Project description:Interferon-stimulated genes (ISGs) form the backbone of innate immune system and are pivotal for limiting intra- and intercellular viral replication and spread. We conducted a mass spectrometry–based survey to understand the fundamental organization of the innate immune system and to explore molecular functions of individual ISGs. We identified interactions between 104 ISGs and 1,401 cellular binding partners engaging in 2,734 high-confidence interactions. 90% of these interactions are unreported so far, and our survey therefore illuminates a far wider activity spectrum of ISGs than currently known. Integration of the resulting ISG-interaction network with published datasets and functional studies allowed us to identify novel regulators of immunity and immune system–related processes. Given the extraordinary robustness of the innate immune system, this ISG network may serve as a blueprint for therapeutic targeting of cellular systems in order to efficiently fight viral infections.
Project description:The meninges are densely innervated by nociceptive sensory neurons that mediate pain and headache. How pain and neuro-immune interactions impact meningeal host defenses is unclear. Bacterial meningitis causes life-threatening infections of the meninges and central nervous system (CNS), affecting over one million people a year. Here we find that Nav1.8+ neuron signaling to immune cells in the meninges via the neuropeptide calcitonin gene-related peptide (CGRP) exacerbates bacterial meningitis. Nociceptor ablation reduced meningeal and brain invasion by two bacterial pathogens: Streptococcus pneumoniae and Streptococcus agalactiae. S. pneumoniae activated nociceptors via Pneumolysin to release CGRP, which acts through its receptor RAMP1 on meningeal macrophages to inhibit chemokine expression, neutrophil recruitment and antimicrobial defenses. Macrophage-specific RAMP1 deficiency or blockade of RAMP1 signaling enhanced immune responses and bacterial clearance in meninges and brain. Therefore, targeting a neuro-immune axis in the meninges can enhance host defenses and may be a potential treatment for bacterial meningitis.
Project description:Groups of samples used in Microarray and comparative genomics-based identification of genes and gene regulatory regions of the mouse immune system profiles.
Project description:The human body is host to large numbers of bacteriophages (phages)⁻a diverse group of bacterial viruses that infect bacteria. Phage were previously regarded as bystanders that only impacted immunity indirectly via effects on the mammalian microbiome. However, it has become clear that phages also impact immunity directly, in ways that are typically anti-inflammatory. Phages can modulate innate immunity via phagocytosis and cytokine responses, but also impact adaptive immunity via effects on antibody production and effector polarization. Phages may thereby have profound effects on the outcome of bacterial infections by modulating the immune response. In this review we highlight the diverse ways in which phages interact with human cells. We present a computational model for predicting these complex and dynamic interactions. These models predict that the phageome may play important roles in shaping mammalian-bacterial interactions.
Project description:The maintenance of intestinal homeostasis is a fundamental process critical for organismal integrity. Sitting at the interface of the gut microbiome and mucosal immunity, adaptive and innate lymphoid populations regulate the balance between commensal micro-organisms and pathogens. Checkpoint inhibitors (CPI), particularly those targeting the CTLA-4 pathway, disrupt this fine balance and can lead to inflammatory bowel disease (IBD) and immune checkpoint colitis (CPI-C). Here, we show that CTLA-4 is expressed by innate lymphoid cells (ILC) and that its expression is regulated by ILC subset-specific cytokine cues in a microbiota-dependent manner. Genetic deletion or antibody blockade of CTLA-4 demonstrates that this pathway plays a key role in intestinal homeostasis and is conserved in human IBD and CPI-induced colitis (CPI-C). We propose that this population of CTLA-4-positive ILC may serve as an important target for the treatment of idiopathic and iatrogenic intestinal inflammation.
Project description:Groups of samples used in Microarray and comparative genomics-based identification of genes and gene regulatory regions of the mouse immune system profiles. Keywords: other