Todd OA, Fidel PL Jr, Harro JM, Hilliard JJ, Tkaczyk C, Sellman BR, Noverr MC, Peters BM. Candida albicans Augments Staphylococcus aureus Virulence by Engaging the Staphylococcal agr Quorum Sensing System. mBio. 2019 Jun 4;10(3):e00910-19. doi: 10.1128/mBio.00910-19. PMID: 31164467; PMCID: PMC6550526.
Todd et al.’s research describes how Candida albicans augments Staphylococcus aureus virulence by the engagement of S. aureus’s accessory gene regulator (agr) quorum sensing system. Quorum sensing is a density-dependent communicative signaling system that regulates coordinated gene expression within a population.1 In bacteria such as S. aureus, the quorum sensing system relies on the accumulation of a signaling molecule that is produced, recognized, and only at certain concentrations, can modulate gene expression. The authors discovered that the agr virulence factor production, such as alpha-toxins, were increased and driven by the modulation of extracellular increase in pH (alkalinization) in co-culture with Candida in vitro. This is an eye-opening revelation of how a coinfection from these two pathogens can proliferate lethal synergism towards the host.2 S. aureus, which is a Gram-positive bacterium, contains an agr quorum-sensing system that senses the local concentrations of cyclic peptide signaling molecules (autoinducing peptides) as its own population density increases to stimulate specific gene expression patterns.3 The study utilized a murine intrabdominal infection (IAI) model and an S. aureus GFP reporter to reveal agr quorum sensing system activation in monomicrobial and polymicrobial in vivo and in vitro growth.2 The significance of this study is that very little was known about the complex “cross talk” interaction between microbes that change signaling pathways and shape health and diseases within humans and other species.
The study illustrated the synergistic virulence of C. albicans and S. aureus in mice, where intraperitoneal co-culture injection resulted in morbidity symptoms, such as hunching and slow reaction, around 12 hours post-inoculation.2 After one day, there was around a 10% survival rate of the co-infected mice and above a 95% survival rate in the mono-cultured mice who went on to survive up to ten days.2 This was fascinating, yet terrifying, to see how drastic lethal coinfections were compared to the mono-infections in mice. The authors found an increased expression of agr toxin production with the presence of C. albicans by qPCR in Figure 32, which wasn’t due to normal growth in measuring the colony forming units (CFUs)/mL clarified in Figure 2.2 The hemolytic activity was also tested to measure red blood cell lysis suggesting a greater hemolytic toxin production observed from co-culture compared to the mono-cultures in Figure 4.
Although the study pointed out the increase in alpha-toxin production, the question remained whether alpha-toxin production alone effected the survival rate and significantly drove lethal synergistic IAIs in mice. The authors concluded in Figure 6 that alpha-toxin was necessary in driving infection, but insufficient in driving lethality during co-infection.2 Perhaps the production of other S. aureus toxins or the heterogeneity of C. albicans strains could be the necessary contributing factor towards driving lethality during co-infection. It remains unclear whether or not the enhancement of agr alpha-toxin production is shared amongst all C. albicans strains to various degrees and responses. Lastly, insight into the bacterial-fungal quorum sensing cross-talk in the agr pathway could further the progress of developing therapies needed for reducing the severity of illness in patients with these co-infections.
References:
- Miller MB, Bassler BL. Quorum sensing in bacteria. Annu Rev Microbiol. 2001;55:165-99. doi: 10.1146/annurev.micro.55.1.165. PMID: 11544353.
- Todd OA, Fidel PL Jr, Harro JM, Hilliard JJ, Tkaczyk C, Sellman BR, Noverr MC, Peters BM. Candida albicans Augments Staphylococcus aureus Virulence by Engaging the Staphylococcal agr Quorum Sensing System. mBio. 2019 Jun 4;10(3):e00910-19. doi: 10.1128/mBio.00910-19. PMID: 31164467; PMCID: PMC6550526.
- Jenul C, Horswill AR. Regulation of Staphylococcus aureus Virulence. Microbiol Spectr. 2019 Apr 5;7(2):10.1128/microbiolspec.GPP3-0031-2018. doi: 10.1128/microbiolspec.GPP3-0031-2018. PMID: 30953424; PMCID: PMC6452892.
