 1BETA; INTERLEUKIN 6; PEPTIDE; UNCLASSIFIED DRUG; CYTOKINE; ECE1 PROTEIN, CANDIDA ALBICANS; FUNGAL PROTEIN; VIRULENCE FACTOR;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CANDIDA ALBICANS; CELL DAMAGE; CONTROLLED STUDY; CYTOKINE PRODUCTION; CYTOKINE RELEASE; DOSE; EPITHELIUM CELL; FEMALE; FUNGAL VIRULENCE; GENE EXPRESSION; GENE INDUCTION; HUMAN; HUMAN CELL; IMMUNOPATHOLOGY; INNATE IMMUNITY; MOUSE; NEUTROPHIL; NONHUMAN; PRIORITY JOURNAL; SIGNAL TRANSDUCTION; SQUAMOUS CELL CARCINOMA CELL LINE; UPREGULATION; VAGINA CANDIDIASIS; VAGINA EPITHELIUM; VAGINAL LAVAGE; ANIMAL; IMMUNOLOGY; METABOLISM; MICROBIOLOGY; MUCOSA; NEUTROPHIL CHEMOTAXIS; PATHOGENICITY; PATHOLOGY; VAGINA;

ANIMALS; CANDIDA ALBICANS; CANDIDIASIS, VULVOVAGINAL; CYTOKINES; EPITHELIAL CELLS; FEMALE; FUNGAL PROTEINS; HUMANS; MICE; MUCOUS MEMBRANE; NEUTROPHIL INFILTRATION; SIGNAL TRANSDUCTION; VAGINA; VIRULENCE FACTORS;

EID: 85040977343     PISSN: 00199567     EISSN: 10985522     Source Type: Journal    
DOI: 10.1128/IAI.00645-17     Document Type: Article

References (44)

1. Achkar JM, Fries BC. 2010. Candida infections of the genitourinary tract. Clin Microbiol Rev 23:253-273. https://doi.org/10.1128/CMR.00076-09
2. Sobel JD. 2007. Vulvovaginal candidosis. Lancet 369:1961-1971. https:// doi.org/10.1016/S0140-6736(07)60917-9
3. Sobel JD. 1997. Vaginitis. N Engl J Med 337:1896-1903. https://doi.org/ 10.1056/NEJM199712253372607
4. Fidel PL, Jr, Barousse M, Espinosa T, Ficarra M, Sturtevant J, Martin DH, Quayle AJ, Dunlap K. 2004. An intravaginal live Candida challenge in humans leads to new hypotheses for the immunopathogenesis of vulvovaginal candidiasis. Infect Immun 72:2939-2946. https://doi.org/10.1128/IAI.72.5.2939-2946.2004
5. Peters BM, Yano J, Noverr MC, Fidel PL, Jr. 2014. Candida vaginitis: when opportunism knocks, the host responds. PLoS Pathog 10:e1003965. https://doi.org/10.1371/journal.ppat.1003965
6. Peters BM, Palmer GE, Nash AK, Lilly EA, Fidel PL, Jr, Noverr MC. 2014. Fungal morphogenetic pathways are required for the hallmark inflammatory response during Candida albicans vaginitis. Infect Immun 82: 532-543. https://doi.org/10.1128/IAI.01417-13
7. Black CA, Eyers FM, Russell A, Dunkley ML, Clancy RL, Beagley KW. 1998. Acute neutropenia decreases inflammation associated with murine vaginal candidiasis but has no effect on the course of infection. Infect Immun 66:1273-1275
8. Moyes DL, Murciano C, Runglall M, Islam A, Thavaraj S, Naglik JR. 2011. Candida albicans yeast and hyphae are discriminated by MAPK signaling in vaginal epithelial cells. PLoS One 6:e26580. https://doi.org/10.1371/ journal.pone.0026580
9. Moyes DL, Murciano C, Runglall M, Kohli A, Islam A, Naglik JR. 2012. Activation of MAPK/c-Fos induced responses in oral epithelial cells is specific to Candida albicans and Candida dubliniensis hyphae. Med Microbiol Immunol 201:93-101. https://doi.org/10.1007/s00430-011-0209-y
10. Moyes DL, Runglall M, Murciano C, Shen C, Nayar D, Thavaraj S, Kohli A, Islam A, Mora-Montes H, Challacombe SJ, Naglik JR. 2010. A biphasic innate immune MAPK response discriminates between the yeast and hyphal forms of Candida albicans in epithelial cells. Cell Host Microbe 8:225-235. https://doi.org/10.1016/j.chom.2010.08.002
11. Bader O, Krauke Y, Hube B. 2008. Processing of predicted substrates of fungal Kex2 proteinases from Candida albicans, C. glabrata, Saccharomyces cerevisiae and Pichia pastoris. BMC Microbiol 8:116. https://doi.org/10.1186/1471-2180-8-116
12. Moyes DL, Wilson D, Richardson JP, Mogavero S, Tang SX, Wernecke J, Hofs S, Gratacap RL, Robbins J, Runglall M, Murciano C, Blagojevic M, Thavaraj S, Forster TM, Hebecker B, Kasper L, Vizcay G, Iancu SI, Kichik N, Hader A, Kurzai O, Luo T, Kruger T, Kniemeyer O, Cota E, Bader O, Wheeler RT, Gutsmann T, Hube B, Naglik JR. 2016. Candidalysin is a fungal peptide toxin critical for mucosal infection. Nature 532:64-68. https://doi.org/10.1038/nature17625
13. Cassone A, Sobel JD. 2016. Experimental models of vaginal candidiasis and their relevance to human candidiasis. Infect Immun 84:1255-1261. https://doi.org/10.1128/IAI.01544-15
14. Schaller M, Zakikhany K, Naglik JR, Weindl G, Hube B. 2006. Models of oral and vaginal candidiasis based on in vitro reconstituted human epithelia. Nat Protoc 1:2767-2773. https://doi.org/10.1038/nprot.2006.474
15. Zakikhany K, Naglik JR, Schmidt-Westhausen A, Holland G, Schaller M, Hube B. 2007. In vivo transcript profiling of Candida albicans identifies a gene essential for interepithelial dissemination. Cell Microbiol 9:2938-2954. https://doi.org/10.1111/j.1462-5822.2007.01009.x
16. Bosanquet DC, Harding KG, Ruge F, Sanders AJ, Jiang WG. 2012. Expression of IL-24 and IL-24 receptors in human wound tissues and the biological implications of IL-24 on keratinocytes. Wound Repair Regen 20:896-903. https://doi.org/10.1111/j.1524-475X.2012.00840.x
17. Ishida Y, Kondo T, Kimura A, Matsushima K, Mukaida N. 2006. Absence of IL-1 receptor antagonist impaired wound healing along with aberrant NF-kappaB activation and a reciprocal suppression of TGF-beta signal pathway. J Immunol 176:5598-5606. https://doi.org/10.4049/jimmunol.176.9.5598
18. Shirakata Y, Komurasaki T, Toyoda H, Hanakawa Y, Yamasaki K, Tokumaru S, Sayama K, Hashimoto K. 2000. Epiregulin, a novel member of the epidermal growth factor family, is an autocrine growth factor in normal human keratinocytes. J Biol Chem 275:5748-5753. https://doi.org/10.1074/jbc.275.8.5748
19. Stoll SW, Rittie L, Johnson JL, Elder JT. 2012. Heparin-binding EGF-like growth factor promotes epithelial-mesenchymal transition in human keratinocytes. J Investig Dermatol 132:2148-2157. https://doi.org/10.1038/jid.2012.78
20. Tomalka J, Ganesan S, Azodi E, Patel K, Majmudar P, Hall BA, Fitzgerald KA, Hise AG. 2011. A novel role for the NLRC4 inflammasome in mucosal defenses against the fungal pathogen Candida albicans. PLoS Pathog 7:e1002379. https://doi.org/10.1371/journal.ppat.1002379
21. Yano J, Lilly E, Barousse M, Fidel PL, Jr. 2010. Epithelial cell-derived S100 calcium-binding proteins as key mediators in the hallmark acute neutrophil response during Candida vaginitis. Infect Immun 78:5126-5137. https://doi.org/10.1128/IAI.00388-10
22. Yano J, Palmer GE, Eberle KE, Peters BM, Vogl T, McKenzie AN, Fidel PL, Jr. 2014. Vaginal epithelial cell-derived S100 alarmins induced by Candida albicans via pattern recognition receptor interactions are sufficient but not necessary for the acute neutrophil response during experimental vaginal candidiasis. Infect Immun 82:783-792. https://doi.org/10.1128/IAI.00861-13
23. Deguchi A, Tomita T, Omori T, Komatsu A, Ohto U, Takahashi S, Tanimura N, Akashi-Takamura S, Miyake K, Maru Y. 2013. Serum amyloid A3 binds MD-2 to activate p38 and NF-kappaB pathways in a MyD88-dependent manner. J Immunol 191:1856-1864. https://doi.org/10.4049/jimmunol.1201996
24. Sandri S, Rodriguez D, Gomes E, Monteiro HP, Russo M, Campa A. 2008. Is serum amyloid A an endogenous TLR4 agonist? J Leukoc Biol 83: 1174-1180. https://doi.org/10.1189/jlb.0407203
25. Yano J, Kolls JK, Happel KI, Wormley F, Wozniak KL, Fidel PL, Jr. 2012. The acute neutrophil response mediated by S100 alarmins during vaginal Candida infections is independent of the Th17-pathway. PLoS One 7:e46311. https://doi.org/10.1371/journal.pone.0046311
26. Bruno VM, Shetty AC, Yano J, Fidel PL, Jr, Noverr MC, Peters BM. 2015. Transcriptomic analysis of vulvovaginal candidiasis identifies a role for the NLRP3 inflammasome. mBio 6:e00182-15. https://doi.org/10.1128/ mBio.00182-15
27. Lasarte S, Samaniego R, Salinas-Munoz L, Guia-Gonzalez MA, Weiss LA, Mercader E, Ceballos-Garcia E, Navarro-Gonzalez T, Moreno-Ochoa L, Perez-Millan F, Pion M, Sanchez-Mateos P, Hidalgo A, Munoz-Fernandez MA, Relloso M. 2016. Sex hormones coordinate neutrophil immunity in the vagina by controlling chemokine gradients. J Infect Dis 213: 476-484. https://doi.org/10.1093/infdis/jiv402
28. Liu Y, Shetty AC, Schwartz JA, Bradford LL, Xu W, Phan QT, Kumari P, Mahurkar A, Mitchell AP, Ravel J, Fraser CM, Filler SG, Bruno VM. 2015. New signaling pathways govern the host response to C. albicans infection in various niches. Genome Res 25:679-689. https://doi.org/10.1101/ gr.187427.114
29. Yano J, Noverr MC, Fidel PL, Jr. 2017. Vaginal heparan sulfate linked to neutrophil dysfunction in the acute inflammatory response associated with experimental vulvovaginal candidiasis. mBio 8:e00211-17. https:// doi.org/10.1128/mBio.00211-17
30. Marcil A, Gadoury C, Ash J, Zhang J, Nantel A, Whiteway M. 2008. Analysis of PRA1 and its relationship to Candida albicans-macrophage interactions. Infect Immun 76:4345-4358. https://doi.org/10.1128/IAI.00588-07
31. Parish CR. 2006. The role of heparan sulphate in inflammation. Nat Rev Immunol 6:633-643. https://doi.org/10.1038/nri1918
32. Nash EE, Peters BM, Lilly EA, Noverr MC, Fidel PL, Jr. 2016. A murine model of Candida glabrata vaginitis shows no evidence of an inflammatory immunopathogenic response. PLoS One 11:e0147969. https://doi.org/10.1371/journal.pone.0147969
33. Matzinger P. 2002. The danger model: a renewed sense of self. Science 296:301-305. https://doi.org/10.1126/science.1071059
34. Joly S, Sutterwala FS. 2010. Fungal pathogen recognition by the NLRP3 inflammasome. Virulence 1:276-280. https://doi.org/10.4161/viru.1.4.11482
35. Borghi M, De Luca A, Puccetti M, Jaeger M, Mencacci A, Oikonomou V, Pariano M, Garlanda C, Moretti S, Bartoli A, Sobel J, van de Veerdonk FL, Dinarello CA, Netea MG, Romani L. 2015. Pathogenic NLRP3 inflammasome activity during Candida infection is negatively regulated by IL-22 via activation of NLRC4 and IL-1Ra. Cell Host Microbe 18:198-209. https://doi.org/10.1016/j.chom.2015.07.004
36. Jaeger M, Carvalho A, Cunha C, Plantinga TS, van de Veerdonk F, Puccetti M, Galosi C, Joosten LA, Dupont B, Kullberg BJ, Sobel JD, Romani L, Netea MG. 2016. Association of a variable number tandem repeat in the NLRP3 gene in women with susceptibility to RVVC. Eur J Clin Microbiol Infect Dis 35:797-801. https://doi.org/10.1007/s10096-016-2600-5
37. Livak KJ, Schmittgen TD. 2001. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402-408. https://doi.org/10.1006/meth.2001.1262
38. Casadevall A, Pirofski LA. 2003. The damage-response framework of microbial pathogenesis. Nat Rev Microbiol 1:17-24. https://doi.org/ 10.1038/nrmicro732
39. Jabra-Rizk MA, Kong EF, Tsui C, Nguyen MH, Clancy CJ, Fidel PL, Jr, Noverr M. 2016. Candida albicans pathogenesis: fitting within the hostmicrobe damage response framework. Infect Immun 84:2724-2739. https://doi.org/10.1128/IAI.00469-16
40. Gillum AM, Tsay EY, Kirsch DR. 1984. Isolation of the Candida albicans gene for orotidine-5=-phosphate decarboxylase by complementation of S. cerevisiae ura3 and E. coli pyrF mutations. Mol Gen Genet 198:179-182. https://doi.org/10.1007/BF00328721
41. Huang Da W, Sherman BT, Lempicki RA. 2009. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 37:1-13. https://doi.org/10.1093/nar/gkn923
42. Huang Da W, Sherman BT, Lempicki RA. 2009. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4:44-57. https://doi.org/10.1038/nprot.2008.211
43. Yano J, Fidel PL, Jr. 2011. Protocols for vaginal inoculation and sample collection in the experimental mouse model of Candida vaginitis. J Vis Exp 58:3382. https://doi.org/10.3791/3382
44. Schönherr FA, Sparber F, Kirchner FR, Guiducci E, Trautwein-Weidner K, Gladiator A, Sertour N, Hetzel U, Le GTT, Pavelka N, d'Enfert C, Bougnoux ME, Corti CF, LeibundGut-Landmann S. 2017. The intraspecies diversity of C. albicans triggers qualitatively and temporally distinct host responses that determine the balance between commensalism and pathogenicity. Mucosal Immunol 10:1335-1350. https://doi.org/10.1038/mi.2017.2