The bacterial signalling molecule indole attenuates the virulence of the fungal pathogen Candida albicans

Abstract

Aims: Indole is a signalling molecule, produced by a number of Gram-positive and Gram-negative bacteria both in nature as well as clinical environments. Here, we explored the effect of bacterial indole and one of its main derivatives on the virulence of the fungal pathogen Candida albicans. Methods and Results: We found that indole and its derivate indole-3-acetonitrile (IAN) did not affect the viability of C. albicans. Interestingly, indole and IAN repressed C. albicans biofilm formation as well as the attachment of C. albicans to intestinal epithelial HT-29 cells and inhibited the ability of the yeast to make filaments that are the main virulence factor of C. albicans. In addition, we used the heterologous model host Caenorhabditis elegans to demonstrate in vivo that the presence of indole or IAN attenuates C. albicans infection (P = 0Á0188 and P < 0Á0001 for indole and IAN, respectively, compared to worms exposed to C. albicans DAY185 alone) and decreases fungal colonization in the nematode gut. Importantly, quantitative real-time polymerase chain reaction (qRT-PCR) results showed that in C. albicans, indole and IAN strongly stimulated the transcription of NRG1. Conclusions: Indole and IAN attenuates fungal virulence by regulating the transcription of NRG1, a transcriptional factor that influences filamentation and biofilm formation in C. albicans. Significance and Impact of the Study: Our findings indicate that the bacterial signalling molecules indole and its derivatives play an inter-kingdom role in dynamic network of microbiota and directly modulate the virulence of fungal C. albicans via NRG1.

Roles of Indole as an Interspecies and Interkingdom Signaling Molecule

“…For example, indole inhibits the attachment of the fungal pathogen Candida albicans to intestinal epithelial HT-29 cells [56] and reduces the production of the virulence factor staphyloxanthin in Staphylococcus aureus [57]; both of these studies demonstrated virulence reduction in a Caenorhabditis elegans model [56,57]. Indole also inhibits cyanobacterial blooms caused by the formation of periphyton biofilms [58], induces biofilm formation by rhizospheric Burkholderia unamae [59], and delays predation by Bdellovibrio bacteriovorus [60].…”

“…Hence, more potent, stable, non-toxic indole derivatives than indole have been proposed as potential antivirulence compounds. For example, plant-derived indolylacetonitrile reduces virulence factor production in P. aeruginosa, in which the compound is stable [42], indolylacetonitrile reduces the virulence of C. albicans more effectively than indole [56], 7-benzyloxyindole attenuates the virulence of S. aureus more than indole [57], and 6-chloroindole inhibits the growth of, and biofilm formation by, algal Cylindrotheca sp. by inducing Ca 2+ efflux [66].…”

Efficacy of 7‐benzyloxyindole and other halogenated indoles to inhibit Candida albicans biofilm and hyphal formation

“…and Penicillium sp., produce indole derivatives that have been reported to inhibit C. albicans biofilm formation and hyphal development (Wang et al ., 2012; You et al ., 2013). Although relatively few reports are available to conclude, indole and indole‐3‐acetonitrile have been shown to suppress biofilm maturation by C. albicans (Jayant et al ., 2012; Oh et al ., 2012). …”

Indole production by the tryptophanase TnaA in Escherichia coli is determined by the amount of exogenous tryptophan

“…Indeed, indole produced from just a few cells can protect a large population of E. coli against several antibiotics . Indole-regulated behaviours also extend to inter-species communication by affecting efflux-mediated multidrug resistance, flagella synthesis, virulence factor expression and host cell invasion by indole-non-producers like Salmonella enterica, Pseudomonas aeruginosa and even the yeast Candida albicans (Lee et al, 2009;Nikaido et al, 2011Nikaido et al, , 2012Oh et al, 2012;Raut et al, 2012). Finally, indole and other tryptophan-derived metabolites balance inflammation in the mammalian intestinal tract (Bansal et al, 2010;Keszthelyi et al, 2012;Nicholson et al, 2012) and strengthen the barrier function of epithelial tight junctions (Bansal et al, 2010;Keszthelyi et al, 2012;Nicholson et al, 2012).…”