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Bacterial infection disrupts established germinal center reactions through monocyte recruitment and impaired metabolic adaptation [Single-cell RNA-seq]

ABSTRACT: Consecutive exposures to different pathogens are very common and often alter host immune responses. Yet, it remains unknown how a secondary bacterial infection interferes with an ongoing adaptive immune response elicited against primary invading pathogens. Here, we demonstrate that pre-existing germinal center (GC) B cells are incapable of enduring radical metabolic changes induced by recruited Sca-1+ monocytes during Salmonella Typhimurium (STm) infection. GCs-induced by influenza, plasmodium and commensals deteriorated upon STm infection. GC collapse was independent of direct bacterial interactions with B cells, but rather, was induced through recruitment of CCR2-dependent Sca-1+ monocytes. GC collapse was dependent on non-B cell TLR-4, TNFα and IFNγ, which was essential for Sca-1+ monocyte differentiation in the bone-marrow. Monocyte recruitment and GC disruption also occurred during LPS-supplemented vaccination and Listeria monocytogenes infection. Thus, systemic activation of the innate immune response upon lethal bacterial infection is induced at the expense of antibody-mediated immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE188475 | GEO | 2022/11/02

REPOSITORIES: GEO

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Bacterial infection disrupts established germinal center reactions through monocyte recruitment and impaired metabolic adaptation [Bulk RNA-seq]

Project description:Consecutive exposures to different pathogens are very common and often alter host immune responses. Yet, it remains unknown how a secondary bacterial infection interferes with an ongoing adaptive immune response elicited against primary invading pathogens. Here, we demonstrate that pre-existing germinal center (GC) B cells are incapable of enduring radical metabolic changes induced by recruited Sca-1+ monocytes during Salmonella Typhimurium (STm) infection. GCs-induced by influenza, plasmodium and commensals deteriorated upon STm infection. GC collapse was independent of direct bacterial interactions with B cells, but rather, was induced through recruitment of CCR2-dependent Sca-1+ monocytes. GC collapse was dependent on non-B cell TLR-4, TNFα and IFNγ, which was essential for Sca-1+ monocyte differentiation in the bone-marrow. Monocyte recruitment and GC disruption also occurred during LPS-supplemented vaccination and Listeria monocytogenes infection. Thus, systemic activation of the innate immune response upon lethal bacterial infection is induced at the expense of antibody-mediated immunity.

2022-11-02 | GSE188474 | GEO

Expression data from human primary monocytes

Project description:We analyzed the delayed LPS-induced expression pattern in monocytes. Activation of monocytes by microbial products is an important mechanism contributing to host protection against invading pathogens. This process has to be tightly controlled to ensure that antimicrobial response does not result in fatal host tissue damage. Therefore we investigated control mechanisms during prolonged monocyte activation by bacterial endotoxin.

2015-03-06 | GSE55608 | GEO

Spatiotemporal proteomics uncovers cathepsin-dependent host cell death during bacterial infection

Project description:Immune cells need to swiftly and effectively respond to invading pathogens. This response relies heavily on rapid protein synthesis and accurate cellular targeting to ensure pathogen destruction. In return, pathogens intercept this response so they can survive and proliferate. To gain insight into this dynamic interface, we combined click-chemistry with pulsed stable isotope labelling of amino acids (pSILAC-AHA) and quantified the newly synthesised host proteome during macrophage infection with the model intracellular bacterial pathogen, Salmonella enterica Typhimurium (STm). We monitored newly synthesized proteins across different compartments and during different infection stages, and used available proteomics data in response to LPS to deconvolute the STm-specific response. Within this rich resource, we detect aberrant trafficking of lysosomal proteases to the extracellular space and the nucleus, the latter of which correlates with signatures of cell death. Pharmacological cathepsin inhibition suppressed caspase-11 dependent macrophage cell death, thus demonstrating an active role for cathepsins during STm induced pyroptosis. Our study illustrates the utility of resolving the host proteome dynamics during infection to drive the discovery of novel biological mechanisms at the host-microbe interface.

2020-01-24 | PXD010179 | Pride

Single-cell profiling identifies ACE+ granuloma macrophages as a non-permissive niche for intracellular bacteria during persistent Salmonella infection

Project description:Macrophages mediate key antimicrobial responses against intracellular bacterial pathogens, such as Salmonella enterica. Yet, they can also act as a permissive niche for these pathogens to persist in infected tissues within granulomas, which are immunological structures comprised of macrophages and other immune cells. We apply single-cell transcriptomics to investigate macrophage functional diversity during persistent Salmonella enterica serovar Typhimurium (STm) infection in mice. We identify determinants of macrophage heterogeneity in infected spleens and describe populations of distinct phenotypes, functional programming, and spatial localization. Using a STm mutant with impaired ability to polarize macrophage phenotypes, we find that angiotensin converting enzyme (ACE) defines a granuloma macrophage population that is non-permissive for intracellular bacteria and their abundance anticorrelates with tissue bacterial burden. Disruption of pathogen control by neutralizing TNF is linked to preferential depletion of ACE+ macrophages in infected tissues. Thus ACE+ macrophages have limited capacity to serve as cellular niche for intracellular bacteria to establish persistent infection.

2022-10-20 | GSE215880 | GEO

The effect of probiotic Lactobacilli strains, inulin-type fructans and oligofructose on gene expression profiles in intestinal Caco-2 cells

Project description:Background: Beneficial microbes can be actors in maintaining or stimulating barrier function, and may counteract pathogen-infection. Lactobacilli are particularly recognized for enhancing intestinal barrier function and to confer protective effects against multiresistant pathogens. Various L. acidophilus strains support intestinal immune barrier function and have been shown to improve resistance to pathogens. Although less extensively studied than beneficial bacteria, other food-based ingredients that can contribute to strengthening barrier function are dietary fibers. For instance, inulin and fructooligosaccharides (FOS) have recently been shown to enhance barrier function and protect against barrier dysfunction. Effects of these ingredients on intestinal barrier function were evaluated by quantifying regulation of gene expression by microarray. Methods: Caco-2 cells were incubated with probiotic strains or inulin-type fibers for 6 hours, total RNA was extracted and Affymterix Human Gene 1.1 ST arrays were used to analyze the gene expression profiles. Results: Only L. acidophilus modulated a group of 26 genes related to tight-junctions. Inulin-type fructans, L. brevis W63 and L. casei W56 regulated other genes, unrelated to tight junctions. L. acidophilus also had unique effects on a group of 6 genes regulating epithelial phenotype towards follicle-associated epithelium. L. acidophilus W37 was therefore selected for a challenge with STM and prevented STM-induced barrier disruption and decreased secretion of IL-8. L. acidophilus W37 increases TEER and can protect against STM induced disruption of gut epithelial cells integrity in vitro. Conclusion: Our results suggest that selection of specific bacterial strains for enforcing barrier function may be a promising strategy to reduce or prevent STM infections.

2018-07-19 | GSE115022 | GEO

Transcription profiling of human HCMV-Infected monocytes study 2

Project description:Human cytomegalovirus induces a pro-inflammatory monocyte following infection. To begin to address how HCMV induces these rapid changes in infected monocytes, we examined the transcriptome of infected monocytes. Global transcriptional profiling using cDNA microarrays revealed a significant number of pro-inflammatory genes were upregulated within 4 hours post infection. Experiment Overall Design: To begin to globally define the HCMV-induced changes in monocyte function, we performed a transcriptome analysis. Specifically, a cDNA microarray containing 12,626 unique probe sets was utilized to assess the modulation of the monocyte transcriptome at 4 hours post infection. A total of 6 replicates from mock-infected and 6 replicates from HCMV-infected monocytes were analyzed in this study.

2008-06-20 | E-GEOD-11408 | biostudies-arrayexpress

Pathogen-specific innate immune response patterns are distinctly affected by genetic diversity

Project description:Innate immune responses vary by pathogen and host genetics. We generated transcriptomes of monocytes from 215 individuals, with and without stimulation (3h or 6h) by fungal, Gram-negative or Gram-positive bacterial pathogens. Monocytes showed a conserved response to bacterial pathogens and a distinct antifungal response. Mapping expression quantitative trait loci (eQTLs) identified 745 response eQTLs (reQTLs) and corresponding genes showing pathogen-specific effects. Compared to all differentially expressed genes, reQTL-regulated genes were more frequently upregulated, indicating cell-activating gene regulation. ReQTL-regulated gene products are essential in NOD-like, C-type lectin, Toll-like and complement receptor-signaling pathways. ReQTLs functionally characterize risk variants identified through genome-wide association studies for autoimmunity, inflammatory or infectious diseases and cancer. Thus, in addition to the transcriptional response of monocytes, their genetic regulation differs for bacterial and fungal pathogens. ReQTLs help explain interindividual variation in immune response to infection and provide candidate genes for variants associated with a range of diseases.

2022-03-03 | GSE177040 | GEO

Monocyte subsets exhibit transcriptional plasticity and a shared response to interferon in SIV-infected rhesus macaques

Project description:The progression to AIDS is influenced by changes in the biology of heterogeneous monocyte subsets. Classical (CD14++CD16-), intermediate (CD14++CD16+), and nonclassical (CD14+CD16++) monocytes may represent progressive stages of monocyte maturation or disparate myeloid lineages with different turnover rates and function. To investigate the relationship between monocyte subsets and the response to SIV infection, we performed microarray analysis of monocyte subsets in rhesus macaques at three timepoints: prior to SIV infection, 26 days post-infection, and necropsy with AIDS. Genes with a 2-fold change between monocyte subsets (2023 genes) or infection timepoints (424 genes) were selected. We identify 172 genes differentially expressed among monocyte subsets in both uninfected and SIV-infected animals. Classical monocytes express genes associated with inflammatory responses and cell proliferation. Nonclassical monocytes express genes associated with activation, immune effector functions, and cell cycle inhibition. The classical and intermediate subsets are most similar at all timepoints, and transcriptional similarity between intermediate and nonclassical monocytes increases with AIDS. Cytosolic sensors of nucleic acids, restriction factors, and interferon-stimulated genes are induced in all three subsets with AIDS. We conclude that SIV infection alters the transcriptional relationship between monocyte subsets and that the innate immune response to SIV infection is conserved across monocyte subsets.

2017-05-10 | GSE98717 | GEO

Inflammation induced by influenza virus impairs innate control of human pneumococcal carriage

Project description:Secondary bacterial pneumonia following influenza infection is a significant cause of mortality worldwide. Upper respiratory tract pneumococcal carriage is important as both determinants of disease and population transmission. The immunological mechanisms that contain pneumococcal carriage are well-studied in mice but remain unclear in humans. Loss of this control of carriage following influenza infection is associated with secondary bacterial pneumonia during seasonal and pandemic outbreaks. We used a human type 6B pneumococcal challenge model to show that carriage acquisition induces early degranulation of resident neutrophils and recruitment of monocytes to the nose. Monocyte function associated with clearance of pneumococcal carriage. Prior nasal infection with live attenuated influenza virus induced inflammation, impaired innate function and altered genome-wide nasal gene responses to pneumococcal carriage. Levels of the cytokine IP-10 promoted by viral infection at the time of pneumococcal encounter was positively associated with bacterial density. These findings provide novel insights in nasal immunity to pneumococcus and viral-bacterial interactions during co-infection.

2018-07-25 | GSE117580 | GEO

Helicobacter pylori induces a novel form of innate immune memory via accumulation of NF-кB proteins

Project description:Helicobacter pylori is a widespread Gram-negative pathogen involved in a variety of gastrointestinal diseases, including gastritis, ulceration, mucosa-associated lymphoid tissue (MALT) lymphoma and gastric cancer. Immune responses aimed at eradication of H. pylori often prove futile, and paradoxically play a crucial role in the degeneration of epithelial integrity and disease progression. We have previously shown that H. pylori infection of primary human monocytes increases their potential to respond to subsequent bacterial stimuli – a process that may be involved in the generation of exaggerated, yet ineffective immune responses directed against the pathogen. In this study, we show that H. pylori-induced monocyte priming is not a common feature of Gram-negative bacteria, as Acinetobacter lwoffii induces tolerance to subsequent Escherichia coli lipopolysaccharide (LPS) challenge. Although the increased reactivity of H. pylori-infected monocytes seems to be specific to H. pylori, it appears to be independent of its virulence factors Cag pathogenicity island (CagPAI), cytotoxin associated gene A (CagA), vacuolating toxin A (VacA) and g-glutamyl transferase (g-GT). Utilizing whole-cell proteomics complemented with biochemical signaling studies, we show that H. pylori infection of monocytes induces a unique proteomic signature compared to other pro-inflammatory priming stimuli, namely LPS and the pathobiont A. lwoffii. Contrary to these tolerance- inducing stimuli, H. pylori priming leads to accumulation of NF-кB proteins, including p65/RelA, and thus to the acquisition of a monocyte phenotype more responsive to subsequent LPS challenge. The plasticity of pro-inflammatory responses based on abundance and availability of intracellular signaling molecules may be a heretofore underappreciated form of regulating innate immune memory as well as a novel facet of the pathobiology induced by H. pylori

2023-11-10 | PXD045072 | Pride

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