Antiviral reaction beyond immune cells

The immune system’s response to disease-causing agents relies on a complex web of immune cell interactions that is underpinned by powerful regulatory mechanisms. Most of our understanding of the immune system revolves around these cells, but cells that are generally thought to have predominantly structural roles can also respond to invading organisms. Writing Nature, Claus Gruber other..¹ We elucidate the role of these cells in signaling networks used for defense purposes and report a multi-organ examination of the gene expression program of such structural cells in mice. The authors found that the structural cell response to external invaders was regulated and tailored to the particular organ in question.

Structural cells such as fibroblasts, endothelial cells, and epithelial cells (Figure 1) are present in most organs and provide more than just support.^2,Three.. Fibroblasts form part of the connective tissue and help maintain the extracellular matrix material that surrounds the cells. Endothelial cells line blood vessels such as blood vessels and, along with epithelial cells present on the surface of organs, may be involved in the response to infection either directly or through interaction with immune cells.^Three..

To understand the role of these three cell types in the immune response, Krausgruber et al. isolated them from 12 different tissues of healthy mice. The authors used RNA sequencing to determine the genes expressed by the cells and searched for known immune-related genes. Claus Gruber other.. We also characterized cellular chromatin, a DNA-protein complex in the nucleus, to identify genomic regions that were ready to initiate gene expression. It determines the accessibility of genome-wide “open” chromatin using a method called ATAC-seq, and the authors are active by tracking a type of change in the DNA-binding histone 3 protein called H3K4me2. Identified the promoter region. Together, these methods open the transcriptional regulatory circuits that govern the identity and function of these cells.

The three cell types can be defined by the expression of genes corresponding to specific marker proteins on the cell surface, but the three cell lines also displayed characteristic features of their local organ environment. Throughout the genome, gene expression, open chromatin, and active promoter data sets have shown that different cell types in organs are more similar to each other than specific cell types for the same cell type in different organs. This is an important observation that provides the basis for future research on the specific role of structural cells in the function of each organ.

The authors search for gene expression data in structural cells, identify the receptors and ligand molecules they expressed, and mine previously published RNA sequence data for immune cells to enable them to interact with each other. Matched with action partner. Next, we construct a computationally derived network to clarify cell-type and organ-specific interactions in which structural cells and immune cells may be involved, and to clarify the daily interactions between immune cells and structural cells. Define the baseline.

To further understand how structural cells prepare to trigger gene expression programs for defense purposes, the authors together with the chromatin accessibility profile of the corresponding gene promoters (DNA sequences that help gene expression) The gene expression data was evaluated. The open chromatin region containing the gene promoter is known to be a reliable indicator of gene expression^Four.. The authors used these binding data to look for outliers, genes that had open accessible promoters but low expression levels. This represents a gene that is likely to respond quickly when an infection occurs. This approach highlighted a group of genes that code for a significant number of immune-related proteins, these examples being most apparent in structural cells of the skin, liver, and spleen. These genes deserve further study focusing on how the structural cells that express them respond to infection and protect their home organs.

The authors have actually identified a gene for a role in the immune response by infecting mice with lymphocytic choriomeningitis virus (LCMV) and monitoring gene expression by RNA sequences in structural cells. confirmed. LCMV is a well-studied virus that affects most organs. This allowed Krausgruber and his colleagues to distinguish between organ-specific and global defense responses. Eight days after infection, up to 57.9% of unrealized genes were activated in structured cells, with particularly high responses in liver, spleen, lung, and colon fibroblasts and endothelial cells.

In addition, the authors found that antiviral response was evident in these gene expression profiles. Comparing infected and uninfected animals, infected animals had higher expression levels of transcription factors and immune-related signaling proteins called cytokines involved in pathways associated with the expression of the antiviral protein interferon. In response to viral infection, structural cells also expressed small proteins called chemokines that attract immune cells. This was surprising because chemokine secretion is primarily associated with immune cells. The authors propose that the predicted interaction network between immune cells and structural cells is altered by LCMV infection, and during infection, structural cells from various organs are immune to monocytes, macrophages, B cells, etc. It has been suggested to increase interaction with cells.

To analyze the effects of signaling in response to LCMV infection, the authors injected individual cytokines of the type detected in the antiviral response into the bloodstream of mice without LCMV infection. Claus Gruber other.. We then sequenced the RNA of the structural cells of the organ with the highest response to LCMV observed previously. They found that changes in gene expression were more pronounced in fibroblasts and endothelial cells than in epithelial cells. Analysis of the gene expression response to each cytokine revealed the part of the antiviral program that it regulates. Among other interactions, this revealed a possibly produced cytokine IL-6 and IFN-γ In vivo Immune cells are responsible for inducing many of the antiviral responses of splenic endothelial cells by promoting the expression of potentially unrealized genes.

Although gene expression programs involved in the immune response have been previously reported in some structural cells, Krausgruber and colleagues’ studies have shown that these cells are crucial for organ-specific and whole-body regulation of the immune response. Emphasizes the role. It also shows how to use a combination of cellular communication networks and analysis of chromatin-mediated regulation to identify functionally related candidate genes. One of the ultimate goals of this research area is to develop cell-type targeted therapies that regulate the immune response. This could be of great benefit to cancer research, for example because fibroblasts associated with cancer play a role in promoting tumor progression.^Five..

Future work is likely to be linked to the Human Cell Atlas initiative and will focus on the protective response of other types and subtypes of human cells.⁶A detailed molecular profile of all human cells has been generated to fully account for cell type diversity. The single-cell approach helps profiling RNA transcripts in all cell types and whole organ conditions in steady-state and post-stimulation scenarios. Using a new method called spatial transcriptomics (monitoring gene expression in intact tissue sections rather than isolated cells) with information on chromatin status, entanglement of the entire cell chain of events, from detection of infection to defense response And to mobilize immune cells, and finally to the removal of infectious agents. By profiling structural cells of various mouse organs, Krausgruber other.. Unleashed a pile of knowledge about antiviral defenses that may be related to other species and may facilitate new ways of targeting human disease.