Dolly Estella Montaño Espinosa

Vulvovaginal candidiasis (VVC) affects millions of women globally and is characterized by multifactorial immunopathology, with Candida albicans virulence driving disease progression through epithelial tissue damage and neutrophil hyperactivation and dysfunction contributing to disease severity. Here, we explored the multifaceted nature of S. cerevisiae as a live-biotherapeutic to attenuate C. albicans virulence and modulate host immune responses during VVC. We identified an S. cerevisiae isolate (Sc3458) that targets multiple aspects of C. albicans virulence, including fungal proliferation, adhesion, and hyphal morphogenesis, collectively impairing biofilm formation and disrupting pathogenic potential. These effects were linked to transcriptional reprogramming in C. albicans, marked by metabolic stress and downregulation of virulence- and biofilm-related genes. Additionally, S. cerevisiae (Sc3458) reduced inflammatory responses and neutrophil hyperactivation, while preserving neutrophil antimicrobial functionality. Altogether, this translated to an improved control of infection and dampened VVC-associated hyperinflammation in a murine VVC model. These findings position S. cerevisiae strain Sc3458 as a promising candidate live biotherapeutic for VVC treatment. Further clinical validation in human cohorts is essential to confirm its therapeutic efficacy and to assess how Sc3458 performs relative to established market-standard formulations.

Vulvovaginal candidiasis (VVC) is a mucosal yeast infection where symptoms are driven by inflammatory responses. The onset of VVC is instigated by the yeast Candida albicans, but the underlying causes of disease-driving hyperinflammation remains incompletely resolved. We found that vaginal albumin concentrations are higher in women with recurrent VVC and during VVC in mice. These albumin levels correlated with inflammatory cytokines in vaginal lavages. While the abundance of this serum protein in the vagina can represent a hallmark of inflammation-induced vascular permeability, we reveal molecular mechanisms by which albumin also drives inflammation. It increased NLRP3 inflammasome activation in human macrophages elicited by C. albicans. Albumin induced fungal adaptations that increased resistance to macrophage-mediated clearance. Further it increased the expression of fungal secreted aspartic protease 1, which we identified as the effector driving inflammasome activation. Moreover, neutrophils show impaired effectivity in clearing C. albicans in presence of albumin. Collectively, vaginal albumin may not only be a consequence of inflammation of the vaginal mucosa, but also can drive hyperinflammatory responses that underlie immunopathology in VVC.

Pathogenic microorganisms can infect a variety of niches in the human body. During infection, these microbes can only persist if they adapt adequately to the dynamic host environment and the stresses imposed by the immune system. While viruses entirely rely on host cells to replicate, bacteria and fungi use their pathogenicity mechanisms for the acquisition of essential nutrients that lie under host restriction. An inappropriate deployment of pathogenicity mechanisms will alert host defence mechanisms that aim to eradicate the pathogen. Thus, these adaptations require tight regulation to guarantee nutritional access without eliciting strong immune activation. To work efficiently, the immune system relies on a complex signalling network, involving a myriad of immune mediators, some of which are quite directly associated with imminent danger for the pathogen. To manipulate the host immune system, viruses have evolved cytokine receptors and viral cytokines. However, among bacteria and fungi, selected pathogens have evolved the capacity to use these inflammatory response-specific signals to regulate their pathogenicity. In this review, we explore how bacterial and fungal pathogens can sense the immune system and use adaptive pathogenicity strategies to evade and escape host defence to ensure their persistence in the host.

Protective immunity to opportunistic fungal infections consists of tightly regulated innate and adaptive immune responses that clear the infection. Immune responses to infections of the vaginal mucosa by Candida species are, however, an exception. In the case of vulvovaginal candidiasis (VVC), the inflammatory response is associated with symptomatic disease, rather than that it results in pathogen clearance. As such VVC can be considered an inflammatory disease, which is a significant public health problem due to its predominance as a female-specific fungal infection. Particularly, women with recurrent VVC (RVVC) suffer from a significant negative impact on their quality of life and mental health. Knowledge of the inflammatory pathogenesis of (R)VVC may guide more effective diagnostic and therapeutic options to improve the quality of life of women with (R)VVC. Here, we review the immunopathogenesis of (R)VVC describing several elements that induce an inflammatory arson, starting with the activation threshold established by vaginal epithelial cells that prevent unnecessary ignition of inflammatory responses, epithelial and inflammasome-dependent immune responses. These inflammatory responses will drive neutrophil recruitment and dysfunctional neutrophil-mediated inflammation. We also review the, sometimes controversial, findings on the involvement of adaptive and systemic responses. Finally, we provide future perspectives on the potential of some unexplored cytokine axes and discuss whether VVC needs to be subdivided into subgroups to improve diagnosis and treatment.

During the last few decades, mucormycosis has emerged as one of the most common fungal infections, following candidiasis and aspergillosis. The fungal order responsible for causing mucormycosis is the Mucorales. The main hallmarks of this infection include the invasion of blood vessels, infarction, thrombosis, and tissue necrosis, which are exhibited at the latest stages of the infection. Therefore, the diagnosis is often delayed, and the rapid progression of the infection severely endangers the life of people suffering from diabetes mellitus, hematological malignancies, or organ transplantation. Given the fact that mortality rates for mucormycosis range from 40 to 80%, early diagnosis and novel therapeutic strategies are urgently needed to battle the infection. However, compared to other fungal infections, little is known about the host immune response against Mucorales and the influence of inflammatory processes on the resolution of the infection. Hence, in this review, we summarized our current understanding of the interplay among pro-inflammatory cytokines, chemokines, and the host-immune cells in response to mucoralean fungi, as well as their potential use for immunotherapies.