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Effect of Candida albicans’ supernatant on biofilm formation and virulence factors of Pseudomonas aeruginosa through las/rhl System

BMC Microbiology volume 25, Article number: 60 (2025) Cite this article

Abstract

Pseudomonas aeruginosa (P. aeruginosa) and Candida albicans (C. albicans) are opportunistic pathogens whose mixed infections can exacerbate microbial dissemination and drug resistance, contributing to high mortality and morbidity rates among infected individuals. Few studies have explored the impact of C. albicans supernatant on P. aeruginosa, and the underlying mechanisms of such mixed infections remain unclear. In this study, we investigated the effects of C. albicans supernatant on biofilm formation and virulence factor activity in wild-type P. aeruginosa PAO1 and its quorum sensing-deficient mutants, ΔlasIrhlI and ΔlasRrhlR. Our results demonstrated that the biofilm formation capability and virulence were significantly higher in the PAO1 group compared to the ΔlasIrhlI and ΔlasRrhlR groups. Furthermore, exposure to C. albicans supernatant significantly enhanced both the biofilm formation and virulence of PAO1, whereas no significant changes were observed in the ΔlasIrhlI and ΔlasRrhlR mutants relative to their respective controls. These findings suggest that C. albicans supernatant may modulate P. aeruginosa biofilm formation and virulence via the las/rhl quorum sensing system.

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Introduction

Among the diverse interactions observed in the context of human infections, the communication between fungi and bacteria has garnered significant attention in recent years [1]. Pseudomonas aeruginosa (P. aeruginosa), a ubiquitously distributed environmental bacterium and opportunistic pathogen, demonstrates remarkable adaptability across various ecological niches. This adaptability contributes to its role in causing substantial morbidity and mortality, particularly in cases of acute nosocomial respiratory infections, such as ventilator-associated pneumonia (VAP), and chronic respiratory conditions, including cystic fibrosis (CF), non-cystic bronchiectasis, and chronic obstructive pulmonary disease (COPD) [2, 3]. Candida albicans (C. albicans) is an opportunistic pathogen capable of causing both superficial mucosal and life-threatening disseminated infections, particularly in immunocompromised individuals, such as those with AIDS, undergoing chemotherapy, receiving organ transplants, or possessing implanted medical devices [4]. Research has demonstrated [5,6,7,8,9] that P. aeruginosa and C. albicans are commonly co-isolated in the lung secretions of cystic fibrosis (CF) and ventilator-associated pneumonia (VAP) patients. These organisms represent the most frequent types of mixed bacterial and fungal infections encountered in P. aeruginosa clinical practice. In addition to the respiratory tract, these pathogens often co-infect or co-colonize multiple body sites, including the intestinal tract, burn wounds, the genitourinary tract, and skin surfaces [10]. A study by Navarro et al. [11] reported that the prognosis for patients with mixed infections of P. aeruginosa and C. albicans was significantly worse compared to those with bacterial infections alone. The emergence of drug-resistant strains of both P. aeruginosa and C. albicans has further complicated the treatment of mixed infections, leading to increased mortality rates and poorer patient outcomes. Consequently, elucidating the interactions between these two pathogens is clinically relevant for guiding the management of mixed infections.

The most critical determinants in the pathogenic mechanism of P. aeruginosa are biofilm formation and the presence of virulence factors. The Quorum Sensing (QS) system, also known as the density-sensing system, is a bacterial intercellular communication mechanism that plays a pivotal role in P. aeruginosa biofilm formation [12]. Additionally, the QS system regulates the production of various virulence factors, including pyocyanin, rhamnolipids, elastase, proteases, exotoxin A, and siderophores. Moreover, the QS system is crucial in mediating mixed infections involving P. aeruginosa and other microorganisms. Through the expression of virulence factors such as pyocyanin, rhamnolipids, elastase, and others regulated by the QS system, P. aeruginosa can inhibit or kill a variety of microorganisms, including C. albicans, Aspergillus fumigatus, and Staphylococcus aureus, during mixed infections [13,14,15].

A number of clinical and in vitro studies have indicated that Candida colonization increases the incidence of P. aeruginosa ventilator-associated pneumonia [16,17,18]. This suggests that P. aeruginosa and C. albicans coexist within the host, and their interspecies interactions determine the fate of microbial populations, potentially influencing the outcomes of diseases associated with mixed infections. However, the pathogenic mechanisms of these mixed infections are still not fully understood, and information regarding the effects and possible mechanisms of C. albicans supernatant on P. aeruginosa biofilm formation and virulence factors remains limited. Therefore, the aim of this study was to investigate the effect of C. albicans supernatant on P. aeruginosa, specifically focusing on the role of the QS system in mixed infections, to provide guidance for clinical treatment and the development of antimicrobial drugs.

Materials and methods

Experimental strain

P. aeruginosa wild-type strain PAO1, defective strains ΔlasIrhlI and ΔlasRrhlR, and C. albicans wild-type strain SC5314 were kindly provided by the Environmental Life Sciences Engineering Center at Nanyang Technological University, Singapore.

In vitro modeling of biological periplasm

C. albicans wild-type strain SC5314 was cultured overnight in YPD broth. The following day, the culture was centrifuged and subsequently filtered through a 0.22 μm filter membrane to obtain the C. albicans supernatant, which was stored for later use. P. aeruginosa wild-type strain PAO1 and the defective strains ΔlasIrhlI and ΔlasRrhlR were cultured overnight in LB broth. The next day, these cultures were diluted to an optical density (OD600) of 0.1, corresponding to approximately 107 CFU/mL, using 2×YPD medium. Equal volumes of C. albicans supernatant and sterile saline were added to 24-well plates containing PAO1, the defective strains ΔlasIrhlI and ΔlasRrhlR, along with sterile polyvinyl chloride (PVC) disc carriers. Biofilms were formed through static incubation at 37 °C for 24 and 72 h, with medium changes performed every 24 h.

Determination of biofilm by crystal violet semi-quantitative

The crystal violet-based assay is widely used to evaluate the early stages of bacterial biofilm formation [19]. Following the above treatment, the culture medium was carefully aspirated from each well, and the plate was gently washed three times with phosphate-buffered saline (PBS) to remove any loosely attached bacterial cells. The plate was then air-dried at room temperature. Subsequently, 0.1% (w/v) crystal violet was added to each well and allowed to stain the samples for 15 min. Excess crystal violet was removed by rinsing the wells three times with PBS. The crystal violet-stained biomass was then dissolved in 95% ethanol, and the absorbance was measured spectrophotometrically at OD550. The experiment was repeated three times to ensure reproducibility.

Determination of the colony counts in the biofilm by serial dilution

The colony count of biofilm was measured using the serial dilution method to evaluate the bacterial load of the biofilm after treatment [20]. Carriers from each group were washed three times with PBS to remove as many planktonic bacteria as possible. Each carrier was then placed into 10 mL centrifuge tubes containing 1 mL of sterile saline. The tubes were subjected to ultrasonic shaking and vortex mixing for 10 min each, to dislodge and suspend the biofilm-associated bacteria. Serial dilutions from each tube were plated onto LB agar plates for colony counting. This experiment was performed in triplicate to ensure reproducibility.

Scanning Electron Microscopy (SEM) to observe the morphology of biofilm

Biofilm formation in the groups was confirmed using scanning electron microscopy (SEM) [21]. Biofilm models were established as previously described. After treatment and rinsing, all samples were fixed in 2.5% glutaraldehyde at 4 °C for 24 h. Each sample was then rinsed three times with PBS for 10 min and dehydrated through a graded ethanol series (50%, 70%, 80%, 90%) for 15 min per step. The samples were subsequently immersed in 100% ethanol for three cycles of 10 min each to prevent drying. Finally, the samples were sputter-coated with gold and examined using SEM (Tescan VEGA 3, Czech Republic) at 30 kV. This experiment was performed in triplicate to ensure reproducibility.

Determination of proteolytic enzyme activity

Proteolytic enzyme activity was determined using the Congo red method [22]. The modeling method was the same as previously described. At 24 h and 72 h, 1 mL of bacterial suspension was extracted from each group and transferred to 10 mL sterilized centrifuge tubes. Excess bacterial cells were removed by centrifugation (5000 rpm, 15 min) and filtration through a 0.22 μm filter membrane to obtain the supernatant. From each sample, 150 µL of sterile supernatant was combined with 250 µL of azocasein-Tris/HCl solution (pH 7.8) and incubated for 4 h at 4 °C. The reaction was terminated by adding 1.2 mL of 10% trichloroacetic acid, followed by centrifugation (10,000 rpm, 10 min) to collect the supernatant. To 200 µL of the supernatant, 1.4 mL of 1 M NaOH solution was added. Finally, the absorbance was measured at OD440. The experiment was repeated three times under the same conditions.

Determination of elastase activity

Elastase activity was determined using the elastin-Congo red method. Sterile supernatants were obtained for each group as described in Method 6. One milliliter of sterile supernatant was combined with one milliliter of elastin-Congo red reaction buffer (ECR) in a 15 mL centrifuge tube and incubated at 37 °C with shaking at 220 rpm for 18 h. The reaction was then terminated by placing the tubes on ice at 4 °C. Insoluble ECR was removed by centrifugation at 4 °C, 5000 rpm for 15 min. Finally, elastase activity was measured indirectly by spectrophotometry at OD495.

Statistical analysis

Data were analyzed using SPSS 22 and are expressed as the mean ± standard deviation (χ ± s). Differences between two groups were evaluated using the t-test, while comparisons among three groups were analyzed using one-way analysis of variance (ANOVA). Statistical significance was set at P < 0.05. Statistical graphs were created using GraphPad Prism 8.0.

Results

Dose-dependent analysisc to clarify the effect of C. albicans supernatant on P. aeruginosa biofilm formation

Mixed infections of C. albicans and P. aeruginosa typically manifest as biofilms. We compared the effects of C. albicans supernatant on P. aeruginosa wild-type strain PAO1 and defective strains ΔlasIrhlI and ΔlasRrhlR using crystal violet semi-quantification and determined the colony counts in the biofilm by serial dilution. Our results indicated that the biofilm formation ability of PAO1 was significantly higher than that of both defective strains ΔlasIrhlI and ΔlasRrhlR (P < 0.05). The addition of C. albicans supernatant significantly increased the biofilm-forming capacity of PAO1 (P < 0.001), while there was no statistically significant difference in the biofilm-forming capacity of ΔlasIrhlI and ΔlasRrhlR (Fig. 1A, B).

Fig. 1
figure 1

In the dose-dependent analysisc, suspensions of P. aeruginosa, ΔlasIrhlI and ΔlasRrhlR were seeded in 24-well flat-bottomed polystyrene microtiter plates exposed to C.albicans’ supernatant for 24 h (A) and 72 h (B), and biofilm mass formation were quantified in triplicate. Values represent the mean ± standard deviation. *P < 0.05, **P < 0.01, ***P < 0.001. Data are shown as the average of three experiments

Full size image

Suspensions of P. aeruginosa wild-type strain PAO1, ΔlasIrhlI, and ΔlasRrhlR were seeded in 24-well flat-bottomed polystyrene microtiter plates and exposed to C. albicans supernatant for 24 and 72 h. Biofilm mass formation was quantified in triplicate. Bacterial counts of P. aeruginosa, ΔlasIrhlI, and ΔlasRrhlR treated with C. albicans supernatant in 2×YPD broth at 37 °C for 24 and 72 h were determined. The data indicated that C. albicans supernatant significantly increased the bacterial counts in the PAO1 group (Fig. 2A, B).

Fig. 2
figure 2

Bacterial counts of P. aeruginosa, ΔlasIrhlI and ΔlasRrhlR treated with C.albicans’ supernatant in 2×YPD broth at 37 °C for 24 h (A) and 72 h (B). Values represent the mean ± standard deviation. *P < 0.05, **P < 0.01, ***P < 0.001. Data are shown as the average of three experiments

Full size image

Effect of C. albicans supernatant on P. aeruginosa biofilm by SEM

Scanning electron microscopy (SEM) revealed that bacteria adhered to the vector surface in all groups after 24 h (Fig. 3). After 72 h, more bacterial colonies were observed adhering and aggregating on the vector surface (Fig. 4), accompanied by the formation of an extracellular matrix and early signs of biofilm development. The biofilm formation of PAO1 was significantly higher than that of the defective strains, ΔlasIrhlI and ΔlasRrhlR. Additionally, the PAO1 + C. albicans supernatant group exhibited higher biofilm formation compared to the PAO1 group (P < 0.05). No significant differences were observed in the carrier surface colonization or biofilm formation between the ΔlasIrhlI + C. albicans supernatant and ΔlasRrhlR + C. albicans supernatant groups compared to their respective control groups.

Fig. 3
figure 3

P. aeruginosa biofilm architectures after 24 h of C.albicans’ supernatant and saline treatment were examined by SEM (5,000× magnification)

Full size image
Fig. 4
figure 4

P. aeruginosa biofilm architectures after 72 h of C.albicans’ supernatant and saline treatment were examined by SEM (5,000× magnification)

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Effects of C. albicans supernatant on the virulence of P. aeruginosa

Measurements of protein hydrolase (Fig. 5A, B) and elastase (Fig. 6A, B) activities at 24 and 72 h showed that both protein hydrolase and elastase activities were significantly higher in the PAO1 group compared to the ΔlasIrhlI and ΔlasRrhlR groups (P < 0.001). Furthermore, both protein hydrolase and elastase activities were significantly elevated in the PAO1 + C. albicans supernatant group compared to the PAO1 group (P < 0.001). There was no statistically significant difference in protein hydrolase and elastase activities between the ΔlasIrhlI + C. albicans supernatant group and the ΔlasIrhlI group, nor between the ΔlasRrhlR + C. albicans supernatant group and the ΔlasRrhlR group.

Fig. 5
figure 5

Protein hydrolase activity of P. aeruginosa wild bacterium PAO1 and its defective strains ΔlasIrhlI and ΔlasRrhlR after treatment with saline and C.albicans’ supernatant for 24 (A) and 72 (B) h. Values represent the mean ± standard deviation. ***P < 0.001. Data are shown as the average of three experiments

Full size image
Fig. 6
figure 6

Analysis of elastase activity in control and C.albicans’ supernatant-treated groups for 24 (A) and 72 (B) hours, Values represent the mean ± standard deviation. *P < 0.05, **P < 0.01, ***P < 0.001. Data are shown as the average of three experiments

Full size image

Discussion

During mixed multiple microbial infections in humans, interactions between different microorganisms can modulate host responses, microbial virulence, and pathogenesis, thereby complicating patient treatment and the resolution of infections [23]. Mixed infections involving P. aeruginosa and C. albicans frequently lead to high levels of drug resistance and mortality, making them a significant concern in clinical settings.

Roux et al. found that C. albicans tracheo-bronchial colonization impairs macrophage function and promotes P. aeruginosa pneumonitis in rats [24]. Alam et al. demonstrated that C. albicans biofilm increases the resistance of P. aeruginosa to meropenem within their mixed-species biofilm [10]. These studies suggest that C. albicans can enhance the pathogenicity of P. aeruginosa in mixed infections. Therefore, this study aimed to investigate the role and possible mechanisms by which C. albicans supernatant affects P. aeruginosa.

Mixed infections of P. aeruginosa and C. albicans typically manifest as biofilms [25, 26]. Chen et al. demonstrated that ethanol production by C. albicans promotes biofilm formation in P. aeruginosa [27]. Phuengmaung et al. also found that C. albicans can enhance biofilm formation in P. aeruginosa by inducing phlosporin-associated protein production [28]. Our data align with these previous studies, showing that C. albicans supernatant favors PAO1 biofilm formation.

The quorum sensing (QS) system is a ubiquitous chemical signaling mechanism used for microbial interactions and has been implicated in the formation of biofilms in various microorganisms, including P. aeruginosa [29]. In this study, we found that the biofilm-forming ability of PAO1 was significantly higher than that of the ΔlasIrhlI and ΔlasRrhlR strains. The supernatant of C. albicans significantly enhanced PAO1 biofilm formation but had no effect on the biofilm formation of the double-deficient QS system strains. These findings suggest that C. albicans supernatant may promote P. aeruginosa biofilm formation by modulating the las/rhl QS system.

The P. aeruginosa las/rhl system regulates a variety of functional components that affect biofilm formation, including PELs, eDNA, chlorophyll, and rhamnolipids. PELs, a type of extracellular polysaccharide, are crucial matrix components of non-mucoid strains’ biofilms and are involved in the initial stages of surface attachment as well as the maintenance of biofilm integrity [30]. Sakuragi et al. [31] confirmed that the las system activates the transcription of the PEL gene, impacting PA14 biofilm formation through the study of P. aeruginosa deficient strains lasI, lasR, and lasIrhlI. Given that the production of these substances is closely linked to the P. aeruginosa las/rhl system, it can be inferred that C. albicans supernatants may regulate the production of these components via the las/rhl system, thereby promoting P. aeruginosa biofilm formation.

P. aeruginosa produces several virulence factors to enhance its pathogenicity and survival in the environment, with elastase A (LasA), elastase B (LasB), and alkaline protein hydrolase being the three major proteases [32]. In the present study, we found that C. albicans supernatant significantly increased elastase and proteolytic enzyme activities. Additionally, both the PAO1 group and the PAO1 + C. albicans supernatant group exhibited significantly higher elastase and proteolytic enzyme activities at 72 h compared to 24 h. This increase may be attributed to the fact that P. aeruginosa was still in the process of gradually forming biofilms during the first three days, during which bacterial metabolism was active and the accumulation of metabolites increased as the biofilm developed. We also found that PAO1 elastase and proteolytic enzyme activities were significantly higher than those of ΔlasIrhlI and ΔlasRrhlR. The addition of C. albicans supernatant significantly increased these activities in PAO1, while no significant differences were observed in the elastase and proteolytic enzyme activities between the defective strains ΔlasIrhlI and ΔlasRrhlR. These findings suggest that the enhancement of P. aeruginosa elastase and proteolytic enzyme activities by C. albicans supernatant may be related to the las/rhl system.

In summary, C. albicans supernatant was able to promote P. aeruginosa PAO1 biofilm formation and increase elastase and proteolytic enzyme activities, but had no effect on the biofilm formation, elastase, and proteolytic enzyme activities of the defective strains ΔlasIrhlI and ΔlasRrhlR. This suggests that the promotion of P. aeruginosa biofilm formation and the enhancement of elastase and proteolytic enzyme activities by C. albicans supernatant may be mediated through the las/rhl system. This study provides insight into a possible mechanism for the mixed infection of P. aeruginosa and C. albicans and offers support for further investigation into the interactions of these mixed infections for targeted prevention and treatment strategies. However, the specific substances in the supernatant of C. albicans responsible for these effects remain unidentified, and future experiments will focus on elucidating these components.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

C. albicans:

Candida albicans

CF:

Cystic fibrosis

COPD:

Chronic obstructive pulmonary disease

ECR:

Elastin-Congo red

LasA:

Elastase A

LasB:

Elastase B

P. aeruginosa:

Pseudomonas aeruginosa

PBS:

Phosphate-buffered saline

PVC:

Polyvinyl chloride

QS:

Quorum Sensing

SEM:

Scanning electron microscopy

VAP:

Ventilator-associated pneumonia

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Acknowledgements

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Funding

This study was supported by Guangxi Zhuang Autonomous Region Health Commission self funded research project (Z20190940); National Natural Science Foundation of China (81760743); Open Project of Key Laboratory of Longevity and Aging-related Diseases (Guangxi Medical University), Ministry of Education (KLLAD202204); Open Project of Guangxi Key Laboratory of Regenerative Medicine (GUIZAICHONGKAI 202206).

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  1. Ke Zhang, Yingying Huang and Yuting Jiang contributed equally to this work and should be considered co-first authors.

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  1. Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Qingxiu District, Nanning City, Guangxi Zhuang Autonomous Region, 530021, China

    Ke Zhang, Yingying Huang, Yuting Jiang, Tangjuan Liu, Jinliang Kong, Shuangqi Cai, Zhongwei Wen & Yiqiang Chen

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Contributions

YJ, YH and KZ conceived the study; TL, JK and SC conducted the experiments; ZW and YC analyzed the data; YJ, YH and KZ wear major contributors in writing the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yiqiang Chen.

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Zhang, K., Huang, Y., Jiang, Y. et al. Effect of Candida albicans’ supernatant on biofilm formation and virulence factors of Pseudomonas aeruginosa through las/rhl System. BMC Microbiol 25, 60 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12866-024-03604-x

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BMC Microbiology

ISSN: 1471-2180

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