Amon, L. M. | bioRxiv Science

bioRxiv2019

A comprehensive map of the dendritic cell transcriptional network engaged upon innate sensing of HIV

Transcriptional programming of the innate immune response is pivotal for host protection. However, the transcriptional mechanisms that link pathogen sensing with innate activation remain poorly understood. During infection with HIV-1, human dendritic cells (DCs) can detect the virus through an innate sensing pathway leading to antiviral interferon and DC maturation. Here, we developed an iterative experimental and computational approach to map the innate response circuitry during HIV-1 infection. By integrating genome-wide chromatin accessibility with expression kinetics, we inferred a gene regulatory network that links 542 transcription factors with 21,862 target genes. We observed that an interferon response is required, yet insufficient to drive DC maturation, and identified PRDM1 and RARA as essential regulators of the interferon response and DC maturation, respectively. Our work provides a resource for interrogation of regulators of HIV replication and innate immunity, highlighting complexity and cooperativity in the regulatory circuit controlling the DC response to infection.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC=\"FIGDIR/small/579920_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (60K):\norg.highwire.dtl.DTLVardef@f57059org.highwire.dtl.DTLVardef@1a2f811org.highwire.dtl.DTLVardef@4c2908org.highwire.dtl.DTLVardef@19e1e9_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2019

Alveolar macrophages up-regulate a non-classical innate response to Mycobacterium tuberculosis infection in vivo

Alveolar macrophages (AMs) are the first cells to be infected during Mycobacterium tuberculosis (Mtb) infection. Thus the AM response to infection is the first of many steps leading to initiation of the adaptive immune response, which is required for efficient control of infection. A hallmark of Mtb infection is the delay of the adaptive response, yet the mechanisms responsible for this delay are largely unknown. We developed a system to identify, sort and analyze Mtb-infected AMs from the lung within the first 10 days of infection. In contrast to what has been previously described using in vitro systems, we find that Mtb-infected AMs up-regulate a cell-protective antioxidant transcriptional signature that is dependent on the lung environment and not dependent on bacterial virulence. Computational approaches including pathway analysis and transcription factor binding motif enrichment analysis identify Nrf2 as a master regulator of the response of AMs to Mtb infection. Using knock-out mouse models, we demonstrate that Nrf2 drives the expression of the cell protective transcriptional program and impairs the ability of the host to control bacterial growth over the first 10 days of infection. Mtb-infected AMs exhibit a highly delayed pro-inflammatory response, and comparisons with uninfected AMs from the same infected animals demonstrate that inflammatory signals in the lung environment are blocked in the Mtb-infected cells. Thus, we have identified a novel lung-specific transcriptional response to Mtb infection that impedes AMs from responding rapidly to intracellular infection and thereby hinders the overall immune response.\n\nOne Sentence SummaryIn response to Mtb infection in vivo, alveolar macrophages fail to up-regulate the canonical pro-inflammatory innate response and instead induce an Nrf2-dependent cell protective transcriptional program, which in turn impairs the hosts control of bacterial growth.

immunology↗