Project description:During an intracellular bacterial infection, the host cell and the infecting pathogen interact through a progressive series of events that may result in many distinct outcomes. To understand the specific strategies our immune system employs to manage attack by diverse pathogens, we sought to identify the unique and the core host and pathogen interactions that occur during infection: We compared in molecular detail the pathways induced across infection by seven diverse bacterial species that constitute many of the main human pathogens: Staphylococcus aureus, Listeria monocytogenes, Enterococcus faecalis, Group B Streptococcus, Yersinia pseudotuberculosis, Shigella flexneri and Salmonella enterica. We infected primary human macrophages with each species and used scRNA-Seq to generate a comprehensive dataset of gene expression profiles during bacterial infection. Examining the expression profiles of the infected macrophages across the pathogens, we discovered different modules of infection representing different states through which the infection progresses. The early module captures intra-cellular activity such as lysosome and degranulation, followed by type I IFN signaling, from which results in a cell death module, with a last mode of inflammatory response through response to IL-1. Comparing these modules across the pathogens, we found that their dynamics differ, with some modules active in all species and others which are present in some, but not all pathogens. Our work defines the hallmarks of host-pathogen interactions by identifying recurring properties of infection that can provide insight into diagnostics and therapeutic timing.
2022-12-14 | GSE145862 | GEO
Project description:Isolation and Characterization of Bacterial Pathogens Associated with Endometritis in Dairy Cows
Project description:The mammalian immune system is constantly challenged by signals from both pathogenic and non-pathogenic microbes. Many of these non-pathogenic microbes have pathogenic potential if the immune system is compromised. The importance of type I interferons (IFNs) in orchestrating innate immune responses to pathogenic microbes has become clear in recent years. However, the control of opportunistic pathogens – and especially intracellular bacteria – by type I IFNs remains less appreciated. In this study, we use the opportunistic, Gram-negative bacterial pathogen Burkholderia cenocepacia (Bc) to show that type I IFNs are capable of limiting bacterial replication in macrophages, preventing illness in immunocompetent mice. Sustained type I IFN signaling through cytosolic receptors allows for increased expression of autophagy and linear ubiquitination mediators, which slows bacterial replication. Transcriptomic analyses and in vivo studies also show that LPS stimulation does not replicate the conditions of intracellular Gram-negative bacterial infection as it pertains to type I IFN stimulation or signaling. This study highlights the importance of type I IFNs in protection against opportunistic pathogens through innate immunity, without the need for damaging inflammatory responses.
Project description:Atlantic salmon scale explants is a promising model for bacterial challenges. Exposure to pathogens (Moritella viscosa and Tenacibaculum finnmarkense) and commensal bacteria consistently upregulated a suite of immune genes in a dose response manner. This panel includes chemokines, cytokines, genes involved in eicosanoid metabolism, and both humoral and cellular effectors. The prevalence of genes related to signaling and communication suggests that salmon scales function as sentinels, mobilizing immune responses upon encountering bacteria. While common immune responses were evident across all trials, scales also revealed differences between bacterial species. Combining commensal bacteria with M. viscosa enhanced responses to pathogens, and differences were observed between M. viscosa and T. finnmarkense. The effects of commensal bacteria varied in magnitude. Exposed cells showed changes in morphology and increased iNOS expression.
Project description:The innate immune response is crucial for defense against microbial pathogens. To investigate the molecular choreography of this response, we carried out a systematic examination of the gene expression program in human peripheral blood mononuclear cells responding to bacteria and bacterial products. We found a remarkably stereotyped program of gene expression induced by bacterial lipopolysaccharide and diverse killed bacteria. An intricately choreographed expression program devoted to communication between cells was a prominent feature of the response. Other features suggested a molecular program for commitment of antigen-presenting cells to antigens captured in the context of bacterial infection. Despite the striking similarities, there were qualitative and quantitative differences in the responses to different bacteria. Modulation of this host-response program by bacterial virulence mechanisms was an important source of variation in the response to different bacteria.