Enterococcus faecalis suppresses Staphylococcus aureus-induced NETosis and promotes bacterial survival in polymicrobial infections


Enterococcus faecalis is an opportunistic pathogen that is frequently co-isolated with other microbes in wound infections. While E. faecalis can subvert the host immune response and promote the survival of other microbes via interbacterial synergy, little is known about the impact of E. faecalis-mediated immune suppression on co-infecting microbes. The authors of this article, led by GCIR Professor Kimberly Kline, hypothesized that E. faecalis can attenuate neutrophil-mediated responses in mixed-species infection to promote survival of the co-infecting species. They found that neutrophils control E. faecalis infection via phagocytosis, ROS production, and degranulation of azurophilic granules, but it does not trigger neutrophil extracellular trap formation (NETosis). However, E. faecalis attenuates Staphylococcus aureus-induced NETosis in polymicrobial infection by interfering with histone citrullination, suggesting E. faecalis can actively suppress NETosis in neutrophils. Residual S. aureus-induced NETs that remain during co-infection do not impact E. faecalis, further suggesting that E. faecalis possess mechanisms to evade or survive NET-associated killing mechanisms. E. faecalis-driven reduction of NETosis corresponds with higher S. aureus survival, indicating that this immunomodulating effect could be a risk factor in promoting virulence during polymicrobial infections. These findings highlight the complexity of the immune response to polymicrobial infections and suggest that attenuated pathogen-specific immune responses contribute to pathogenesis in the mammalian host.

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Why is this important?

Chronic infections, such as those in cystic fibrosis and diabetic wounds, often involve a variety of bacterial species, making them more difficult to eliminate and increasing the likelihood of antibiotic resistance. These microbial communities employ several mechanisms to enhance their survival, such as the exchange of metabolites as energy sources, the formation of biofilms to resist immune and antibiotic actions, and the transmission of virulence factors between community members. This study aimed to expand knowledge of these processes and to analyse the influence of polymicrobial infection on the host immune response.

Injured or infected tissues are first infiltrated by neutrophils, which are one of the main types of leukocytes involved in this type of immune response. Because of this, there is a marked presence of neutrophil infiltration in the initial three days of wound infection, indicating their involvement in the initial decrease in bacterial load. However, neutrophils are unable to completely eradicate the infection and prevent its persistence.

This study demonstrates that neutrophils use different mechanisms to eliminate E. faecalis and S. aureus. Furthermore, in the presence of E. faecalis, the bacterial load of S. aureus increases compared to infection by a single species, and this is shown to occur through a mechanism of immunomodulation. Therefore, E. faecalis is a risk factor in polymicrobial S. aureus infection by affecting the neutrophil immune response.

As infections are often polymicrobial, future immunotherapies designed to support the immune clearance of pathogens will need to take this complexity into account to ensure treatment efficacy and prevent the development of antibiotic resistance.

©The Author(s) 2023. Confocal microscopy (single slice) image of mouse neutrophils after undergoing NETosis (triggered by ionomycin). Can see DNA in cyan (stained with Syto9), Citrullinated histone in magenta, and myeloperoxidase in green.

©The Author(s) 2023. Transmission Electron Microscopy image of a mouse neutrophil infected with E. faecalis bacteria, taken at 24h post-infection.

21 Dec 2023