Pathogen Cell-to-Cell Variability Drives Heterogeneity in Host Immune Responses

Graphical Abstract Highlights d Single-cell RNA-seq reveals heterogeneity of host-pathogen encounters d PhoP-mediated LPS modifications occur in only a subset of bacteria during infection d Intracellular recognition of modified LPS induces heterogeneous type I IFN response d Heterogeneity is a key feature of pathogen population during infection In Brief Functional heterogeneity in the response of host cells to infection is driven by cell-to-cell transcriptional variations in the population of infecting pathogens.

[1]  G. Hong,et al.  Nucleic Acids Research , 2015, Nucleic Acids Research.

[2]  Colin N. Dewey,et al.  RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome , 2011, BMC Bioinformatics.

[3]  Jacob T. Robinson,et al.  Systematic Discovery of TLR Signaling Components Delineates Viral-Sensing Circuits , 2011, Cell.

[4]  R. Dudani,et al.  Type I interferon induces necroptosis in macrophages during infection with Salmonella enterica serovar Typhimurium , 2012, Nature Immunology.

[5]  Eduardo A. Groisman,et al.  The Pleiotropic Two-Component Regulatory System PhoP-PhoQ , 2001, Journal of bacteriology.

[6]  C. Jenkin,et al.  The functional heterogeneity of macrophages at the single cell level. , 1967, The Australian journal of experimental biology and medical science.

[7]  Daniel R. Zerbino,et al.  Ensembl 2014 , 2013, Nucleic Acids Res..

[8]  Steve Horvath,et al.  WGCNA: an R package for weighted correlation network analysis , 2008, BMC Bioinformatics.

[9]  Hiroyuki Ogata,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 1999, Nucleic Acids Res..

[10]  W. Huber,et al.  which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. MAnorm: a robust model for quantitative comparison of ChIP-Seq data sets , 2011 .

[11]  Terrence S. Furey,et al.  The UCSC Table Browser data retrieval tool , 2004, Nucleic Acids Res..

[12]  Nicholas A. Ruggero,et al.  Single-Cell and Population NF-κB Dynamic Responses Depend on Lipopolysaccharide Preparation , 2013, PloS one.

[13]  S. Vogel,et al.  SHORT COMMUNICATION: Bone Marrow Progenitors Cultured in the Presence of Granulocyte‐Macrophage Colony‐Stimulating Factor Versus Macrophage Colony‐Stimulating Factor Differentiate Into Macrophages With Distinct Tumoricidal Capacities , 1988, Journal of leukocyte biology.

[14]  Jeffrey W. Smith,et al.  Stochastic Gene Expression in a Single Cell , 2022 .

[15]  D. Morrison,et al.  Endotoxins and disease mechanisms. , 1987, Annual review of medicine.

[16]  Christine E. Becker,et al.  TRIF Licenses Caspase-11-Dependent NLRP3 Inflammasome Activation by Gram-Negative Bacteria , 2012, Cell.

[17]  A. Regev,et al.  Preparation of Single‐Cell RNA‐Seq Libraries for Next Generation Sequencing , 2014, Current protocols in molecular biology.

[18]  S. Miller,et al.  Constitutive expression of the phoP regulon attenuates Salmonella virulence and survival within macrophages , 1990, Journal of bacteriology.

[19]  Wolf-Dietrich Hardt,et al.  Self-destructive cooperation mediated by phenotypic noise , 2008, Nature.

[20]  B. Stecher,et al.  Real-time imaging of type III secretion: Salmonella SipA injection into host cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[21]  B. Cookson,et al.  In vivo, fliC expression by Salmonella enterica serovar Typhimurium is heterogeneous, regulated by ClpX, and anatomically restricted , 2006, Molecular microbiology.

[22]  Xiao-Zhe Huang,et al.  Differential Bacterial Survival, Replication, and Apoptosis-Inducing Ability of Salmonella Serovars within Human and Murine Macrophages , 2000, Infection and Immunity.

[23]  Xia Zhang,et al.  The Isolation and Characterization of Murine Macrophages , 2008, Current protocols in immunology.

[24]  I. Amit,et al.  Massively Parallel Single-Cell RNA-Seq for Marker-Free Decomposition of Tissues into Cell Types , 2014, Science.

[25]  Nir Hacohen,et al.  Identification of regulators of the innate immune response to cytosolic DNA and retroviral infection by an integrative approach , 2012, Nature Immunology.

[26]  S. Leibler,et al.  Phenotypic Diversity, Population Growth, and Information in Fluctuating Environments , 2005, Science.

[27]  C. Galanos,et al.  A new method for the extraction of R lipopolysaccharides. , 1969, European journal of biochemistry.

[28]  J. Galán,et al.  Type III Secretion Machines: Bacterial Devices for Protein Delivery into Host Cells , 1999 .

[29]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[30]  Arthur Thompson,et al.  Unravelling the biology of macrophage infection by gene expression profiling of intracellular Salmonella enterica , 2002, Molecular microbiology.

[31]  Anne E Carpenter,et al.  CellProfiler: free, versatile software for automated biological image analysis. , 2007, BioTechniques.

[32]  M. Bernardini,et al.  Intracellular Shigella remodels its LPS to dampen the innate immune recognition and evade inflammasome activation , 2013, Proceedings of the National Academy of Sciences.

[33]  B. Finlay,et al.  Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. , 2007, Cell host & microbe.

[34]  Jessica A. Thompson,et al.  Dynamics of intracellular bacterial replication at the single cell level , 2010, Proceedings of the National Academy of Sciences.

[35]  J. Levin,et al.  Clottable Protein in Limulus: Its Localization and Kinetics of Its Coagulation by Endotoxin , 1968, Thrombosis and Haemostasis.

[36]  B. Finlay,et al.  Salmonella typhimurium Infection and Lipopolysaccharide Stimulation Induce Similar Changes in Macrophage Gene Expression1 , 2000, The Journal of Immunology.

[37]  Hiroaki Kitano,et al.  Biological robustness , 2008, Nature Reviews Genetics.

[38]  E. Groisman,et al.  Acid pH activation of the PmrA/PmrB two-component regulatory system of Salmonella enterica , 2007, Molecular microbiology.

[39]  Xiufen Zou,et al.  Characterizing and controlling the inflammatory network during influenza A virus infection , 2014, Scientific Reports.

[40]  R. Gazzinelli.  Faculty Opinions recommendation of LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF. , 2003 .

[41]  Roland R. Regoes,et al.  Stabilization of cooperative virulence by the expression of an avirulent phenotype , 2013, Nature.

[42]  Rona S. Gertner,et al.  Single-cell transcriptomics reveals bimodality in expression and splicing in immune cells , 2013, Nature.

[43]  S. Miller,et al.  Regulation of lipid A modifications by Salmonella typhimurium virulence genes phoP-phoQ. , 1997, Science.

[44]  A. DeFranco.  Faculty Opinions recommendation of TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta. , 2008 .

[45]  S. Falkow,et al.  Salmonella typhimurium invasion induces apoptosis in infected macrophages. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[46]  K. Honda,et al.  IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors , 2006, Nature Reviews Immunology.

[47]  J. Gunn,et al.  Cathelicidin Antimicrobial Peptide Expression Is Not Induced or Required for Bacterial Clearance during Salmonella enterica Infection of Human Monocyte-Derived Macrophages , 2012, Infection and Immunity.

[48]  Rona S. Gertner,et al.  Single cell RNA Seq reveals dynamic paracrine control of cellular variation , 2014, Nature.

[49]  D. Bumann,et al.  Phenotypic Variation of Salmonella in Host Tissues Delays Eradication by Antimicrobial Chemotherapy , 2014, Cell.

[50]  Michele A. Busby,et al.  Simultaneous generation of many RNA-seq libraries in a single reaction , 2015, Nature Methods.