Candida species are the most common infectious fungal species in humans; out of the approximately 150 known species, Candida albicans is the leading pathogenic species, largely affecting immunocompromised individuals. Apart from its role as the primary etiology for various types of candidiasis, C. albicans is known to contribute to polymicrobial infections. Polymicrobial interactions, particularly between C. albicans and bacterial species, have gained recent interest in which polymicrobial biofilm virulence mechanisms have been studied including adhesion, invasion, quorum sensing, and development of antimicrobial resistance. These trans-kingdom interactions, either synergistic or antagonistic, may help modulate the virulence and pathogenicity of both Candida and bacteria while uniquely impacting the pathogen-host immune response. As antibiotic and antifungal resistance increases, there is a great need to explore the intermicrobial cross-talk with a focus on the treatment of Candida-associated polymicrobial infections. This article explores the current literature on the interactions between Candida and clinically important bacteria and evaluates these interactions in the context of pathogenesis, diagnosis, and disease management.

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Invasive Staphylococcus aureus infections account for 15 to 50% of fatal bloodstream infections annually. These disseminated infections often arise without a defined portal of entry into the host but cause high rates of mortality. The fungus Candida albicans and the Gram-positive bacterium S. aureus can form polymicrobial biofilms on epithelial tissue, facilitated by the C. albicans adhesin encoded by ALS3. While a bacterium-fungus interaction is required for systemic infection, the mechanism by which bacteria disseminate from the epithelium to internal organs is unclear. In this study, we show that highly immunogenic C. albicans hyphae attract phagocytic cells, which rapidly engulf adherent S. aureus and subsequently migrate to cervical lymph nodes. Following S. aureus-loaded phagocyte translocation from the mucosal surface, S. aureus produces systemic disease with accompanying morbidity and mortality. Our results suggest a novel role for the host in facilitating a bacterium-fungus infectious synergy, leading to disseminated staphylococcal disease.

ABSTRACT Bacterial biofilms are responsible for a variety of serious human infections and are notoriously difficult to treat due to their recalcitrance to antibiotics. Further work is necessary to elicit a full understanding of the mechanism of this antibiotic tolerance. The arginine deiminase (ADI) pathway is responsible for bacterial pH maintenance and is highly expressed during biofilm growth in multiple bacterial species. Using the group A Streptococcus (GAS) as a model human pathogen, the ADI pathway was demonstrated to contribute to biofilm growth. The inability of antibiotics to reduce GAS populations when in a biofilm was demonstrated by in vitro studies and a novel animal model of nasopharyngeal infection. However, disruption of the ADI pathway returned GAS biofilms to planktonic levels of antibiotic sensitivity, suggesting the ADI pathway is influential in biofilm-related antibiotic treatment failure and provides a new strategic target for the treatment of biofilm infections in GAS and potentially numerous other bacterial species. IMPORTANCE Biofilm-mediated bacterial infections are a major threat to human health because of their recalcitrance to antibiotic treatment. Through the study of Streptococcus pyogenes, a significant human pathogen that is known to form antibiotic-tolerant biofilms, we demonstrated the role that a bacterial pathway known for responding to acid stress plays in biofilm growth and antibiotic tolerance. This not only provides some insight into antibiotic treatment failure in S. pyogenes infections but also, given the widespread nature of this pathway, provides a potentially broad target for antibiofilm therapies. This discovery has the potential to impact the treatment of many different types of recalcitrant biofilm infections.

Staphylococcus aureus is a causative agent of chronic biofilm-associated infections that are recalcitrant to resolution by the immune system or antibiotics. To combat these infections, an antistaphylococcal, biofilm-specific quadrivalent vaccine against an osteomyelitis model in rabbits has previously been developed and shown to be effective at eliminating biofilm-embedded bacterial populations. However, the addition of antibiotics was required to eradicate remaining planktonic populations. In this study, a planktonic upregulated antigen was combined with the quadrivalent vaccine to remove the need for antibiotic therapy. Immunization with this pentavalent vaccine followed by intraperitoneal challenge of BALB/c mice with S. aureus resulted in 16.7% and 91.7% mortality in pentavalent vaccine and control groups, respectively (P < 0.001). Complete bacterial elimination was found in 66.7% of the pentavalent cohort, while only 8.3% of the control animals cleared the infection (P < 0.05). Further protective efficacy was observed in immunized rabbits following intramedullary challenge with S. aureus, where 62.5% of the pentavalent cohort completely cleared the infection, versus none of the control animals (P < 0.05). Passive immunization of BALB/c mice with serum IgG against the vaccine antigens prior to intraperitoneal challenge with S. aureus prevented mortality in 100% of mice and eliminated bacteria in 33.3% of the challenged mice. These results demonstrate that targeting both the planktonic and biofilm stages with the pentavalent vaccine or the IgG elicited by immunization can effectively protect against S. aureus infection.