RESUMEN
Cytolytic proteins and peptide toxins are classical virulence factors of several bacterial pathogens which disrupt epithelial barrier function, damage cells and activate or modulate host immune responses. Such toxins have not been identified previously in human pathogenic fungi. Here we identify the first, to our knowledge, fungal cytolytic peptide toxin in the opportunistic pathogen Candida albicans. This secreted toxin directly damages epithelial membranes, triggers a danger response signalling pathway and activates epithelial immunity. Membrane permeabilization is enhanced by a positive charge at the carboxy terminus of the peptide, which triggers an inward current concomitant with calcium influx. C. albicans strains lacking this toxin do not activate or damage epithelial cells and are avirulent in animal models of mucosal infection. We propose the name 'Candidalysin' for this cytolytic peptide toxin; a newly identified, critical molecular determinant of epithelial damage and host recognition of the clinically important fungus, C. albicans.
Asunto(s)
Candida albicans/metabolismo , Candida albicans/patogenicidad , Citotoxinas/metabolismo , Proteínas Fúngicas/toxicidad , Micotoxinas/toxicidad , Factores de Virulencia/metabolismo , Calcio/metabolismo , Candida albicans/inmunología , Candidiasis/metabolismo , Candidiasis/microbiología , Candidiasis/patología , Permeabilidad de la Membrana Celular/efectos de los fármacos , Citotoxinas/genética , Citotoxinas/toxicidad , Células Epiteliales/efectos de los fármacos , Células Epiteliales/inmunología , Células Epiteliales/patología , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Interacciones Huésped-Patógeno/inmunología , Humanos , Membrana Mucosa/microbiología , Membrana Mucosa/patología , Micotoxinas/genética , Micotoxinas/metabolismo , Transducción de Señal/efectos de los fármacos , Virulencia/efectos de los fármacos , Factores de Virulencia/genética , Factores de Virulencia/toxicidadRESUMEN
Candida albicans produces an important virulence factor, the hypha-associated Ece1-derived secreted peptide toxin candidalysin, which is crucial for the establishment of mucosal and systemic infections. C. albicans has also long been known to be hemolytic, yet the hemolytic factor has not been clearly identified. Here, we show that candidalysin is the hemolytic factor of C. albicans. Its hemolytic activity is modulated by fragments of another Ece1 peptide, P7. Hemolysis by candidalysin can be neutralized by the purinergic receptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS). PPADS also affects candidalysin's ability to intercalate into synthetic membranes. We also describe the neutralization potential of two anti-candidalysin nanobodies, which are promising candidates for future anti-Candida therapy. This work provides evidence that the historically proposed hemolytic factor of C. albicans is in fact candidalysin and sheds more light on the complex roles of this toxin in C. albicans biology and pathogenicity.
Asunto(s)
Candida albicans , Hemólisis , Proteínas Fúngicas , Candida , Membrana Mucosa , Factores de Virulencia/toxicidadRESUMEN
The interaction between Candida albicans and its host cells is characterized by a complex interplay between the expression of fungal virulence factors, which results in adherence, invasion and cell damage, and the host immune system, which responds by secreting proinflammatory cytokines, activating antimicrobial activities and killing the fungal pathogen. In this review we describe this interplay by taking a closer look at how C. albicans pathogenicity is induced and executed, how the host responds in order to prevent and clear an infection, and which mechanisms C. albicans has evolved to bypass these immune responses to avoid clearance. Furthermore, we review studies that show how the presence of other microorganisms affects this interplay.