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Toll-like receptor 4 (TLR4) is the major pattern recognition receptor triggering the protective effect of a extracellular vesicle-based vaccine prototype in murine systemic candidiasis. | LitMetric

AI Article Synopsis

  • - Systemic candidiasis poses a major health threat worldwide, with high death rates and increasing drug-resistant strains, prompting the need for new treatment methods like vaccination.
  • - Extracellular vesicles (EVs) are small particles that contain fungal antigens and have been shown to activate the immune system, leading to the production of antibodies and providing protection in infected mice.
  • - The study explored how EVs can engage with immune cells through specific receptors, pinpointing that the effectiveness of using wild-type EVs for vaccination relies on the activation of Toll-like receptor 4 (TLR4), suggesting a new strategy for vaccine development against candidiasis.

Article Abstract

Systemic candidiasis remains a significant public health concern worldwide, with high mortality rates despite available antifungal drugs. Drug-resistant strains add to the urgency for alternative therapies. In this context, vaccination has reemerged as a prominent immune-based strategy. Extracellular vesicles (EVs), nanosized lipid bilayer particles, carry a diverse array of native fungal antigens, including proteins, nucleic acids, lipids, and glycans. Previous studies from our laboratory demonstrated that EVs triggered the innate immune response, activating bone marrow-derived dendritic cells (BMDCs) and potentially acting as a bridge between innate and adaptive immunity. Vaccination with EVs induced the production of specific antibodies, modulated cytokine production, and provided protection in immunosuppressed mice infected with lethal inoculum. To elucidate the mechanisms underlying EV-induced immune activation, our study investigated pathogen-associated molecular patterns (PAMPs) and pattern recognition receptors (PRRs) involved in EVs-phagocyte engagement. EVs from wild-type and mutant strains with truncated mannoproteins were compared for their ability to stimulate BMDCs. Our findings revealed that EV decoration with - and -linked mannans and the presence of -1,3-glucans and chitin oligomers may modulate the activation of specific PRRs, in particular Toll-like receptor 4 (TLR4) and dectin-1. The protective effect of vaccination with wild-type EVs was found to be dependent on TLR4. These results suggest that fungal EVs can be harnessed in vaccine formulations to selectively activate PRRs in phagocytes, offering potential avenues for combating or preventing candidiasis.IMPORTANCESystemic candidiasis is a serious global health concern with high mortality rates and growing drug resistance. Vaccination offers a promising solution. A unique approach involves using tiny lipid-coated particles called extracellular vesicles (EVs), which carry various fungal components. Previous studies found that EVs activate the immune response and may bridge the gap between innate and adaptive immunity. To understand this better, we investigated how these EVs activate immune cells. We demonstrated that specific components on EV surfaces, such as mannans and glucans, interact with receptors on immune cells, including Toll-like receptor 4 (TLR4) and dectin-1. Moreover, vaccinating with these EVs led to strong immune responses and full protection in mice infected with . This work shows how harnessing fungal EVs might lead to effective vaccines against candidiasis.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11351041PMC
http://dx.doi.org/10.1128/msphere.00467-24DOI Listing

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