Biology subjects

Dockrell, D.

Publications and source records attributed to Dockrell, D..

5 recordsLinked to original sources

bioRxiv2025

A novel vaccination strategy induces vaccine-specific mucosal responses at port of viral entry and exit: using systemic SARS-CoV-2 vaccination as a test case

Respiratory infectious diseases are associated with substantial morbidity and mortality rates worldwide, especially at the extremes of age and in immunocompromised individuals. Over the past two decades, respiratory viruses have driven nine epidemics and pandemics (including the COVID-19 pandemic); and their ongoing emergence, persistence and evolution continue to threat global health security. The upper respiratory tract (URT) represents the primary access point for respiratory viruses, where initial host infection occurs. Vaccine-mediated URT mucosal memory responses can control infection, prevent transmission and limit viral evolution. However, vaccines against respiratory viruses predominantly have systemic administration routes that elicit strong responses in the circulation to prevent severe respiratory disease, but do not effectively block infection and onward community transmission. To overcome the limitations of systemic vaccination alone, we present a novel intervention combining systemic vaccination with targeted non-antigenic inflammatory stimulation of the URT, to induce vaccine-specific immune responses in the URT mucosa. Using SARS-CoV-2 vaccination as a test case, we demonstrate for the first time, that intranasal coadministration of exogenous IFN- as a targeted inflammatory URT signal, alongside systemic vaccination, induces vaccine-specific T-cell responses in the URT.

immunology↗

bioRxiv2022

Hypoxia shapes the immune landscape in lung injury promoting inflammation persistence

Acute Respiratory Distress Syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, has no cure. Hypoxemia is a defining feature, yet its impact on inflammation is often neglected. Patients with ARDS are monocytopenic early in the onset of the disease. Endotoxin or Streptococcus pneumoniae acute lung injury (ALI) in the context of hypoxia replicates this finding, through hypoxia-driven suppression of type I interferon signalling. This results in failed lung monocyte-derived interstitial macrophages (IM) niche expansion and unchecked neutrophilic inflammation. Administration of colony stimulating factor 1 (CSF1) rescues the monocytopenia, alters the circulating classical monocyte phenotype in hypoxic endotoxin-driven ALI and enables lung IM population expansion, thus limiting lung injury in endotoxin- and virally-induced hypoxic ALI. Hypoxia directly alters immune dynamics to the detriment of the host and manipulation of this aberrant response offers new therapeutic strategies for ARDS.

cell biology↗

bioRxiv2019

Origin and microenvironment contribute to the sexually dimorphic phenotype and function of peritoneal macrophages.

Macrophages reside in the body cavities where they maintain serosal homeostasis and provide immune surveillance. Peritoneal macrophages are implicated in the aetiology of pathologies including peritonitis, endometriosis and metastatic cancer thus understanding the factors that govern their behaviour is vital. Using a combination of fate mapping techniques, we have investigated the impact of sex and age on murine peritoneal macrophage differentiation, turnover and function. We demonstrate that the sexually dimorphic replenishment of peritoneal macrophages from the bone marrow, which is high in males and very low in females, is driven by changes in the local microenvironment that arise upon sexual maturation. Population and single cell RNAseq revealed striking dimorphisms in gene expression between male and female peritoneal macrophages that was in part explained by differences in composition of these populations. By estimating the time of residency of different subsets within the cavity and assessing development of dimorphisms with age and in monocytopenic Ccr2-/- mice, we demonstrate that key sex-dependent features of peritoneal macrophages are a function of the differential rate of replenishment from the bone marrow while others are reliant on local microenvironment signals. Importantly, we demonstrate that the dimorphic turnover of peritoneal macrophages contributes to differences in the ability to protect against pneumococcal peritonitis between the sexes. These data highlight the importance of considering both sex and age in susceptibility to inflammatory and infectious disease.

immunology↗

bioRxiv2019

Inhibition of ErbB kinase signalling promotes resolution of neutrophilic inflammation

Neutrophilic inflammation with prolonged neutrophil survival is common to many inflammatory conditions, including chronic obstructive pulmonary disease (COPD). There are few specific therapies that reverse neutrophilic inflammation, but uncovering mechanisms regulating neutrophil survival is likely to identify novel therapeutic targets. Screening of 367 kinase inhibitors in human neutrophils and a zebrafish tail fin injury model identified ErbBs as common targets of compounds that accelerated inflammation resolution. The ErbB inhibitors gefitinib, CP-724714, erbstatin and tyrphostin AG825 significantly accelerated apoptosis of human neutrophils, including neutrophils from people with COPD. Neutrophil apoptosis was also increased in Tyrphostin AG825 treated-zebrafish in vivo. Tyrphostin AG825 decreased peritoneal inflammation in zymosan-treated mice, and increased lung neutrophil apoptosis and macrophage efferocytosis in a murine acute lung injury model. Tyrphostin AG825 and knockdown of egfra and erbb2 by CRISPR/Cas9 reduced inflammation in zebrafish. Our work shows that inhibitors of ErbB kinases have therapeutic potential in neutrophilic inflammatory disease.

immunology↗

bioRxiv2019

Macrophages utilize mitochondrial fission to enhance mROS production during responses to Streptococcus pneumoniae

Immunometabolism and regulation of mitochondrial reactive oxygen species (mROS) are critical determinants of the immune effector phenotype of differentiated macrophages. Mitochondrial function requires dynamic fission and fusion, but whether effector function is associated with altered dynamics during bacterial responses is unknown. We show that macrophage mitochondria undergo fission after 12 h of progressive ingestion of live Streptococcus pneumoniae (pneumococci). Fission is associated with progressive reduction in oxidative phosphorylation but increased mROS generation. Fission is enhanced by mROS production, PI3K{gamma} signaling and by cathepsin B, but not by inflammasome activation or IL-1{beta} generation. Reduced fission following PI3K{gamma} or cathepsin B inhibition is associated with reduced mROS generation and bacterial killing. Fission is associated with Parkin recruitment to mitochondria, but not mitophagy. Fission occurs upstream of apoptosis induction and independently of caspase activation. During macrophage innate responses to live bacteria mitochondria shift from oxidative phosphorylation and ATP generation to mROS production and microbicidal responses with a progressive shift towards mitochondrial fission.

immunology↗