Biology subjects

Priestnall, S.

Publications and source records attributed to Priestnall, S..

4 recordsLinked to original sources

bioRxiv2026

Diverse lung challenges elicit a conserved monocyte-to-macrophage differentiation blueprint

Alveolar macrophages (AM) form a first line of defence to lung insults. These insults often lead to replacement of foetal-derived tissue-resident AMs (fAMs) by monocyte-derived AMs (mono-AMs) with different functionality, which impacts lung immunity long-term. However, whether these alterations are conserved or insult-specific is not well understood. Here, we show that respiratory syncytial virus (RSV) infection remodels the AM compartment long-term. We perform comparative analyses of fAMs and mono-AMs after RSV infection, influenza (IAV) infection and clodronate liposome administration to derive rules governing the functional and transcriptional changes in AM across insults. We identify a crucial tissue integration checkpoint of CD11b+ mono-AMs which involves acquisition of proliferative capacity and requires EGR2-mediated transcriptional rewiring. Mono-AMs elicited by RSV, influenza or clodronate liposomes have a hard-wired ontogeny-dependent stereotypical profile of transcription, metabolism and enhanced immunoreactivity despite a substantially different inflammatory environment during differentiation; accordingly, mono-AMs, whether elicited by infection or sterile depletion, protect from subsequent S. pneumoniae infection. By contrast, fAMs are more susceptible to subtle, context-dependent transcriptional alterations. Our findings highlight that long-term changes in the AM compartment show origin-dependent phenotypic divergence and that mono-AM integration follows a hard-wired trajectory fine-tuned by environmental factors.

immunology↗

bioRxiv2024

Branched actin networks in innate immune cells mediate host microbiota homeostasis.

Assembly of branched actin networks, driven by the Arp2/3 complex are essential for the function and integrity of the immune system. Patients with loss-of-function mutations in the ARPC5 subunit of the Arp2/3 complex develop inflammation and immunodeficiency after birth, leading to early mortality. However, the mechanistic basis for these phenotypes remains obscure. Here we demonstrate that loss of Arpc5 in the murine hematopoietic system, but not the corresponding Arpc5l isoform causes early-onset intestinal inflammation after weaning. This condition is initiated by microbiota breaching the ileal mucosa, leading to local and systemic inflammation. Macrophage and neutrophils infiltrate into the ileum, but in the absence of Arpc5 fail to restrict microbial invasion. Loss of Arpc5 compromises the ability of macrophages to phagocytose and kill intra-cellular bacteria. Our results underscore the indispensable role of Arpc5, but not Arpc5l containing Arp2/3 complexes in mononuclear phagocytes function and host-microbiota homeostasis. One-Sentence SummaryArpc5 containing Arp2/3 complexes are essential for host-microbiota homeostasis

immunology↗

bioRxiv2023

Palmitoyl transferase ZDHHC20 promotes pancreatic cancer metastasis

Metastasis is one of the defining features of pancreatic ductal adenocarcinoma (PDAC) that contributes to poor prognosis. In this study, the palmitoyl transferase ZDHHC20 was identified in an in vivo shRNA screen as critical for metastatic outgrowth, with no effect on proliferation and migration in vitro, or primary PDAC growth in mice. This phenotype is abrogated in immunocompromised animals, and in animals with depleted natural killer (NK) cells, indicating that ZDHHC20 affects the interaction of tumour cells and the innate immune system. Using a chemical genetics platform for ZDHHC20-specific substrate profiling, a number of novel substrates of this enzyme were identified. These results describe a role for palmitoylation in enabling distant metastasis that could not have been detected using in vitro screening approaches and identify potential effectors through which ZDHHC20 promotes metastasis of PDAC.

cancer biology↗

bioRxiv2020

APOBEC3B expression generates an immunogenic model of Kras mutant lung cancer

Mutations in oncogenes such as KRAS and EGFR cause a high proportion of lung cancers. Drugs targeting these proteins cause tumour regression but ultimately fail to cure these cancers, leading to intense interest in how best to combine them with other treatments, such as immunotherapies. However, preclinical systems for studying the interaction of lung tumours with the host immune system are inadequate, in part due to the low tumour mutational burden in genetically engineered mouse models. Here we set out to develop mouse models of mutant KRAS-driven lung cancer with an elevated tumour mutational burden by expressing the human DNA cytosine deaminase, APOBEC3B, to mimic the mutational signature seen in human lung cancer. This failed to substantially increase clonal tumour mutational burden and autochthonous tumours remained refractory to immunotherapy. However, by establishing clonal cell lines from these tumours we generated an immunogenic syngeneic transplantation model of KRAS mutant lung adenocarcinoma that was sensitive to immunotherapy. Unexpectedly, we found that anti-tumour immune responses were not directed against neoantigens but instead targeted derepressed endogenous retroviral antigens. The ability of KRASG12C inhibitors to cause regression of KRASG12C-expressing versions of these tumours was markedly potentiated by the adaptive immune system, providing a unique opportunity for the study of combinations of targeted and immunotherapies in immune-hot lung cancer.

cancer biology↗