Biology subjects

Britton, W.

Publications and source records attributed to Britton, W..

4 recordsLinked to original sources

bioRxiv2025

Single-cell transcriptomic analysis of HPV-related multiphenotypic sinonasal carcinoma uncovers MYB-HPV association

Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC) is a rare tumor that morphologically resembles high grade adenoid cystic carcinoma (ACC), yet exhibits indolent clinical behavior. Both demonstrate MYB proto-oncogene upregulation, but HMSC lacks the MYB translocation typically seen in ACC. Transcriptional changes in HMSC tumors remain uncharacterized. We performed single-cell RNA sequencing (scRNA-seq) on a human HMSC tumor and compared expression profiles with published ACC and oropharyngeal squamous cell carcinoma (OPSCC) scRNA-seq datasets. Primary malignant cells from HMSC (n=134) and ACC (n=980) clustered separately, and HMSC lacked bicellular differentiation into luminal and myoepithelial cells, distinguishing it from ACC. A greater proportion of HMSC cells expressing HPV-related genes (HPVon) expressed MYB (83% vs. 62%, p=0.022) and MYB targets (p=6.4*10-6), suggesting an HPV-MYB association. This finding was validated in HPV-positive OPSCC, with 7/10 tumors showing MYB upregulation in HPVon versus HPVoff cells (p<0.05). A 264-gene signature from HPVon HMSC cells was also associated with worse prognosis in HPV+ OPSCC (p<0.003), suggesting an alternate role for HPV that has not been well characterized. Further validation of the HPV-MYB association and prognostically relevant HPV gene signature may improve patient stratification and therapeutic strategies in HPV-related malignancies.

cancer biology↗

bioRxiv2025

Tissue-wide profiling of human lungs reveals spatial sequestration of macrophages in tuberculosis

The immune response to human tuberculosis (TB), particularly in the context of complex lung pathology, remains incompletely understood. Here, we employed whole-slide spatial proteomics to map immune cell organization in TB-affected human lung tissues. Our analysis revealed pronounced spatial segregation of major immune cell populations in non-necrotizing TB lesions. At the tissue level, macrophages and lymphocytes formed distinct cellular communities associated with specific pathological features. At the lesion level, macrophages and B cells showed an inverse relationship in both abundance and spatial distribution. Proinflammatory T cells preferentially accumulated in macrophage-rich lesions but remained largely separated from macrophages. Interestingly, lesions exhibiting clear segregation between T cells and macrophages were more common in subclinical TB than in active disease. These findings suggest that spatial isolation of macrophages from effector lymphocytes may help temper inflammation and potentially prevent lesion progression to necrosis, while also enabling immune evasion by Mycobacterium tuberculosis. One Sentence SummaryXiao et al. reveal spatial segregation of immune cells in TB-lung tissue and link the microenvironmental dynamics to disease states of tuberculosis.

immunology↗

bioRxiv2020

A single dose, BCG-adjuvanted SARS-CoV-2 vaccine induces Th1-polarized immunity and high-titre neutralizing antibodies in mice

Global control of COVID-19 requires broadly accessible vaccines that are effective against SARS-CoV-2 variants. In this report, we exploit the immunostimulatory properties of bacille Calmette-Guerin (BCG), the existing tuberculosis vaccine, to deliver a vaccination regimen with potent SARS-CoV-2-specific protective immunity. Combination of BCG with a stabilized, trimeric form of SARS-CoV-2 spike antigen promoted rapid development of virus-specific IgG antibodies in the blood of vaccinated mice, that was further augmented by the addition of alum. This vaccine formulation, BCG:CoVac, induced high-titre SARS-CoV-2 neutralizing antibodies (NAbs) and Th1-biased cytokine release by vaccine-specific T cells, which correlated with the early emergence of T follicular helper cells in local lymph nodes and heightened levels of antigen-specific plasma B cells after vaccination. Vaccination of K18-hACE2 mice with a single dose of BCG:CoVac almost completely abrogated disease after SARS-CoV-2 challenge, with minimal inflammation and no detectable virus in the lungs of infected animals. Boosting BCG:CoVac-primed mice with a heterologous vaccine further increased SARS-CoV-2-specific antibody responses, which effectively neutralized B.1.1.7 and B.1.351 SARS-CoV-2 variants of concern. These findings demonstrate the potential for BCG-based vaccination to protect against major SARS-CoV-2 variants circulating globally.

microbiology↗

bioRxiv2018

Pathogenic mycobacteria manipulate host low density lipoprotein metabolism

Changes to lipid metabolism are well-characterised consequences of human tuberculosis infection but their functional relevance are not clearly elucidated in these or other host-mycobacterial systems. The zebrafish-Mycobacterium marinum infection model is used extensively to model many aspects of human-M. tuberculosis pathogenesis but has not been widely used to study the role of infection-induced lipid metabolism. We find mammalian mycobacterial infection-induced alterations in host Low Density Lipoprotein metabolism are conserved in the zebrafish model of mycobacterial pathogenesis. Depletion of LDLR, a key lipid metabolism node, decreased M. marinum burden, and corrected infection-induced altered lipid metabolism resulting in decreased LDL and reduced the rate of macrophage transformation into foam cells. Our results demonstrate a conserved role for infection-induced alterations to host lipid metabolism, and specifically the LDL-LDLR axis, across host-mycobacterial species pairings.\n\nFundingThis work was supported by the Australian National Health and Medical Research Council (APP1099912 and APP1053407 to S.H.O.); Meat and Livestock Australia (P.PSH. 0813 to A.C.P. and K. dS); the Marie Bashir Institute for Infectious Diseases and Biosecurity (grant to S.H.O., A.C.P. and K. dS); the Kenyon Family Foundation Inflammation Award (grant to S.H.O.); the University of Sydney (fellowship to S.H.O.); Conselleria de Economia, Emprego e Industria (GAIN), Xunta de Galicia (grant IN607B 2016/12 to Institute of Marine Research (IIM-CSIC)).

immunology↗