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Candida/Staphylococcal Polymicrobial Intra-Abdominal Infection: Pathogenesis and Perspectives for a Novel Form of
Shannon K Esher1,2, Paul L Fidel3, Mairi C Noverr4,5
1Center of Excellence in Oral and Craniofacial Biology, School of Dentistry, Louisiana State University Health Sciences Center, New Orleans, LA 70119, USA. sesher1@tulane.edu.
Abstract:
Polymicrobial sepsis is difficult to diagnose and treat and causes significant morbidity and mortality, especially when fungi are involved. In vitro, synergism between Candida albicans and various bacterial species has been described for many years. Our laboratory has developed a murine model of polymicrobial intra-abdominal infection with Candida albicans and Staphylococcus aureus, demonstrating that polymicrobial infections cause high levels of mortality, while monoinfections do not. By contrast, closely related Candida dubliniensis does not cause synergistic lethality and rather provides protection against lethal polymicrobial infection. This protection is thought to be driven by a novel form of trained innate immunity mediated by myeloid-derived suppressor cells (MDSCs), which we are proposing to call "trained tolerogenic immunity". MDSC accumulation has been described in patients with sepsis, as well as in in vivo sepsis models. However, clinically, MDSCs are considered detrimental in sepsis, while their role in in vivo models differs depending on the sepsis model and timing. In this review, we will discuss the role of MDSCs in sepsis and infection and summarize our perspectives on their development and function in the spectrum of trained innate immune protection against fungal-bacterial sepsis.
Insights
Candida dubliniensis protects against lethal fungal-bacterial sepsis by inducing trained tolerogenic immunity via myeloid-derived suppressor cells (MDSCs). This contrasts with Candida albicans, highlighting a novel immune protective mechanism.
Area of Science:
- Immunology
- Microbiology
- Infectious Diseases
Background:
- Polymicrobial sepsis, especially with fungal involvement, presents diagnostic and therapeutic challenges, leading to significant morbidity and mortality.
- Synergistic interactions between Candida albicans and bacteria in vitro are well-documented.
- Existing murine models often focus on monomicrobial infections or specific polymicrobial combinations.
Purpose of the Study:
- To investigate the differential roles of Candida albicans and Candida dubliniensis in polymicrobial sepsis.
- To explore the underlying mechanisms of protection observed with Candida dubliniensis infection.
- To examine the role of myeloid-derived suppressor cells (MDSCs) in trained innate immunity during fungal-bacterial sepsis.
Main Methods:
- Development of a murine model of polymicrobial intra-abdominal infection using Candida albicans and Staphylococcus aureus.
- Comparison of mortality rates between polymicrobial and monomicrobial infections.
- Analysis of the protective effects of Candida dubliniensis in lethal polymicrobial sepsis models.
- Investigation of myeloid-derived suppressor cells (MDSCs) as mediators of trained innate immunity.
Main Results:
- Polymicrobial infections with Candida albicans and Staphylococcus aureus resulted in high mortality, unlike monoinfections.
- Candida dubliniensis conferred protection against lethal polymicrobial infection, rather than causing synergistic lethality.
- This protection is associated with a novel form of trained innate immunity mediated by MDSCs, termed 'trained tolerogenic immunity'.
Conclusions:
- Candida dubliniensis exhibits a unique protective role in fungal-bacterial sepsis, mediated by MDSCs and trained tolerogenic immunity.
- Understanding the dual role of MDSCs in sepsis is crucial, as they can be detrimental clinically but protective in specific experimental models.
- This research offers new perspectives on immune regulation and potential therapeutic strategies for complex polymicrobial infections.
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