Biology subjects

Kaye, P.

Publications and source records attributed to Kaye, P..

6 recordsLinked to original sources

bioRxiv2025

Spatial profiling of central nervous system cellular markers in murine breast cancer to brain metastases

BackgroundBrain metastasis occurs in approximately 16% of metastatic breast cancer patients, and incidence is increasing. Patients with breast cancer brain metastases frequently develop neurological problems including cognitive impairments and seizures. We previously demonstrated accumulation of activated microglia around the tumour site in a breast cancer brain metastasis model, which co-localised with spontaneously occurring local field potential events that resembled interictal epileptic discharges. However, the mechanisms underlying these spatially restricted effects on neuronal excitability are poorly understood. MethodsTo better understand the underlying cellular changes and potential mechanisms, we used digital spatial profiling of brain cell subtype-specific markers to chart the spatial organisation of neurons, oligodendrocytes, astrocytes, and microglia in relation to metastatic lesion site. We developed a novel chordline-based approach to analyse these spatial changes in biomarker distribution. ResultsSeveral protein markers associated with proliferation (Ki67), astrocytes (GFAP) and microglia (CD11b, IBA1, CD45, MSR1) were upregulated in the tumour compared to healthy contralateral brain parenchyma. In contrast, some neuroglial markers (MAP2, Neurofilament light, NeuN, S100B and TMEM119) were lower in the lesion compared to normal tissue. ConclusionsOverall, the protein marker changes in the lesion are indicative of neuronal cell loss and changes in the immune microenvironment of the metastatic lesion involving activated microglia, astrocytes and recruitment of peripheral immune cells. Such cellular changes may contribute to the changes in electrical activity resulting from brain metastases observed in mice and patients.

neuroscience↗

bioRxiv2024

Thrombocytopenia in murine schistosomiasis is associated with platelet uptake by liver macrophages that have a distinct activation phenotype

Alongside their well-established role in hemostasis, platelets are key modulators of immune cell function. This is particularly the case for macrophages, as platelets can either promote or dampen macrophage activation in a context-specific manner. Whilst the role of platelets in modulating classical (M1) macrophage activation following bacterial challenge is relatively well understood, whether platelets control other macrophage responses is less clear. We investigated the role of platelets in type 2 inflammation using a mouse model of chronic schistosomiasis. Schistosome infection caused thrombocytopenia which was partially reversed after drug-induced parasite death. Reduced platelet levels in infection were coincident with impaired thrombopoietin production by hepatocytes, reflecting the extensive liver damage caused by parasite eggs. Infection also reduced the ploidy and size (but not number) of bone marrow megakaryocytes, which was associated with reduced platelet output. We show schistosome infection accelerated platelet clearance and promoted the formation of platelet-leukocyte aggregates. This was particularly the case for liver macrophages and monocytes. Phenotypic analysis shows that platelet-associated liver macrophages had a distinct activation phenotype that included elevated expression of the alternative (M2) activation marker RELM. Despite this, in vitro studies indicated that platelets do not directly promote macrophage alternative activation. Similarly, whilst in vivo pharmacological treatment with a TPO mimetic enhanced platelet numbers and platelet-leukocyte aggregates, this did not alter macrophage phenotype. Conversely, antibody-mediated depletion of platelets or use of platelet-deficient mice both led to extensive bleeding following infection which impacted host survival. Together, these data indicate that whilst platelets are essential to prevent excessive disease pathology in schistosomiasis, they have a more nuanced role in myeloid cell activation and type 2 immune responses Author SummaryPlatelets are the second most abundant blood cell and are best known for their role in stopping bleeding after blood vessel damage. More recent studies have revealed another important function of platelets is their ability to control immune cell activation. Here, we investigate the role of platelets in immune responses to schistosomes, parasitic worms that cause the disease schistosomiasis that affects hundreds of millions worldwide. Schistosome worms live in our blood vessels and release large numbers of eggs that must exit the blood and move through our tissues to exit the body for onward transmission. However, a large number of eggs become trapped in different organs causing inflammation and disease pathology. We find that schistosome infection reduces the numbers of platelets in the blood of laboratory mice. Platelets are taken up by liver macrophages, and whilst these macrophages have a distinct activation profile compared to other cells, platelets themselves do not cause these changes. However, platelets are essential to survive schistosomiasis due to excessive bleeding in their absence. Together, this work shows that platelets are key to surviving schistosome infection but this reflects more their role in preventing bleeding rather than controlling immune cell function.

immunology↗

bioRxiv2023

UVB modifies skin immune-stroma cross-talk and promotes effector T cell recruitment during cryptic Leishmania donovani infection

Many parasites of significant public health importance assume skin residency without causing overt pathlogy. How immune and stromal cells respond to such "cryptic" infections and how exposure to UVB alters such responses in poorly understood. We combined scRNA-seq, spatial transcriptomics and inferential network analysis to address these questions in a model of cryptic skin infection by Leishmania donovani. In infected C57BL/6 mice, p-selectin and CXCL12 interactions dominate intercellular communication between leucocytes, fibroblast and endothelial cells, but effector T cell function remains muted. Following UVB exposure, increased numbers of IFN{gamma}+ CD4+ Th1 cells and NK cells enter the skin, communicating with stromal cells via CCL5-CCR5 and LFA-1-ICAM1/2. However, spatial mapping indicated that Th1 cells and macrophages occupied distinct niches after UVB exposure, likely limiting effector function. Our data provide the first holistic view of the immune landscape during cryptic L. donovani infection and demonstrate how UVB exposure fundamentally reshapes this response. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/526940v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1238cbaorg.highwire.dtl.DTLVardef@ec350eorg.highwire.dtl.DTLVardef@18f412corg.highwire.dtl.DTLVardef@1ffd468_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

Tissue specific dual RNA-seq defines host-parasite interplay in murine visceral leishmaniasis caused by Leishmania donovani and Leishmania infantum

Visceral leishmaniasis is associated with hepato-splenomegaly and altered immune and haematological parameters in both pre-clinical animal models and humans. We studied mouse experimental visceral leishmaniasis caused by Leishmania infantum and Leishmania donovani in BALB/c mice using dual RNA-seq to investigate the transcriptional response of host and parasite in liver and spleen. We identified only 4 species-specific parasite expressed genes (SSPEGs; log2FC >1, FDR <0.05) in the infected spleen, and none in the infected liver. For the host transcriptome, we found 789 differentially expressed genes (DEGs; log2FC >1, FDR <0.05) in the spleen that were common to both infections, with IFN{gamma} signaling and complement and coagulation cascade pathways highly enriched, and an additional 286 and 186 DEGs that were selective to L. donovani and L. infantum infection respectively. Among those, there were network interactions between genes of amino acid metabolism and PPAR signaling in L. donovani infection and increased IL1{beta} and positive regulation of fatty acid transport in L. infantum infection, although no pathway enrichment was observed. In the liver, there were 1939 DEGs in mice infected with either L. infantum or L. donovani in comparison to uninfected mice, and the most enriched pathways were IFN{gamma} signaling, neutrophil mediated immunity, complement and coagulation, cytokine-chemokine responses and hemostasis. Additionally, 221 DEGs were selective in L. donovani and 429 DEGs in L. infantum infections. These data show that the host response for these two visceral leishmaniasis infection models is broadly similar, and [~]10% of host DEGs vary in infections with either parasite species. ImportanceVisceral leishmaniasis (VL) is caused by two species of Leishmania parasites, L. donovani in the Old World and L. infantum in the New World and countries bordering the Mediterranean. Although cardinal features such as hepato-splenomegaly and alterations in blood and immune function are evident, clinical presentation may vary by geography, with for example severe bleeding often associated with VL in Brazil. Although animal models of both L. donovani and L. infantum have been widely used to study disease pathogenesis, a direct side-by-side comparison of how these parasites species impact the infected host and/or how they might respond to the stresses of mammalian infection has not been previously reported. Identifying common and distinct pathways to pathogenesis will be important to ensure that new therapeutic or prophylactic approaches will be applicable across all forms of VL.

microbiology↗

bioRxiv2020

Characterization of a new Leishmania major isolate for use in a controlled human infection model

Leishmaniasis is widely regarded as a vaccine-preventable disease, but the costs required to reach pivotal Phase 3 studies and uncertainty about which candidate vaccines should be progressed into human studies significantly limits progress in vaccine development for this neglected tropical disease. Controlled human infection models (CHIM) provide a pathway for accelerating vaccine development and to more fully understand disease pathogenesis and correlates of protection. Here, we describe the isolation, characterization and GMP manufacture of a new clinical isolate of Leishmania major. Two fresh isolates of L. major from Israel were initially compared by genome sequencing, in vivo infectivity and drug sensitivity in mice, and development and transmission competence in sand flies, allowing one (L. major_MRC-02) to be selected for GMP production. This study addresses a major roadblock in the development of vaccines for leishmaniasis, providing a key resource for CHIM studies of sand fly transmitted cutaneous leishmaniasis.

microbiology↗

bioRxiv2019

The impact of leishmaniasis on mental health and psychosocial well-being: A systematic review

BackgroundLeishmaniasis is a neglected tropical parasitic disease endemic in South Asia, East Africa, South America and the Middle East. It is associated with low socioeconomic status (SES) and responsible for considerable mortality and morbidity. Reports suggest that patients with leishmaniasis may have a higher risk of mental illness (MI), psychosocial morbidity (PM) and reduced quality of life (QoL), but this is not well characterised. The aim of this study was to conduct a systematic review to assess the reported impact of leishmaniasis on mental health and psychosocial wellbeing.\n\nMethodsA systematic review of the literature was carried out. Pre-specified criteria were applied to identify publications including observational quantitative studies or systematic reviews. Two reviewers screened all of the titles, abstracts and full-studies and a third reviewer was consulted for disagreements. Data was extracted from papers meeting the criteria and quality appraisal of the methods was performed using the Newcastle-Ottowa Scale or the Risk of Bias in Systematic Review tool.\n\nResultsA total of 14 studies were identified from 12,517 records. Nine cross-sectional, three case-control, one cohort study and one systematic review were included. Eleven assessed MI outcomes and were measured with tools specifically designed for this; nine measured PM and 12 measured QoL using validated measurement tools. Quality appraisal of the studies showed that six were of good quality. Cutaneous leishmaniasis and post kala-azar dermal leishmaniasis showed evidence of associated MI and PM including depression, anxiety and stigma, while all forms of disease showed decreased QoL. The findings were used to inform a proposed model and conceptual framework to show the possible links between leishmaniasis and mental health outcomes.\n\nConclusionThere is evidence that leishmaniasis has an impact on MI, PM or QoL of patients and their families and this occurs in all the main subtypes of the disease. There are however large gaps in the evidence. Further research is required to understand the full extent of this problem and its mechanistic basis.\n\nAUTHOR SUMMARYLeishmaniasis is a parasitic disease prevalent in many low-and middle-income countries worldwide. In this study the authors looked for evidence as to whether leishmaniasis affected the mental health and quality of life of patients. To conduct the review, a wide search of the literature was conducted, where a total of 14 full articles were included and analysed. It was found that different forms of leishmaniasis (visceral leishmaniasis, cutaneous leishmaniasis and post kala-azar dermal leishmaniasis) do cause a significant impact on patients mental health and quality of life through societal factors such as stigma, lack of knowledge, culture and low self-esteem among others. However, no evidence of biological mechanisms was found linking leishmaniasis to mental illness or decreased quality of life. Despite being a very incapacitating disease physically, leishmaniasis also leads to mental illness and decreased quality of life, and should therefore be a priority on the global health agenda for both researchers and policy makers.

epidemiology↗