Biology subjects

Dos Santos Dias, L.

Publications and source records attributed to Dos Santos Dias, L..

3 recordsLinked to original sources

bioRxiv2026

An innate immune circuit involving the lectin pathway, complement and lung epithelial cells enforce barrier immunity to inhaled fungal disease

The lung mucosal barrier thwarts many inhaled pathogens, including Coccidioides, the causative agent of Valley Fever. Because the earliest stages of pathogen recognition in the lung remain obscure, we investigated the initial events of barrier immunity in a murine model involving inhalation of Coccidioides sp. arthroconidia. Neutrophils accumulated rapidly, within 24 hours, near fungal spores in the bronchiolar airways. This response was driven by pattern recognition via the lectin complement pathway. Bronchiolar club cells propagated C3a signals and amplified the response via convergent C3aR and P2X7 signaling. We identified several MBL2 and P2RX7 polymorphisms that correlated with progressive disease in humans. Our assays revealed that these mutations caused functional impairments in C3a generation and P2X7 responsiveness. Our findings establish how complement signaling and epithelial sensing coordinate early immune responses to fungal infection, offering insights into essential host defense mechanisms and risk factors for disease progression in coccidioidomycosis.

microbiology↗

bioRxiv2022

Novel populations of CD4+ T cells associated with vaccine efficacy

Memory T cells underpin vaccine-induced immunity but are not yet fully understood. To distinguish features of memory cells that confer protective immunity, we used single cell transcriptome analysis to compare antigen-specific CD4+ T cells recalled to lungs of mice that received a protective or nonprotective subunit vaccine followed by challenge with a fungal pathogen. We unexpectedly found populations specific to protection that expressed a strong type I interferon response signature, whose distinctive transcriptional signature appeared unconventionally dependent on IFN-{gamma} receptor. We also detected a unique population enriched in protection that highly expressed the gene for the natural killer cell marker NKG7. Lastly, we detected differences in TCR gene use and in Th1- and Th17-skewed responses after protective and nonprotective vaccine, respectively, reflecting heterogeneous Ifng- and Il17a-expressing populations. Our findings highlight key features of transcriptionally diverse and distinctive antigen-specific T cells associated with protective vaccine-induced immunity.

immunology↗

bioRxiv2020

Structural basis of Blastomyces Endoglucanase-2adjuvancy in anti-fungal and -viral immunity

The development of safe subunit vaccines requires adjuvants that augment immunogenicity of non-replicating protein-based antigens. Current vaccines against infectious diseases preferentially induce protective antibodies driven by adjuvants such as alum. However, the contribution of antibody to host defense is limited for certain classes of infectious diseases such as fungi, whereas animal studies and clinical observations implicate cellular immunity as an essential component of the resolution of fungal pathogens. Here, we decipher the structural bases of a newly identified glycoprotein ligand of Dectin-2 with potent adjuvancy, Blastomyces endoglucanase-2 (Bl-Eng2). We also pinpoint the developmental steps of antigen-specific CD4+ and CD8+ T responses augmented by Bl-Eng2 including expansion, differentiation and tissue residency. Dectin-2 ligation led to successful systemic and mucosal vaccination against invasive fungal infection and Influenza A infection, respectively. O-linked glycans on Bl-Eng2 applied at the skin and respiratory mucosa greatly augment vaccine subunit induced protective immunity against lethal influenza and fungal pulmonary challenge. AUTHOR SUMMARYFungal disease remains a challenging clinical and public health problem in part because there is no commercial vaccine available. The lack of suitable adjuvants is a critical barrier to developing safe and effective vaccines against fungal pathogens. Current adjuvants such as alum preferentially induce antibody responses which may be limited in mediating protection against fungi. Clinical observations and animal studies implicate cellular immunity as the essential component for the resolution of fungal infections. We have recently discovered an adjuvant that augments cell mediated immune responses and vaccine induced protection against fungi. Here, we identified the structural and mechanistic requirements by which this newly discovered adjuvant induces cell mediated immunity against fungi. As a proof of principle we also demonstrate that the adjuvant drives cellular immune responses against viruses such as influenza. We anticipate that our adjuvant can be used for vaccination with safe subunit vaccines against many microbial pathogens including viruses, intracellular bacteria, fungi and parasites that require cell mediated immune responses.

immunology↗