Biology subjects

Houlder, E. L.

Publications and source records attributed to Houlder, E. L..

4 recordsLinked to original sources

bioRxiv2025

Pre-clinical studies of Schistosoma mansoni vaccines: a scoping review

BackgroundSchistosomiasis is caused by infection with worms of the genus Schistosoma including S. mansoni. Over 200 million people are infected, sterile immunity does not naturally develop, and no vaccine is available. A vaccine could be a critical tool to achieve control and elimination. Numerous candidates have been tested in pre-clinical models, but there is not yet an approved vaccine. Methodology/Principal FindingsWe conducted a scoping review using a keyword search on Web of Science and a MeSH term search on PubMed. Articles were screened and included if they tested a defined vaccine candidate in a pre-clinical protection assay against S. mansoni between 1994-2024. Vaccine formulation, study design, and efficacy parameters from all articles were extracted. This data was summarised graphically, with the influence of different parameters appraised. A total of 141 candidate antigens were tested in 108 articles over the last 30 years, with most antigens tested only once and three (Sm-CatB, Sm-p80, and Sm-14) tested over 20 times. The median protective efficacy against worms was 35%. 10 antigens achieved over 60% efficacy, and only two (Sm-p80 and Sm-CatB) over 90%. Large variations in efficacy were observed with all repeatedly tested antigens, likely attributable to differing formulations and study designs. The effect of these varying parameters on the resultant efficacy was evaluated. ConclusionsA few vaccine candidates have achieved promising efficacy in pre-clinical studies. Most vaccines tested however have efficacy that falls short of that required for an impactful schistosomiasis vaccine. The diversity in study designs makes comparing vaccine targets a challenge. Use of consistent and optimized vaccine formulation (including adjuvant and platform) and study design parameters is critical to expedite the development of a schistosome vaccine. Author SummarySchistosomiasis, a major neglected tropical disease, is caused by infection with parasitic worms of the Schistosoma species, including Schistosoma mansoni. Individuals can be repeatedly re-infected, and there is no available vaccine. An initial stage of vaccine development is testing in a pre-clinical animal model. Here we have summarised tests of Schistosoma mansoni vaccines in the last three decades. 100+ vaccine candidates have been tested, with only 10 of these achieving efficacy of over 60%, and only 2 at over 90%. When the same vaccine candidate (antigen) is tested in a different formulation, or using different study design the efficacy varies greatly. We have summarised the formulations and study designs used, and highlighted how certain parameters affect efficacy. Finally, we have assembled a series of recommendations to researchers on how to perform vaccine tests in the future.

immunology↗

bioRxiv2024

Aspergillus-mediated allergic airway inflammation is triggered by dendritic cell recognition of a defined spore morphotype, a process that can be targeted via antifungal therapeutics.

BackgroundExposure to fungi, especially Aspergillus fumigatus (A.f.), can elicit potent allergic inflammation that triggers and worsens asthmatic disease. Dendritic cells (DCs), initiate allergic inflammatory responses to allergic stimuli. However, it is unclear if A.f. spores during isotropic growth (early spore swelling) can activate DCs to initiate allergic responses or if germination is required. This lack of basic understanding of how A.f. causes disease is a barrier to the development of new treatments. ObjectiveTo show that a precise A.f. morphotype stage during spore swelling can trigger DCs to mediate allergic inflammatory responses and ascertain if antifungal therapeutics can be effective at suppressing this process. MethodsWe employed an A.f. strain deficient in pyrimidine biosynthesis ({Delta}pyrG) to generate populations of A.f. spores arrested at different stages of isotropic growth (swelling) via temporal removal of uracil and uridine from growth media. These arrested spore stages were cultured with bone marrow derived DCs (BMDCs), and their activation measured via flow cytometry and ELISA to interrogate which growth stage was able to activate BMDCs. These BMDCs were then adoptively transferred into the airways, to assess if they were able to mediate allergic inflammation in naive recipient mice. Allergic airway inflammation in vivo was determined via flow cytometry, ELISA and qPCR. This system was also used to determine if antifungal drug (itraconazole) treatment could alter early stages of spore swelling and therefore BMDC activation and in vivo allergic inflammation upon adoptive transfer. ResultsWe found that A.f. isotropic growth is essential to trigger BMDC activation and mediate allergic airway inflammation. Furthermore, using time arrested A.f. stages, we found that least 3h in growth media enabled spores to swell sufficiently to activate BMDCs to elicit allergic airway inflammation in vivo. Incubation of germinating A.f. with itraconazole reduced spore swelling and partially reduced their ability to activate BMDCs to elicit in vivo allergic airway inflammation. ConclusionIn summary, our results have pinpointed the precise stage of A.f. development when germinating spores are able to activate DCs to mediate downstream allergic airway inflammation. Furthermore, we have identified that antifungal therapeutics can be effective in reducing the potential of A.f. spores to stimulate allergic responses, highlighting a potential mechanism by which antifungal treatment might help to prevent the development of fungal allergy.

immunology↗

bioRxiv2023

Mgl2+ cDC2s coordinate fungal allergic airway type 2, but not type 17, inflammation.

Fungal spores are abundant in the environment and a major cause of asthma. Originally characterised as a type 2 inflammatory disease, allergic airway inflammation that underpins asthma can also involve type 17 inflammation, which can exacerbate disease causing failure of treatments tailored to inhibit type 2 factors. However, the mechanisms that determine the host response to fungi, which can trigger both type 2 and type 17 inflammation in allergic airway disease, remain unclear. We found that CD11c+ DCs and CD4+ T cells are essential for development of both type 2 and type 17 airway inflammation in mice when repeatedly exposed to inhaled spores. Single cell RNA-sequencing enabled the development of multi-parameter cytometry that identified allergic inflammation dramatically altered the proportion of numerous DC clusters in the lung, but that only two of these (Mgl2+ cDC2s and CCR7+ DCs) migrated to the dLNs. Targeted removal of several DC subsets revealed that only Mgl2+ cDC2 depletion dramatically reduced type 2, but not type 17, anti-fungal allergic airway inflammation. These data highlight distinct DC subsets are potential therapeutic targets for the treatment of pulmonary fungal disease.

immunology↗

bioRxiv2021

Genotype and Th2 cells control monocyte to tissue resident macrophage differentiation during nematode infection of the pleural cavity

The recent revolution in tissue-resident macrophage biology has resulted largely from murine studies performed in the C57BL/6 strain. Here, we provide a comprehensive analysis of immune cells in the pleural cavity using both C57BL/6 and BALB/c mice. Unlike C57BL/6 mice, naive tissue-resident Large Cavity Macrophages (LCM) of BALB/c mice failed to fully implement the tissue residency program. Following infection with a pleural-dwelling nematode these pre-existing differences were accentuated with LCM expansion occurring in C57BL/6 but not BALB/c mice. While infection drove monocyte recruitment in both strains, only in C57BL/6 mice were monocytes able to efficiently integrate into the resident pool. Monocyte to macrophage conversion required both T cells and IL-4R signalling. Host genetics are therefore a key influence on tissue resident macrophage biology, and during nematode infection Th2 cells control the differentiation pathway of tissue resident macrophages. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/472661v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@bba5e1org.highwire.dtl.DTLVardef@1876aa4org.highwire.dtl.DTLVardef@16a6b1corg.highwire.dtl.DTLVardef@19e18b6_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗