VIRULENCE 2016, VOL. 7, NO. 7, 737–739 http://dx.doi.org/10.1080/21505594.2016.1206170

EDITORIAL

Secretory aspartyl proteinases induce neutrophil chemotaxis in vivo Arielle M. Bryana and Maurizio Del Poetaa,b a Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY, USA; bVeterans Administration Medical Center, Northport, NY, USA

ARTICLE HISTORY Received 20 June 2016; Accepted 21 June 2016 KEYWORDS Candida albicans; chemotaxis; Il-1b; IL-8; MIP-2; neutrophil; Saps; vaginal candidiasis

Candida albicans is a medically important human commensal fungus, which is capable of causing opportunistic infections of the skin, oral cavity, gastrointestinal tract and vascular system. It is the fourth leading cause of nosocomial infections and has a mortality rate of 35%.1,2 Additionally it is responsible for causing the second most common vaginal infection and affects nearly 75% of all women during their lifetimes.3 Despite the importance of this pathogen, there is still much that is unknown about the development of candida-associated diseases. Understanding the virulence factors and progression of disease remains an important goal in the field. Secretory aspartyl proteinases (Saps) are a family of 10 extracellular proteinases produced by C. albicans.4 Of these 10 members, Sap2 is the most abundant.4 Early studies on Saps revealed a correlation between in vitro Sap proteolytic activity and virulence of Candida species.4,5 By 1988 these proteinases were found to have functions that lend to the attachment and penetration stages of C. albicans infection.6,7 Since this initial discovery, much work has been done to establish the importance of Saps in mucosal infections, such as vaginal candidiasis.4 It has long been thought that neutrophils play a central role in immune defense against invasive C. albicans infections. This is because neutrophils are efficient at killing C. albicans8,9 and neutrophil deficiency is a known risk factor for Candida infection.10 Experiments in mice also support the importance of neutrophils. Indeed, neutrophil depletion in mice results in increased susceptibility to systemic, vaginal, and oropharyngeal candidiasis.11,12 Despite these

findings, recent work has revealed that in the case of vaginal candidiasis, inflammation associated with neutrophil infiltration may exacerbate the disease and add to tissue damage and pathology.13,14 Interestingly, it was found that Saps are capable of modulating interactions between C. albicans and human neutrophils by inducing chemotaxis in vitro.15,16 Studies with Sap knockout strains showed significantly less neutrophil recruitment, as well as altered recognition and killing by neutrophils.15,17 Furthermore, purified Saps were found to be capable of mediating vaginitis in mice and inducing inflammatory response independently of proteolytic activity.18-20 In the current issue of Virulence, Elena Gabrielli and colleagues further explore the role of Saps in vaginal candidiasis. They show how Sap2 and Sap6 are capable of directly inducing neutrophil migration independently of enzyme activity, and are also capable of inducing chemoattractive cytokines, macrophage inflammato ry protein 2 (MIP-2) and interleukin 8 (IL-8) in vaginal epithelial cells to further enhance neutrophil recruitment (Fig. 1).21 Additionally, they show that some factor produced during experimental vaginal infection with C. albicans (produced by either pathogen or host), but not Sap2 or 6, modulates the killing activity of neutrophils (Fig. 1).21 These experiments, which utilized cell free vaginal fluids from Sap or Candida exposed vaginal epithelium, are particularly novel as they are an important first step toward identifying the cause of neutrophil inhibition during Candida infection. Together these findings are important progress toward the mechanisms of vaginal candidiasis, and provide results that

CONTACT Maurizio Del Poeta [email protected] Department of Molecular Genetics and Microbiology, Stony Brook University, 150 Life Science Building, Stony Brook, NY 11794, USA. Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/kvir. Comment on: Gabrielli E, et al. In vivo induction of neutrophil chemotaxis by secretory aspartyl proteinases of Candida albicans. Virulence 2016; 7(7):819-825; http://dx.doi.org/10.1080/21505594.2016.1184385 © 2016 Taylor & Francis

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A. M. BRYAN AND M. DEL POETA

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Figure 1. Interaction of Saps with neutrophils and vaginal epithelium. Saps are capable of directly inducing neutrophil migration and are capable of inducing chemoattractive cytokines, macrophage inflammatory protein 2 (MIP-2) and interleukin 8 (IL-8) in vaginal epithelial cells to further enhance neutrophil recruitment. An unknown factor produced during experimental vaginal infection with C. albicans modulates the killing activity of neutrophils.

encourage the further study of anti-Sap therapies as well as future work into soluble factors of pathogen or host origin, which may modulate and dampen neutrophil killing.

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Disclosure of potential conflicts of interest Maurizio Del Poeta is a cofounder and CSO of MicroRid Technologies, Inc.

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Funding This work was supported by NIH grants AI56168, AI100631, AI116420 and by a Merit Review grant I01BX002624 from the Veterans Affairs Program in Biomedical Laboratory Research and Development to MDP and T32AI007539 to AMB. MDP is Burroughs Wellcome Investigator in Infectious Diseases.

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[15] Hornbach A, Heyken A, Schild L, Hube B, L€offler J, Kurzai O. The glycosylphosphatidylinositol-anchored protease Sap9 modulates the interaction of Candida albicans with human neutrophils. Infect Immun 2009; 77:5216-24. PMID:19805528; http://dx.doi.org/10.1128/ IAI.00723-09 [16] Ran Y, Iwabuchi K, Yamazaki M, Tsuboi R, Ogawa H. Secreted aspartic proteinase from Candida albicans acts as a chemoattractant for peripheral neutrophils. J Dermatol Sci 2013; 72:191-3. PMID:23849944; http://dx.doi.org/10.1016/j. jdermsci.2013.06.006 [17] Bruno VM, Shetty AC, Yano J, Fidel PL, Noverr MC, Peters BM. Transcriptomic analysis of vulvovaginal candidiasis identifies a role for the NLRP3 inflammasome. MBio 2015; 6; 1-15. PMID:25900651; http://dx.doi.org/ 10.1128/mBio.00182-15. [18] Pericolini E, Gabrielli E, Amacker M, Kasper L, Roselletti E, Luciano E, Sabbatini S, Kaeser M, Moser C, Hube B, et al. Secretory Aspartyl Proteinases Cause Vaginitis and Can Mediate Vaginitis Caused by Candida albicans in

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Mice. MBio 2015; 6:e00724. PMID:26037125; http://dx. doi.org/10.1128/mBio.00724-15 [19] Gabrielli E, Pericolini E, Luciano E, Sabbatini S, Roselletti E, Perito S, Kasper L, Hube B, Vecchiarelli A. Induction of caspase-11 by aspartyl proteinases of Candida albicans and implication in promoting inflammatory response. Infect Immun 2015; 83:1940-8. PMID:25712931; http:// dx.doi.org/10.1128/IAI.02895-14 [20] Pietrella D, Rachini A, Pandey N, Schild L, Netea M, Bistoni F, Hube B, Vecchiarelli A. The Inflammatory response induced by aspartic proteases of Candida albicans is independent of proteolytic activity. Infect Immun 2010; 78:4754-62. PMID:20713630; http://dx.doi.org/ 10.1128/IAI.00789-10 [21] Gabrielli E, Sabbatini S, Roselletti E, Kasper L, Perito S, Hube B, Cassone A, Vecchiarelli A, Pericolini E. In vivo induction of neutrophil chemotaxis by secretory aspartyl proteinases of Candida albicans. Virulence 2016; 7(7): 819-825; PMID:27127904; http://dx.doi. org/10.1080/21505594.2016.1184385

Secretory aspartyl proteinases induce neutrophil chemotaxis in vivo.

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