Biology subjects

Phipps, S.

Publications and source records attributed to Phipps, S..

7 recordsLinked to original sources

bioRxiv2026

Curcumin and Sulforaphane Preserve Mobility in Aging Caenorhabditis elegans via Distinct yet Complementary Transcriptional Signatures

Aging involves a progressive decline in bodily functions, underscoring the need for interventions that enhance healthspan. In this study, we screened nine natural products in Caenorhabditis elegans using whole-organism phenotyping to assess mobility endpoints, and subsequently focused on curcumin, sulforaphane, and their combination. In replicated follow-up experiments, all three interventions improved late-adult mobility after Day 2 of adulthood. Sulforaphane and the combination provided the strongest gains, whereas curcumin showed a distinct benefit profile, with more pronounced effects on time active measures than on speed-based metrics. To examine associated molecular changes, we performed transcriptomic profiling on Day 3 adults. Curcumin was associated with lipid and sphingolipid remodeling together with reduced expression of several innate immune effectors, whereas sulforaphane induced glutathione-linked detoxification signatures involving multiple gst genes. The combination retained major features of both single-compound responses while adding combination-specific changes that broadened detoxification-associated signatures and extended repression of lectin-and lysozyme-associated genes. Transcription factor activity inference further supported SKN-1-linked detoxification responses under sulforaphane and the combination. Overall, these results suggest that curcumin and sulforaphane engage distinct yet partially convergent maintenance-related programs, and that their combination broadens the underlying molecular response without producing additive mobility gains. These findings motivate further testing of natural product combinations in healthspan-related contexts.

Systems Biology↗

bioRxiv2025

Nasopharyngeal colonisation by Streptococcus pneumoniae enhances host anti-viral responses to respiratory virus infection

Viral-bacterial interactions during co-infection are often synergistic and can increase disease severity. However, emerging evidence indicates that some bacteria can antagonise viral infection, although the host responses driving this process remains unclear. Using infant mice co-infected with the nasopharyngeal inhabitant and pathogen Streptococcus pneumoniae and pneumonia virus of mice (PVM) to model antagonistic interactions, we found that prior bacterial colonisation enhances and prolongs anti-viral immune responses during co-infection, compared with viral infection alone. Transcriptomic, immunological, and histological analyses showed that pneumococcal colonisation prior to PVM infection enhanced and prolonged interferon signalling, increased anti-viral cytokine and chemokine protein levels and CD8+ cell responses. Notably, over 50% of differentially expressed host genes during co-infection were not differentially expressed in either infection alone. Our work shows that bacterial colonisation can modulate host immunity, shaping how the immune system responds to incoming viral infections, which has the potential to open novel therapeutic applications. HighlightsO_LIPneumococcal mono-infection in infant mice resulted in a delayed host transcriptomic response that was not detectable until 12 days post-infection. C_LIO_LIHost transcriptomic and immune responses to PVM were minimal except at the peak of viral replication and rapidly returned to baseline levels. C_LIO_LIPrior pneumococcal colonisation enhanced anti-viral immune responses to PVM infection, with more than half of the differentially expressed genes unique to co-infection. C_LIO_LIPneumococcal nasopharyngeal colonisation shapes the immune response, changing how the host responds to incoming viral infections with multiple anti-viral responses that were only transiently activated during PVM mono-infection being active for a longer duration during co-infection C_LI

microbiology↗

bioRxiv2024

A maternal high-fat diet predisposes to infant lung disease via increased neutrophil-mediated IL-6 trans-signaling

Poor maternal diet during pregnancy predisposes to severe lower respiratory tract infections (sLRI) in infancy, which in turn, increases childhood asthma risk, however the underlying mechanisms remain poorly understood. Here, we show that the offspring of high fat diet (HFD)-fed mothers ( HFD-reared pups) developed a sLRI following pneumovirus inoculation in early-life and subsequent asthma in later-life upon allergen exposure. Prior to infection, HFD-reared pups developed microbial dysbiosis and low-grade systemic inflammation (LGSI), characterized by hyper-granulopoiesis in the liver and elevated inflammatory cytokine expression, most notably IL-17A, IL-6 and sIL-6R (indicative of IL-6 trans-signaling) in the circulation and multiple organs, but most prominently the liver. Inhibition of IL-6 trans-signaling, using sgp130Fc transgenic mice or via specific genetic deletion of IL-6Ra on neutrophils, conferred protection against both diseases. Taken together, our findings suggest that a maternal HFD induces neonatal LGSI that predisposes to sLRI and subsequent asthma via neutrophil-mediated IL-6 trans-signaling.

immunology↗

bioRxiv2023

Dual therapy with corticosteroid ablates the beneficial effect of DP2 antagonism in chronic experimental asthma.

BackgroundProstaglandin D2 (PGD2) signals via the DP1 and DP2 receptors. In Phase II trials, DP2 antagonism decreased airway inflammation and airway smooth muscle (ASM) area in patients with moderate-to-severe asthma, but in the Phase III clinical trials, DP2 antagonism failed to significantly lower the rate of exacerbations. Here, we hypothesised that DP2 antagonism resolves established ASM remodeling via endogenous PGD2/DP1 activation and that this beneficial effect is ablated by dual corticosteroid therapy. MethodsNeonatal mice were co-exposed to pneumonia virus of mice (PVM) and cockroach extract in early life to induce severe bronchiolitis, then re-infected with PVM and challenged to cockroach extract in adulthood to progress disease to chronic experimental asthma (CEA). The efficacy of DP2 antagonism monotherapy or various dual therapies was assessed in the setting of a rhinovirus (RV)-induced exacerbation. ResultsRV inoculation increased PGD2 release, mucus production, collagen deposition, transforming growth factor (TGF)-{beta}1 expression and type-2 inflammation. Treatment with a DP2 antagonist or DP1 agonist ablated the aforementioned phenotypes, increased type-1 immunity, and decreased ASM area. Dual DP1-DP2 antagonism or dual corticosteroid/DP2 antagonism, which attenuated endogenous PGD2 levels, prevented the resolution of ASM area induced by DP2 antagonism alone. The resolution of ASM remodelling following DP2 antagonism was mediated by IFN-{gamma} and associated with decreased TGF-{beta}1 expression. ConclusionDP2 antagonism resolved ASM remodelling via PGD2/DP1-mediated upregulation of interferon-{gamma} expression. Dual DP2 antagonism/corticosteroid therapy, as occurred in many of the human trials, suppressed PGD2 and IFN-{gamma} production, impairing the efficacy of DP2 antagonism.

immunology↗

bioRxiv2023

The maternal microbiome regulates infant respiratory disease susceptibility via intestinal Flt3L expression and plasmacytoid dendritic cell hematopoiesis

Severe lower respiratory infection (sLRI) are a major cause of infant morbidity and mortality, and predispose to later chronic respiratory diseases such as asthma. Poor maternal diet during pregnancy is a risk factor for sLRI in the offspring. Here we demonstrate in mice that a maternal low-fibre diet (LFD) disrupts plasmacytoid and conventional dendritic cell (DC) hematopoiesis in the offspring, predisposing to sLRI and subsequent asthma. The LFD alters the composition of the maternal milk microbiome and assembling infant gut microbiome, ablating the induction of a developmental wave of the non-redundant DC growth factor Flt3L by neonatal intestinal epithelial cells. Therapy with a propionate-producing bacteria isolated from the milk of high-fibre diet-fed mothers, or supplementation with propionate, confers protection against sLRI by restoring gut Flt3L expression and pDC hematopoiesis. Our findings identify a microbiome-dependent Flt3L axis in the gut that regulates pDC hematopoiesis in early life and confers disease resistance. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=51 SRC="FIGDIR/small/522516v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@1a39990org.highwire.dtl.DTLVardef@1b6fe67org.highwire.dtl.DTLVardef@f8440dorg.highwire.dtl.DTLVardef@13bc67e_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

IL-33-induced neutrophilic inflammation and NETosis underlie rhinovirus-triggered exacerbations of asthma

Rhinovirus-induced neutrophil extracellular traps (NETs) contribute to acute asthma exacerbations, however the molecular factors that trigger NETosis in this context remain ill-defined. Here, we sought to implicate a role for IL-33, an epithelial cell-derived alarmin rapidly released in response to infection. In mice with chronic experimental asthma (CEA), but not naive controls, rhinovirus inoculation induced an early (1 day post infection; dpi) inflammatory response dominated by neutrophils, neutrophil-associated cytokines (IL-1, IL-1{beta}, CXCL1) and NETosis, followed by a later, type-2 inflammatory phase (3-7 dpi), characterized by eosinophils, elevated IL-4 levels, and goblet cell hyperplasia. Notably, both phases were ablated by HpARI (Heligmosomoides polygyrus Alarmin Release Inhibitor), which blocks IL-33 release and signalling. Instillation of exogenous IL-33 recapitulated the rhinovirus-induced early phase, including the increased presence of NETs in the airway mucosa, in a PAD4-dependent manner. Ex vivo IL-33-stimulated neutrophils from mice with CEA, but not naive mice, underwent NETosis, and produced greater amounts of IL-1/{beta}, IL-4, and IL-5. In nasal samples from rhinovirus-infected people with asthma, but not healthy controls, IL-33 levels correlated with neutrophil elastase and dsDNA. Our findings suggest that IL-33 blockade ameliorates the severity of an asthma exacerbation by attenuating neutrophil recruitment and the downstream generation of NETs.

immunology↗

bioRxiv2020

Synergism and antagonism of bacterial-viral co-infection in the upper respiratory tract

Streptococcus pneumoniae (the pneumococcus) is a leading cause of pneumonia in children under five years old. Co-infection by pneumococci and respiratory viruses enhances disease severity. Little is known about pneumococcal co-infections with Respiratory Syncytial Virus (RSV). Here, we developed a novel infant mouse model of co-infection using Pneumonia Virus of Mice (PVM), a murine analogue of RSV, to examine the dynamics of co-infection in the upper respiratory tract, an anatomical niche that is essential for host-to-host transmission and progression to disease. Coinfection increased damage to the nasal tissue and increased production of the chemokine CCL3. Pneumococcal nasopharyngeal density and shedding in nasal secretions were increased by co-infection. In contrast, co-infection reduced PVM loads in the nasopharynx, an effect that was independent of pneumococcal strain and the order of infection. We showed this antagonistic effect was abrogated using a pneumococcal mutant deficient in capsule production and incapable of nasopharyngeal carriage. The pneumococcal-mediated reduction in PVM loads was caused by accelerated viral clearance from the nasopharynx. Although these synergistic and antagonistic effects occurred with both wild-type pneumococcal strains used in this study, the magnitude of the effects was strain dependent. Lastly, we showed that pneumococci can also antagonize influenza virus. Taken together, our study has uncovered multiple novel facets of bacterial-viral co-infection. Our findings have important public health implications, including for bacterial and viral vaccination strategies in young children.

microbiology↗