Exposure to lung-migrating helminth protects against murine SARS-CoV-2 infection through macrophage-dependent T cell activation
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ABSTRACT: Helminth infection leads to lung remodelling. We used single cell ATAC sequencing (scRNA-seq) to analyze the changes in lung cells following exposure to N. brasiliensis at day 28 and day 45 post helminth infection
Project description:Helminth infection leads to lung remodelling. We used single cell RNA sequencing (scRNA-seq) to analyze the changes in lung cells following exposure to N. brasiliensis followed by subsequent exposure to SARS-COV2
Project description:Goal: To examine the effects of human resistin during helminth infection. Methodology: To examine the function of human resistin (hResistin), we utilized transgenic mice expressing the human resistin gene along with its entire regulatory region (hRetnTg+). Following infection with the helminth Nippostrongylus brasiliensis, whole lung RNA was sequenced in hRetnTg+ mice, control hRetnTg- and naïve mice. Conclusion: In hRetnTg+ mice, many genes involved in inflammation and the immune system, specifically toll-like receptor signaling and chemokines, are significantly upregulated, suggesting that human resistin promotes TLR signaling and inflammation during helminth infection. Examination of whole lung mRNA from Nippostrongylus brasiliensis-infected lungs at day 7 in mice expressing human resistin
Project description:Goal: To examine the effects of human resistin during helminth infection. Methodology: To examine the function of human resistin (hResistin), we utilized transgenic mice expressing the human resistin gene along with its entire regulatory region (hRetnTg+). Following infection with the helminth Nippostrongylus brasiliensis, whole lung RNA was sequenced in hRetnTg+ mice, control hRetnTg- and naïve mice. Conclusion: In hRetnTg+ mice, many genes involved in inflammation and the immune system, specifically toll-like receptor signaling and chemokines, are significantly upregulated, suggesting that human resistin promotes TLR signaling and inflammation during helminth infection.
Project description:The goal of this experiment was to examine the innate immune response to helminth infection in the lung. Hookworms (like many other helminths) use an obligate migration pathway through the lung. Their infection has been characterized in the gut in detail, but early immune responses in the lung have not been fully characterized. Experiment Overall Design: SCID mice were used to examine the innate immune response. SCID mice have no functional B or T cells but a fully functional innate immune system. SCID and WT mice were infected with 500 L3 stage infectious Nippostrongylus brasiliensis SC and their lungs were removed at days 2,3,4,8 and 12 post infection.
Project description:Distinct subsets of T lymphocytes express CX3CR1 under inflammatory conditions, but little is known about CX3CR1+ CD4+ T cells during Type 2 inflammation in helminth infections. Here, we used a fate-mapping mouse model to characterize CX3CR1+ CD4+ T cells during both acute Nippostrongylus brasiliensis and chronic Schistosoma mansoni helminth infections, revealing CX3CR1+ CD4+ T cells to be an activated tissue homing subset with varying capacity for cytokine production. Tracking these cells over time revealed that maintenance of CX3CR1 itself along with a TH2 phenotype conferred a survival advantage in the inflamed tissue. Single-cell RNA-sequencing analysis of fate-mapped CX3CR1+ CD4+ T cells from both the peripheral tissue and the spleen revealed a considerable level of diversity and identified a distinct population of BCL6+ TCF-1+ PD1+ CD4+ T cells in the spleen during helminth infections. Conditional deletion of BCL6 in CX3CR1+ cells result in fewer CX3CR1+ CD4+ during infection, indicating a role in sustaining CD4+ T cell responses to helminth infections. Overall, our studies revealed the behavior and heterogeneity of CX3CR1+ CD4+ T cells during Type 2 inflammation in helminth infections and identified BCL6 to be important in their maintenance
Project description:Infection with Nippostrongylus brasiliensis results in persistent changes to the lung environment. Cytokine profiling reveals a sustained increase in both Th1 and Th2 transcripts. Cellular populations of macrophages display an alternative phenotype, with upregulation of YM1, Arg1, Mrc1 as well as Class II MHC. These alternatively activated alveolar macrophages (AAAMs) also increase drastically in number. Subsequent challenge with house dust mite (HDM) Dermatophagoides pteronyssinus shows a reduced allergic phenotype, with decreased fold changes in effector cell cytokines of both the Th1 and Th2 variety indicative of the new regulatory environment established in the lung by helminth infection. Histological examination of the lung environment reveals a significant decrease in eosinophila and reduced mucous production by bronchial epithelial cells. Experiment Overall Design: BALB/c mice were challenged with 500 infectious L3 stage Nippostrongylus brasiliensis larvae subcutaneously. Mice were allowed to resolve their infection, then were sensitized twice with 75 allergy units (AU) of HDM bound to 1mg of alum intraperitoneally. Two challenge doses of 50AU HDM in PBS were given intranasally one day apart, then lungs were harvested at 6, 24 and 72 hours post challenge. Mice were analyzed by histology, immunohistochemistry, real time RT-PCR and affymetrix gene array analysis using full genome chips.
Project description:Gene expression in the lung and intestine of wild-type and stat6 deficient mice on BALB/c background infected with the helminth parasite Nippostrongylus brasiliensis was compared by competitive hybridization to spotted 70-mer oligonucleotide arrays.