Bacterial infection leads to consumption of short-lived innate immune effector cells, which then need to be replenished from hematopoietic stem and progenitor cells (HSPCs). HSPCs express pattern recognition receptors, such as Toll-like receptors (TLRs), and ligation of these receptors induces HSPC mobilization, cytokine production, and myeloid differentiation. The underlying mechanisms involved in pathogen signal transduction in HSCs and the resulting biological consequences remain poorly defined. Here, we show that in vivo lipopolysaccharide (LPS) application induces proliferation of dormant HSCs directly via TLR4 and that sustained LPS exposure impairs HSC self-renewal and competitive repopulation activity. This process is mediated via TLR4-TRIF-ROS-p38, but not MyD88 signaling, and can be inhibited pharmacologically without preventing emergency granulopoiesis. Live Salmonella Typhimurium infection similarly induces proliferative stress in HSCs, in part via TLR4-TRIF signals. Thus, while direct TLR4 activation in HSCs might be beneficial for controlling systemic infection, prolonged TLR4 signaling has detrimental effects and may contribute to inflammation-associated HSPC dysfunction.

The emergence of antibiotic resistant bacteria by mutations or by acquisition of genetic material like resistance plasmids represents a major public health issue 1,2 (Extended Data Fig. 1a). Persisters are bacterial subpopulations surviving antibiotics by reversibly adapting their Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Bacteriophage transfer (lysogenic conversion) promotes bacterial virulence evolution. There is limited understanding of the factors that determine lysogenic conversion dynamics within infected hosts. A murine Typhimurium (Tm) diarrhea model was used to study the transfer of SopEΦ, a prophage from Tm SL1344, toTm ATCC14028S. Gut inflammation and enteric disease triggered >55% lysogenic conversion of ATCC14028S within 3 days. Without inflammation, SopEΦ transfer was reduced by up to 10-fold. This was because inflammation (e.g., reactive oxygen species, reactive nitrogen species, hypochlorite) triggers the bacterial SOS response, boosts expression of the phage antirepressor Tum, and thereby promotes free phage production and subsequent transfer. Mucosal vaccination prevented a dense intestinal Tm population from inducing inflammation and consequently abolished SopEΦ transfer. Vaccination may be a general strategy for blocking pathogen evolution that requires disease-driven transfer of temperate bacteriophages.

Protein modification by the ubiquitin-like protein ISG15 is an interferon (IFN) effector system, which plays a major role in antiviral defense. ISG15 modification is counteracted by the isopeptidase USP18, a major negative regulator of IFN signaling, which was also shown to exert its regulatory function in an isopeptidase-independent manner. To dissect enzymatic and nonenzymatic functions of USP18 in vivo, we generated knock-in mice (USP18 C61A/C61A mice was completely reversed in USP18 C61A/C61A mice, which additionally lack ISG15, providing evidence that the observed reduction in viral titers is ISG15 dependent. These results suggest that increasing ISGylation by specific inhibition of USP18 protease activity could constitute a promising antiviral strategy with only a minimal risk of severe adverse effects.rotein modification by the ubiquitin-like (UBL) modifier interferon (IFN)-stimulated gene 15 (ISG15) is strongly induced by type I IFNs and represents one of the major antiviral IFN effector systems (1). ISG15 has weak sequence identity to ubiquitin and is structurally characterized by two ubiquitin-like domains connected by a short linker region (2). In analogy to ubiquitin, ISG15 is covalently conjugated to protein targets via the consecutive action of an E1-activating enzyme (Ube1L) (3), an E2-conjugating enzyme (UbcH8) (4), and a few E3 ligases. All enzymes involved in the conjugation process are themselves strongly inducible by type I IFNs. The major E3 ligases for human and murine ISG15 modification (ISGylation) are hHERC5 (5, 6) and mHERC6 (7, 8), respectively. hHERC5 is associated with polyribosomes and newly synthesized proteins are modified by ISG15 in a cotranslational manner (9). Thus, it was suggested that ISG15 modification of virusderived proteins, which are the most prevalent translational products in a virus-infected cell, mediates the antiviral activity of the ISGylation system. In line with this suggestion, ISG15 modification of the human papilloma virus protein HPV16 L1 interfered with virus assembly and decreased the infectivity of HPV in a dominant manner (9). Moreover, ISGylation of the influenza virus protein NS1A prevents interaction with importin-α and thereby interferes with the capability of NS1A to counteract host defense (10). ISG15 is also conjugated to cellular proteins. For example, ISGylation increases the stability of the IFN regulatory factor 3 (IRF3), resulting in enhanced activation of IRF3 target genes (11,12). Consistent with the antiviral function, mice lacking ISG15 are more susceptible to influenza A and B, Sindbis, and herpes virus infections (13). However, antiviral responses against vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV) are not altered (14). For both influenza B and Sindbis virus infection, the antiviral function of ISG15 is dependent on its ability to form conjugates because mice lacking the ISG15 E1 enzyme, UbE1L, are also susceptible to these infections (15, 16). Several viruses including influenza B virus, vaccinia vir...

The microbiota confers colonization resistance, which blocks Salmonella gut colonization 1. As diet affects microbiota composition, we studied whether food-composition shifts enhance susceptibility to infection. Shifting mice to diets with reduced fiber or elevated fat contents for 24h boosted S. Typhimurium or E. coli gut colonization and plasmid transfer. Here, we studied the effect of dietary fat. Colonization resistance was restored within 48h of return to maintenance diet. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: