Biology subjects

Strickland, D. H.

Publications and source records attributed to Strickland, D. H..

9 recordsLinked to original sources

bioRxiv2026

Bacterial diversity and strain dynamics in the infant respiratory microbiome during the first year of life

BackgroundMicrobial colonisation of the human body begins immediately after birth, with each body site forming a distinct ecological niche. While early gut microbial dynamics and their links to paediatric health have been considerably studied, the bacterial colonisation of the early infant respiratory system remains poorly understood, particularly at the species and strain level. ResultsHere, we generated and analysed whole genome sequencing of 925 isolates from six dominant genera in nasopharyngeal samples from 58 healthy infants enrolled in the Childhood Asthma Study (CAS) in Western Australia, collected longitudinally from birth (2, 6, and 12 months old). Our results expanded genomic reference catalogues and uncovered substantial strain-level diversity in dominant infant airway taxa. Plate-sweep metagenomics identified four microbiome profile groups (MPGs) with age-dependent membership, confirming prior observations while enabling high-resolution species and strain analyses. Community maturation was characterised by a shift from early Staphylococcus aureus dominance to increased Moraxella catarrhalis dominance by 12 months of age, alongside marked temporal changes in prevalence and cohort-level strain diversity. ConclusionsThese findings resolve infant nasopharyngeal microbiota composition at the species and strain level, revealing taxon-specific colonisation patterns. By substantially expanding publicly available reference genomes for underrepresented airway taxa, this work also provides a foundation for functional follow-up studies of the early respiratory microbiota and respiratory outcomes.

microbiology↗

bioRxiv2023

Mapping lung hematopoietic progenitors: Developmental kinetics and response to Influenza A viral infection

The bone marrow is a specialised niche responsible for the maintenance of hematopoietic stem and progenitor cells during homeostasis and inflammation. Recent studies however have extended this essential role to the extramedullary and extravascular lung microenvironment. Here, we provide further evidence for a reservoir of hematopoietic stem and progenitor cells within the lung from embryonic day 18.5 until adulthood. These lung progenitors display distinct microenvironment-specific developmental kinetics compared to their bone marrow counterparts, exemplified by a rapid shift from a common myeloid to megakaryocyte-erythrocyte progenitor dominated niche with increasing age. In adult mice, Influenza A viral infection results in a transient reduction in multipotent progenitors within the lungs, with a parallel increase in downstream granulocyte-macrophage progenitors and dendritic cell populations associated with acute viral infections. Our findings suggest lung hematopoietic progenitors play a role in re-establishing immunological homeostasis in the respiratory mucosa, which may have significant clinical implications for maintaining pulmonary health following inflammatory perturbation.

immunology↗

bioRxiv2023

Single cell transcriptomics reveals cell type specific features of developmentally regulated responses to lipopolysaccharide between birth and 5 years.

Human perinatal life is characterized by a period of extraordinary change during which newborns encounter abundant environmental stimuli and exposure to potential pathogens. To meet such challenges, the neonatal immune system is equipped with unique functional characteristics that adapt to changing conditions as development progresses across the early years of life, but the molecular characteristics of such adaptations remain poorly understood. The application of single cell genomics to birth cohorts provides an opportunity to investigate changes in gene expression programs elicited downstream of innate immune activation across early life at unprecedented resolution. In this study, we performed single cell RNA-sequencing of mononuclear cells collected from matched birth cord blood and 5-year peripheral blood samples following stimulation (18hrs) with two well-characterized innate stimuli; lipopolysaccharide (LPS) and Polyinosinic:polycytidylic acid (Poly(I:C)). We found that the transcriptional response to LPS was constrained at birth and predominantly partitioned into classical proinflammatory gene upregulation primarily by monocytes and IFN-signaling gene upregulation by lymphocytes. Moreover, these responses featured substantial cell-to-cell communication which appeared markedly strengthened between birth and 5 years. In contrast, stimulation with Poly(I:C) induced a robust IFN-signalling response across all cell types identified at birth and 5 years. Analysis of gene regulatory networks revealed IRF1 and STAT1 were key drivers of the LPS-induced IFN-signaling response in lymphocytes with a potential developmental role for IRF7 regulation. Additionally, we observed distinct activation trajectory endpoints for monocytes derived from LPS-treated cord and 5-year blood, which was not apparent among Poly(I:C)-induced monocytes. Taken together, our findings provide new insight into the gene regulatory landscape of immune cell function between birth and 5 years and point to regulatory mechanisms relevant to future investigation of infection susceptibility in early life.

immunology↗

bioRxiv2021

Early-life respiratory viral infection results in impairment of adult lung function

Respiratory viral infections in early-life are linked to the development of chronic lung diseases that persist into adulthood. The aim of this study was to develop a mouse model of early-life respiratory viral infection that would lead to impaired lung function in adulthood. BALB/c pups were infected at seven days of life with one of the following respiratory viruses: influenza A/Mem/1/71 "M71", influenza A/Puerto Rico/8/34 "PR8" or attenuated mengovirus "Mengo". Lung function and airways responsiveness (AHR) to methacholine were assessed seven weeks later, using the forced oscillation technique, and data were compared between male and female mice. PR8 infection was associated with significantly increased responsiveness to methacholine (for airway resistance, tissue damping, tissue elastance and hystersivity) for both sexes. M71 infection resulted in less severe responses especially in adult males. Early-life Mengo infection led to significantly higher responsiveness to MCh for males only (for airway resistance and tissue damping), suggesting sex dependant effects in lung function parameters measured. In summary, we have established a murine model where respiratory viral infection on day seven of life leads to AHR in adulthood. Importantly, the model recapitulates key variations in susceptibility related to sex and nature of viral pathogen that have previously been observed in human epidemiological studies. Our findings reveal new insights into the early origins of AHR and provide a tractable model system for future studies to unlock the mechanisms that determine pathogenesis.

immunology↗

bioRxiv2021

Metabolic dysfunction induced by high-fat diet modulates hematopoietic stem and myeloid progenitor cells in brown adipose tissue of mice

Brown adipose tissue (BAT) may be an important metabolic regulator of whole-body glucose. While important roles have been ascribed to macrophages in regulating metabolic functions in BAT, little known is known of the roles of other immune cells subsets, particularly dendritic cells (DCs). Eating a high fat diet may compromise the development of hematopoietic stem and progenitor cells (HSPC) - which give rise to DCs - in bone marrow, with less known of its effects in BAT. We have previously demonstrated that ongoing exposure to low-dose ultraviolet radiation (UVR) significantly reduced the whitening effect of eating a high-fat diet upon interscapular (i)BAT of mice. Here, we examined whether this observation may be linked to changes in the phenotype of HSPC and myeloid-derived immune cells in iBAT and bone marrow of mice using 12-colour flow cytometry. Many HSPC subsets declined in both iBAT and bone marrow with increasing metabolic dysfunction. Conversely, with rising adiposity and metabolic dysfunction, conventional (c)DCs increased in both of these tissues. When compared to low-fat diet, consumption of high-fat diet significantly reduced proportions of myeloid, common myeloid and megakaryocyte-erythrocyte progenitors in iBAT, and short-term hematopoietic stem cells in bone marrow. In mice fed a high-fat diet, exposure to low-dose UVR significantly reduced proportions of cDCs in iBAT, independently of nitric oxide release from irradiated skin (blocked using the scavenger, cPTIO), but did not significantly modify HSPC subsets in either tissue. Further studies are needed to determine whether changes in these cell populations contribute towards metabolic dysfunction.

cell biology↗

bioRxiv2021

Protection against neonatal respiratory viral infection via maternal treatment during pregnancy with the benign immune training agent OM-85

ObjectivesIncomplete maturation of immune regulatory functions at birth are antecedent to the heightened risk for severe respiratory infections during infancy. Our forerunner animal model studies demonstrated that maternal treatment with the benign microbial-derived immune modulating agent OM-85 during pregnancy promotes accelerated maturation of immune regulatory networks in the developing fetal bone marrow. Here, we aimed to establish proof-of-concept that this would enhance resilience to severe early life respiratory viral infection during the neonatal period. MethodsPregnant BALB/c mice were treated orally with OM-85 during gestation and their offspring infected intranasally with a mouse-adapted rhinovirus (vMC0) at postnatal day 2. We then assessed clinical course, lung viral titres and lung immune parameters to determine whether offspring from OM-85 treated mothers demonstrate enhanced immune protection against neonatal vMC0 infection. ResultsOffspring from OM-85 treated mothers display enhanced capacity to clear an otherwise lethal respiratory viral infection during the neonatal period, with a concomitant reduction in the exaggerated nature of the ensuing immune response. These treatment effects were associated with accelerated postnatal myeloid cell seeding of neonatal lungs and enhanced expression of microbial sensing receptors in lung tissues, coupled in particular with enhanced capacity to rapidly expand and maintain networks of lung dendritic cells expressing function-associated markers crucial for maintenance of local immune homeostasis in the face of pathogen challenge. ConclusionMaternal OM-85 treatment may represent a novel therapeutic strategy to reduce the burden, and potential long-term sequlae, of severe neonatal respiratory viral infection by accelerating development of innate immune competence.

immunology↗

bioRxiv2020

High-Dimensional Immunophenotyping of Murine T-cell and B-cell Subsets

Purpose and appropriate sample typesThis 19-parameter, 18-colour flow cytometry panel was designed and optimised to enable the comprehensive and simultaneous immunophenotyping of distinct T-cell and B-cell subsets within murine lymphoid tissues (Table 1). Cellular populations identified by employing this OMIP include 4 major subsets of B-cells (memory, activated, plasma cells and plasmablasts) and 7 major subsets of CD4+ T-cells (naive, central memory, effector memory, helper, regulatory, follicular helper and follicular regulatory). Staining was performed on freshly isolated splenocytes from 21-day-old neonatal BALB/c mice, however due to the omission of mouse strain-specific markers, this OMIP can be implemented across a range of murine models where in-depth immunophenotyping of the diverse repertoire of T-cell and B-cell populations localised within lymphoid tissues is required. O_TBL View this table: org.highwire.dtl.DTLVardef@1b488fdorg.highwire.dtl.DTLVardef@18dd356org.highwire.dtl.DTLVardef@2dce91org.highwire.dtl.DTLVardef@154cc27org.highwire.dtl.DTLVardef@27237c_HPS_FORMAT_FIGEXP M_TBL O_FLOATNOTable 1.C_FLOATNO O_TABLECAPTIONSummary Table C_TABLECAPTION C_TBL

cell biology↗

bioRxiv2019

Transplacentally mediated immune training to accelerate fetal immune competence

We recently reported that the offspring of mice treated during pregnancy with the microbial-derived immunomodulator OM-85 manifest striking resistance postnatally to allergic airways inflammation, and localised the potential treatment target to the fetal cDC progenitor compartment which expands to increase the pool of precursors available at birth, enabling accelerated postnatal seeding of the lung mucosal cDC network required for establishment of immunological homeostasis in the airways. Here, we profile maternal OM-85 treatment-associated transcriptomic signatures in fetal bone marrow, and identify a series of immunometabolic pathways which provide essential metabolites for accelerated myelopoiesis, that are hallmarks of classical "immune training". In addition, the cDC progenitor compartment displayed treatment-associated activation of the XBP1-ERN1 signalling axis which has previously been shown to be essential for tissue survival of cDC, particularly within the lung microenvironment. Our forerunner studies indicate uniquely rapid turnover of airway mucosal cDCs at baseline, with further large-scale upregulation of population dynamics during aeroallergen and/or pathogen challenge. XBP1-ERN1 signalling plays a key role in mitigation of ER stress-associated toxicity which frequently accompanies DC hyper-activation during intense immunoinflammatory responses, and we suggest that enhanced capacity for XBP1-ERN1-dependent cDC survival within the airway mucosal tissue microenvironment may be a crucial element of the OM-85-mediated transplacental "innate immune training" process which results in enhanced resistance to airway inflammatory disease during the high-risk early postnatal period.

immunology↗

bioRxiv2017

Transplacental protection against asthma by maternal treatment with a bacterial-derived immunomodulatory agent

Studies in European and US farming populations have documented major reductions in asthma prevalence in offspring of mothers exposed to microbial breakdown products present in farm dusts and unprocessed foods. This was associated with enhancement of innate immune competence in the offspring. We sought to (i) identify a safe therapeutic that would reproduce these immunomodulatory effects in a murine model, (ii) elucidate underlying mechanism(s)-of-action, and (iii) develop a scientific rationale for progressing this approach to human trials. We demonstrate in mice that maternal treatment during pregnancy with the microbial-derived immunomodulator OM85, which has been used clinically in adults and children in Europe for >30 years for bolstering resistance to infection-associated airways inflammation, markedly reduces the susceptibility of the offspring of treated mothers to development of experimental atopic asthma. We identify bone marrow precursors of the dendritic cell populations responsible for airway mucosal immune surveillance as the primary targets for the asthma-protective effects of maternal OM85 treatment in the offspring.

immunology↗