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1.
Cell Host Microbe ; 23(5): 644-652.e5, 2018 05 09.
Article in English | MEDLINE | ID: mdl-29746835

ABSTRACT

In physiological settings, the complement protein C3 is deposited on all bacteria, including invasive pathogens. However, because experimental host-bacteria systems typically use decomplemented serum to avoid the lytic action of complement, the impact of C3 coating on epithelial cell responses to invasive bacteria remains unexplored. Here, we demonstrate that following invasion, intracellular C3-positive Listeria monocytogenes is targeted by autophagy through a direct C3/ATG16L1 interaction, resulting in autophagy-dependent bacterial growth restriction. In contrast, Shigella flexneri and Salmonella Typhimurium escape autophagy-mediated growth restriction in part through the action of bacterial outer membrane proteases that cleave bound C3. Upon oral infection with Listeria, C3-deficient mice displayed defective clearance at the intestinal mucosa. Together, these results demonstrate an intracellular role of complement in triggering antibacterial autophagy and immunity against intracellular pathogens. Since C3 indiscriminately associates with foreign surfaces, the C3-ATG16L1 interaction may provide a universal mechanism of xenophagy initiation.


Subject(s)
Autophagy/drug effects , Autophagy/immunology , Bacteria/immunology , Carrier Proteins/immunology , Complement C3/immunology , Complement C3/pharmacology , Host-Pathogen Interactions/immunology , Animals , Autophagy-Related Proteins , Bacteria/pathogenicity , Bacterial Outer Membrane Proteins/immunology , Dysentery, Bacillary/immunology , Dysentery, Bacillary/microbiology , Epithelial Cells , Female , HCT116 Cells , HEK293 Cells , HeLa Cells , Humans , Intestinal Mucosa/immunology , Intestinal Mucosa/microbiology , Listeria monocytogenes/immunology , Listeria monocytogenes/pathogenicity , Listeriosis/immunology , Listeriosis/microbiology , Male , Mice , Mice, Inbred C57BL , Salmonella Infections/immunology , Salmonella Infections/microbiology , Salmonella typhimurium/immunology , Salmonella typhimurium/pathogenicity , Shigella flexneri/immunology , Shigella flexneri/pathogenicity , THP-1 Cells
2.
Nucleic Acids Res ; 44(22): 10571-10587, 2016 12 15.
Article in English | MEDLINE | ID: mdl-27604870

ABSTRACT

To understand the epigenetic regulation of transcriptional response of macrophages during early-stage M. tuberculosis (Mtb) infection, we performed ChIPseq analysis of H3K4 monomethylation (H3K4me1), a marker of poised or active enhancers. De novo H3K4me1 peaks in infected cells were associated with genes implicated in host defenses and apoptosis. Our analysis revealed that 40% of de novo regions contained human/primate-specific Alu transposable elements, enriched in the AluJ and S subtypes. These contained several transcription factor binding sites, including those for members of the MEF2 and ATF families, and LXR and RAR nuclear receptors, all of which have been implicated in macrophage differentiation, survival, and responses to stress and infection. Combining bioinformatics, molecular genetics, and biochemical approaches, we linked genes adjacent to H3K4me1-associated Alu repeats to macrophage metabolic responses against Mtb infection. In particular, we show that LXRα signaling, which reduced Mtb viability 18-fold by altering cholesterol metabolism and enhancing macrophage apoptosis, can be initiated at response elements present in Alu repeats. These studies decipher the mechanism of early macrophage transcriptional responses to Mtb, highlighting the role of Alu element transposition in shaping human transcription programs during innate immunity.


Subject(s)
Alu Elements , Gene Expression Regulation/immunology , Macrophages/metabolism , Mycobacterium tuberculosis/immunology , Tuberculosis/metabolism , Base Sequence , Binding Sites , Cell Line , Humans , Immunity, Innate , Liver X Receptors/physiology , Macrophages/immunology , Macrophages/microbiology , Male , Microbial Viability , Transcription Factors/physiology , Transcriptome , Tuberculosis/immunology , Tuberculosis/microbiology
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