Try a new search

Format these results:

Searched for:

person:shopsb01

in-biosketch:true

Total Results:

75


Staphylococcus aureus senses human neutrophils via PerR to coordinate the expression of the toxin LukAB

Savin, Avital; Anderson, Exene E; Dyzenhaus, Sophie; Podkowik, Magdalena; Shopsin, Bo; Pironti, Alejandro; Torres, Victor J
PMCID:10863418
PMID: 38235972
ISSN: 1098-5522
CID: 5635242

Transcription-replication interactions reveal bacterial genome regulation

Pountain, Andrew W; Jiang, Peien; Yao, Tianyou; Homaee, Ehsan; Guan, Yichao; McDonald, Kevin J C; Podkowik, Magdalena; Shopsin, Bo; Torres, Victor J; Golding, Ido; Yanai, Itai
Organisms determine the transcription rates of thousands of genes through a few modes of regulation that recur across the genome1. In bacteria, the relationship between the regulatory architecture of a gene and its expression is well understood for individual model gene circuits2,3. However, a broader perspective of these dynamics at the genome scale is lacking, in part because bacterial transcriptomics has hitherto captured only a static snapshot of expression averaged across millions of cells4. As a result, the full diversity of gene expression dynamics and their relation to regulatory architecture remains unknown. Here we present a novel genome-wide classification of regulatory modes based on the transcriptional response of each gene to its own replication, which we term the transcription-replication interaction profile (TRIP). Analysing single-bacterium RNA-sequencing data, we found that the response to the universal perturbation of chromosomal replication integrates biological regulatory factors with biophysical molecular events on the chromosome to reveal the local regulatory context of a gene. Whereas the TRIPs of many genes conform to a gene dosage-dependent pattern, others diverge in distinct ways, and this is shaped by factors such as intra-operon position and repression state. By revealing the underlying mechanistic drivers of gene expression heterogeneity, this work provides a quantitative, biophysical framework for modelling replication-dependent expression dynamics.
PMID: 38267581
ISSN: 1476-4687
CID: 5625052

Transcription"“replication interactions reveal bacterial genome regulation

Pountain, Andrew W.; Jiang, Peien; Yao, Tianyou; Homaee, Ehsan; Guan, Yichao; McDonald, Kevin J.C.; Podkowik, Magdalena; Shopsin, Bo; Torres, Victor J.; Golding, Ido; Yanai, Itai
Organisms determine the transcription rates of thousands of genes through a few modes of regulation that recur across the genome1. In bacteria, the relationship between the regulatory architecture of a gene and its expression is well understood for individual model gene circuits2,3. However, a broader perspective of these dynamics at the genome scale is lacking, in part because bacterial transcriptomics has hitherto captured only a static snapshot of expression averaged across millions of cells4. As a result, the full diversity of gene expression dynamics and their relation to regulatory architecture remains unknown. Here we present a novel genome-wide classification of regulatory modes based on the transcriptional response of each gene to its own replication, which we term the transcription"“replication interaction profile (TRIP). Analysing single-bacterium RNA-sequencing data, we found that the response to the universal perturbation of chromosomal replication integrates biological regulatory factors with biophysical molecular events on the chromosome to reveal the local regulatory context of a gene. Whereas the TRIPs of many genes conform to a gene dosage-dependent pattern, others diverge in distinct ways, and this is shaped by factors such as intra-operon position and repression state. By revealing the underlying mechanistic drivers of gene expression heterogeneity, this work provides a quantitative, biophysical framework for modelling replication-dependent expression dynamics.
SCOPUS:85183015326
ISSN: 0028-0836
CID: 5629352

Priorities and Progress in Gram-positive Bacterial Infection Research by the Antibacterial Resistance Leadership Group: A Narrative Review

Doernberg, Sarah B; Arias, Cesar A; Altman, Deena R; Babiker, Ahmed; Boucher, Helen W; Creech, C Buddy; Cosgrove, Sara E; Evans, Scott R; Fowler, Vance G; Fritz, Stephanie A; Hamasaki, Toshimitsu; Kelly, Brendan J; Leal, Sixto M; Liu, Catherine; Lodise, Thomas P; Miller, Loren G; Munita, Jose M; Murray, Barbara E; Pettigrew, Melinda M; Ruffin, Felicia; Scheetz, Marc H; Shopsin, Bo; Tran, Truc T; Turner, Nicholas A; Williams, Derek J; Zaharoff, Smitha; Holland, Thomas L; ,
The Antibacterial Resistance Leadership Group (ARLG) has prioritized infections caused by gram-positive bacteria as one of its core areas of emphasis. The ARLG Gram-positive Committee has focused on studies responding to 3 main identified research priorities: (1) investigation of strategies or therapies for infections predominantly caused by gram-positive bacteria, (2) evaluation of the efficacy of novel agents for infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci, and (3) optimization of dosing and duration of antimicrobial agents for gram-positive infections. Herein, we summarize ARLG accomplishments in gram-positive bacterial infection research, including studies aiming to (1) inform optimal vancomycin dosing, (2) determine the role of dalbavancin in MRSA bloodstream infection, (3) characterize enterococcal bloodstream infections, (4) demonstrate the benefits of short-course therapy for pediatric community-acquired pneumonia, (5) develop quality of life measures for use in clinical trials, and (6) advance understanding of the microbiome. Future studies will incorporate innovative methodologies with a focus on interventional clinical trials that have the potential to change clinical practice for difficult-to-treat infections, such as MRSA bloodstream infections.
PMCID:10578051
PMID: 37843115
ISSN: 1537-6591
CID: 5609602

Antimicrobial overproduction sustains intestinal inflammation by inhibiting Enterococcus colonization

Jang, Kyung Ku; Heaney, Thomas; London, Mariya; Ding, Yi; Putzel, Gregory; Yeung, Frank; Ercelen, Defne; Chen, Ying-Han; Axelrad, Jordan; Gurunathan, Sakteesh; Zhou, Chaoting; Podkowik, Magdalena; Arguelles, Natalia; Srivastava, Anusha; Shopsin, Bo; Torres, Victor J; Keestra-Gounder, A Marijke; Pironti, Alejandro; Griffin, Matthew E; Hang, Howard C; Cadwell, Ken
Loss of antimicrobial proteins such as REG3 family members compromises the integrity of the intestinal barrier. Here, we demonstrate that overproduction of REG3 proteins can also be detrimental by reducing a protective species in the microbiota. Patients with inflammatory bowel disease (IBD) experiencing flares displayed heightened levels of secreted REG3 proteins that mediated depletion of Enterococcus faecium (Efm) from the gut microbiota. Efm inoculation of mice ameliorated intestinal inflammation through activation of the innate immune receptor NOD2, which was associated with the bacterial DL-endopeptidase SagA that generates NOD2-stimulating muropeptides. NOD2 activation in myeloid cells induced interleukin-1β (IL-1β) secretion to increase the proportion of IL-22-producing CD4+ T helper cells and innate lymphoid cells that promote tissue repair. Finally, Efm was unable to protect mice carrying a NOD2 gene variant commonly found in IBD patients. Our findings demonstrate that inflammation self-perpetuates by causing aberrant antimicrobial activity that disrupts symbiotic relationships with gut microbes.
PMID: 37652008
ISSN: 1934-6069
CID: 5618182

Bacterial contact induces polar plug disintegration to mediate whipworm egg hatching

Robertson, Amicha; Sall, Joseph; Venzon, Mericien; Olivas, Janet J; Zheng, Xuhui; Cammer, Michael; Antao, Noelle; Zhou, Chunyi; Devlin, Joseph C; Saes Thur, Rafaela; Bethony, Jeffrey; Nejsum, Peter; Shopsin, Bo; Torres, Victor J; Liang, Feng-Xia; Cadwell, Ken
The bacterial microbiota promotes the life cycle of the intestine-dwelling whipworm Trichuris by mediating hatching of parasite eggs ingested by the mammalian host. Despite the enormous disease burden associated with Trichuris colonization, the mechanisms underlying this transkingdom interaction have been obscure. Here, we used a multiscale microscopy approach to define the structural events associated with bacteria-mediated hatching of eggs for the murine model parasite Trichuris muris. Through the combination of scanning electron microscopy (SEM) and serial block face SEM (SBFSEM), we visualized the outer surface morphology of the shell and generated 3D structures of the egg and larva during the hatching process. These images revealed that exposure to hatching-inducing bacteria catalyzed asymmetric degradation of the polar plugs prior to exit by the larva. Unrelated bacteria induced similar loss of electron density and dissolution of the structural integrity of the plugs. Egg hatching was most efficient when high densities of bacteria were bound to the poles. Consistent with the ability of taxonomically distant bacteria to induce hatching, additional results suggest chitinase released from larva within the eggs degrade the plugs from the inside instead of enzymes produced by bacteria in the external environment. These findings define at ultrastructure resolution the evolutionary adaptation of a parasite for the microbe-rich environment of the mammalian gut.
PMID: 37738244
ISSN: 1553-7374
CID: 5627842

Capsular Polysaccharide Is Essential for the Virulence of the Antimicrobial-Resistant Pathogen Enterobacter hormaechei

St John, Amelia; Perault, Andrew I; Giacometti, Sabrina I; Sommerfield, Alexis G; DuMont, Ashley L; Lacey, Keenan A; Zheng, Xuhui; Sproch, Julia; Petzold, Chris; Dancel-Manning, Kristen; Gonzalez, Sandra; Annavajhala, Medini; Beckford, Colleen; Zeitouni, Nathalie; Liang, Feng-Xia; van Bakel, Harm; Shopsin, Bo; Uhlemann, Anne-Catrin; Pironti, Alejandro; Torres, Victor J
Nosocomial infections caused by multidrug-resistant (MDR) Enterobacter cloacae complex (ECC) pathogens are on the rise. However, the virulence strategies employed by these pathogens remain elusive. Here, we study the interaction of ECC clinical isolates with human serum to define how this pathogen evades the antimicrobial action of complement, one of the first lines of host-mediated immune defense. We identified a small number of serum-sensitive strains, including Enterobacter hormaechei strain NR3055, which we exploited for the in vitro selection of serum-resistant clones. Comparative genomics between the serum-sensitive NR3055 strain and the isolated serum-resistant clones revealed a premature stop codon in the wzy gene of the capsular polysaccharide biosynthesis locus of NR3055. The complementation of wzy conferred serum resistance to NR3055, prevented the deposition of complement proteins on the bacterial surface, inhibited phagocytosis by human neutrophils, and rendered the bacteria virulent in a mouse model of peritonitis. Mice exposed to a nonlethal dose of encapsulated NR3055 were protected from subsequent lethal infections by encapsulated NR3055, whereas mice that were previously exposed to unencapsulated NR3055 succumbed to infection. Thus, capsule is a key immune evasion determinant for E. hormaechei, and it is a potential target for prophylactics and therapeutics to combat these increasingly MDR human pathogens. IMPORTANCE Infections caused by antimicrobial resistant bacteria are of increasing concern, especially those due to carbapenem-resistant Enterobacteriaceae pathogens. Included in this group are species of the Enterobacter cloacae complex, regarding which there is a paucity of knowledge on the infection biology of the pathogens, despite their clinical relevance. In this study, we combine techniques in comparative genomics, bacterial genetics, and diverse models of infection to establish capsule as an important mechanism of Enterobacter pathogens to resist the antibacterial activity of serum, a first line of host defense against bacterial infections. We also show that immune memory targeting the Enterobacter capsule protects against lethal infection. The further characterization of Enterobacter infection biology and the immune response to infection are needed for the development of therapies and preventative interventions targeting these highly antibiotic resistant pathogens.
PMID: 36779722
ISSN: 2150-7511
CID: 5421192

MRSA lineage USA300 isolated from bloodstream infections exhibit altered virulence regulation

Dyzenhaus, Sophie; Sullivan, Mitchell J; Alburquerque, Bremy; Boff, Daiane; van de Guchte, Adriana; Chung, Marilyn; Fulmer, Yi; Copin, Richard; Ilmain, Juliana K; O'Keefe, Anna; Altman, Deena R; Stubbe, François-Xavier; Podkowik, Magdalena; Dupper, Amy C; Shopsin, Bo; van Bakel, Harm; Torres, Victor J
The epidemic community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) USA300 lineage has recently become a leading cause of hospital-associated bloodstream infections (BSIs). Here, we leveraged this recent introduction into hospitals and the limited genetic variation across USA300 isolates to identify mutations that contribute to its success in a new environment. We found that USA300 BSI isolates exhibit altered virulence regulation. Using comparative genomics to delineate the genes involved in this phenotype, we discovered repeated and independent mutations in the transcriptional regulator sarZ. Mutations in sarZ resulted in increased virulence of USA300 BSI isolates in a murine model of BSI. The sarZ mutations derepressed the expression and production of the surface protein ClfB, which was critical for the pathogenesis of USA300 BSI isolates. Altogether, these findings highlight ongoing evolution of a major MRSA lineage and suggest USA300 strains can optimize their fitness through altered regulation of virulence.
PMID: 36681080
ISSN: 1934-6069
CID: 5426472

Gut microbiome dysbiosis in antibiotic-treated COVID-19 patients is associated with microbial translocation and bacteremia

Bernard-Raichon, Lucie; Venzon, Mericien; Klein, Jon; Axelrad, Jordan E; Zhang, Chenzhen; Sullivan, Alexis P; Hussey, Grant A; Casanovas-Massana, Arnau; Noval, Maria G; Valero-Jimenez, Ana M; Gago, Juan; Putzel, Gregory; Pironti, Alejandro; Wilder, Evan; Thorpe, Lorna E; Littman, Dan R; Dittmann, Meike; Stapleford, Kenneth A; Shopsin, Bo; Torres, Victor J; Ko, Albert I; Iwasaki, Akiko; Cadwell, Ken; Schluter, Jonas
Although microbial populations in the gut microbiome are associated with COVID-19 severity, a causal impact on patient health has not been established. Here we provide evidence that gut microbiome dysbiosis is associated with translocation of bacteria into the blood during COVID-19, causing life-threatening secondary infections. We first demonstrate SARS-CoV-2 infection induces gut microbiome dysbiosis in mice, which correlated with alterations to Paneth cells and goblet cells, and markers of barrier permeability. Samples collected from 96 COVID-19 patients at two different clinical sites also revealed substantial gut microbiome dysbiosis, including blooms of opportunistic pathogenic bacterial genera known to include antimicrobial-resistant species. Analysis of blood culture results testing for secondary microbial bloodstream infections with paired microbiome data indicates that bacteria may translocate from the gut into the systemic circulation of COVID-19 patients. These results are consistent with a direct role for gut microbiome dysbiosis in enabling dangerous secondary infections during COVID-19.
PMID: 36319618
ISSN: 2041-1723
CID: 5358262

The tempo and mode of gene regulatory programs during bacterial infection

Avital, Gal; Kuperwaser, Felicia; Pountain, Andrew W; Lacey, Keenan A; Zwack, Erin E; Podkowik, Magdalena; Shopsin, Bo; Torres, Victor J; Yanai, Itai
Innate immune recognition of bacterial pathogens is a key determinant of the ensuing systemic response, and host or pathogen heterogeneity in this early interaction can impact the course of infection. To gain insight into host response heterogeneity, we investigate macrophage inflammatory dynamics using primary human macrophages infected with Group B Streptococcus. Transcriptomic analysis reveals discrete cellular states within responding macrophages, one of which consists of four sub-states, reflecting inflammatory activation. Infection with six additional bacterial species-Staphylococcus aureus, Listeria monocytogenes, Enterococcus faecalis, Yersinia pseudotuberculosis, Shigella flexneri, and Salmonella enterica-recapitulates these states, though at different frequencies. We show that modulating the duration of infection and the presence of a toxin impacts inflammatory trajectory dynamics. We provide evidence for this trajectory in infected macrophages in an in vivo model of Staphylococcus aureus infection. Our cell-state analysis defines a framework for understanding inflammatory activation dynamics in response to bacterial infection.
PMID: 36223751
ISSN: 2211-1247
CID: 5352072