Gene expression variability across cells and species helps shape innate immunity

The innate immune response is a cell-intrinsic defense program that is rapidly up-regulated upon infection in most cell types. It acts to inhibit pathogen (i.e. virus, bacteria, fungus) replication, while signaling the pathogen’s presence to other cells. This program involves modulation of several cellular pathways, including production of antiviral and inflammatory cytokines (a broad and loose category of small proteins such as interferon, interleukin, and growth factors that are secreted by certain cells of our immune system and exert an effect on other cells), up-regulation of genes that restrict pathogens, and induction of cell death. An important characteristic of the innate immune response is the rapid evolution that many of its genes have undergone evolutionarily, as one proceeds along the vertebrate lineage. This rapid evolution is often attributed to pathogen-driven selection (gene-environment interactions here = genes responding to pathogens as the environment).

Another hallmark of the innate immune response is its high level of heterogeneity among responding cells: there is extensive cell-to-cell variability in response to pathogen infection, as well as to pathogen-associated molecular patterns. The functional importance of this variability is unclear. These two characteristics — rapid evolutionary divergence, and large cell-to-cell variability — would seem to be at odds with the strong regulatory constraints imposed on the host’s immune response. We see this need to execute a well-coordinated and carefully balanced program, while avoiding tissue damage and pathological immune conditions. How this tight regulation is maintained, despite rapid evolutionary divergence and high cell-to-cell variability remains unclear — but this is central to our understanding of the innate immune response and its evolution.

Authors [see attached article] characterized the innate immune response’s transcriptional divergence (DNA of genes transcribed into messenger RNA) between species, and the variability in expression among cells. Using multicellular, versus single-cell, transcriptomics (DNA transcribed into mRNA in fibroblasts and mononuclear phagocytes from different species that had been challenged with immune stimuli), authors mapped the genetic architecture of the innate immune response. Transcriptionally diverging genes including those that encode cytokines and chemokines vary across cells and have distinct promoter structures (chemokines = subclass of cytokines with functions that specifically include attracting white blood cells to sites of infection).

Conversely, genes involved in regulation of the innate immune response such as those that encode transcription factors and kinases (enzymes that catalyze transfer of a phosphate group from ATP to another specified molecule) are evolutionarily conserved between species and display low cell-to-cell variability in expression. Authors suggest that this expression pattern, which is observed across species and conditions, has evolved as a mechanism for fine-tuned regulation to achieve an effective, but well balanced, response to pathogens.


Nature   8 Nov 2o18; 563: 197–202

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