Biology subjects

Bibby, J.

Publications and source records attributed to Bibby, J..

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↗

bioRxiv2020

An autocrine Vitamin D-driven Th1 shutdown program can be exploited for COVID-19

Pro-inflammatory immune responses are necessary for effective pathogen clearance, but cause severe tissue damage if not shut down in a timely manner1,2. Excessive complement and IFN-{gamma}-associated responses are known drivers of immunopathogenesis3 and are among the most highly induced immune programs in hyper-inflammatory SARS-CoV2 lung infection4. The molecular mechanisms that govern orderly shutdown and retraction of these responses remain poorly understood. Here, we show that complement triggers contraction of IFN-{gamma} producing CD4+ T helper (Th) 1 cell responses by inducing expression of the vitamin D (VitD) receptor (VDR) and CYP27B1, the enzyme that activates VitD, permitting T cells to both activate and respond to VitD. VitD then initiates the transition from pro-inflammatory IFN-{gamma}+ Th1 cells to suppressive IL-10+ Th1 cells. This process is primed by dynamic changes in the epigenetic landscape of CD4+ T cells, generating superenhancers and recruiting c-JUN and BACH2, a key immunoregulatory transcription factor5-7. Accordingly, cells in psoriatic skin treated with VitD increased BACH2 expression, and BACH2 haplo-insufficient CD4+ T cells were defective in IL-10 production. As proof-of-concept, we show that CD4+ T cells in the bronchoalveolar lavage fluid (BALF) of patients with COVID-19 are Th1-skewed and that VDR is among the top regulators of genes induced by SARS-CoV2. Importantly, genes normally down-regulated by VitD were de-repressed in CD4+ BALF T cells of COVID-19, indicating that the VitD-driven shutdown program is impaired in this setting. The active metabolite of VitD, alfacalcidol, and cortico-steroids were among the top predicted pharmaceuticals that could normalize SARS-CoV2 induced genes. These data indicate that adjunct therapy with VitD in the context of other immunomodulatory drugs may be a beneficial strategy to dampen hyperinflammation in severe COVID-19.

immunology↗

bioRxiv2019

Multi-colour DNA-qPAINT reveals how Csk nano-clusters regulate T-cell receptor signalling

Phosphorylation of the negative regulatory element of the tyrosine kinase Lck by Csk down-modulates T-cell receptor induced signalling. Being constitutively active, Csk spatial organization is responsible for regulating this signalling interaction. Here, we used stoichiometrically accurate, multiplexed, single-molecule super-resolution microscopy (DNA-qPAINT) to image the nanoscale spatial architecture of Csk and two binding partners implicated in its membrane association - PAG and TRAF3. Combined with a newly developed co-clustering analysis framework, we provide a powerful resource for dissecting signalling pathways regulated by spatio-temporal organisation. We found that Csk forms nanoscale clusters proximal to the plasma membrane that are lost post-stimulation and re-recruited at later time points. Unexpectedly, these clusters do not directly co-localise with PAG at the membrane, but instead provide a ready pool of monomers to down-regulate signalling. By generating CRISPR/Cas9 knock-out T-cells, our data also identify that protein tyrosine phosphatase non-receptor type 22 (PTPN22) is essential for Csk nanocluster re-recruitment and for maintenance of the synaptic PAG population.

immunology↗