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253


SARS-CoV-2 infection predisposes patients to coinfection with Staphylococcus aureus

Lubkin, Ashira; Bernard-Raichon, Lucie; DuMont, Ashley L; Valero Jimenez, Ana Mayela; Putzel, Gregory G; Gago, Juan; Zwack, Erin E; Olusanya, Olufolakemi; Boguslawski, Kristina M; Dallari, Simone; Dyzenhaus, Sophie; Herrmann, Christin; Ilmain, Juliana K; Isom, Georgia L; Pawline, Miranda; Perault, Andrew I; Perelman, Sofya; Sause, William E; Shahi, Ifrah; St John, Amelia; Tierce, Rebecca; Zheng, Xuhui; Zhou, Chunyi; Noval, Maria G; O'Keeffe, Anna; Podkowik, Magda; Gonzales, Sandra; Inglima, Kenneth; Desvignes, Ludovic; Hochman, Sarah E; Stapleford, Kenneth A; Thorpe, Lorna E; Pironti, Alejandro; Shopsin, Bo; Cadwell, Ken; Dittmann, Meike; Torres, Victor J
UNLABELLED:isolates with low intrinsic virulence. IMPORTANCE/OBJECTIVE:infection.
PMCID:11323729
PMID: 39037272
ISSN: 2150-7511
CID: 5695982

Dietary and water restriction leads to increased susceptibility to antimicrobial resistant pathogens

Lacey, Keenan A; Pickrum, Adam M; Gonzalez, Sandra; Bartnicki, Eric; Castellaw, Ashley H; Rodrick, Tori C; Jones, Drew R; Khanna, Kamal M; Torres, Victor J
Dehydration and malnutrition are common and often underdiagnosed in hospital settings. Multidrug-resistant bacterial infections result in more than 35,000 deaths a year in nosocomial patients. The effect of temporal dietary and water restriction (DWR) on susceptibility to multidrug-resistant pathogens is unknown. We report that DWR markedly increased susceptibility to systemic infection by ESKAPE pathogens. Using a murine bloodstream model of methicillin-resistant Staphylococcus aureus infection, we show that DWR leads to significantly increased mortality and morbidity. DWR causes increased bacterial burden, severe pathology, and increased numbers of phagocytes in the kidney. DWR appears to alter the functionality of these phagocytes and is therefore unable to control infection. Mechanistically, we show that DWR impairs the ability of macrophages to phagocytose multiple bacterial pathogens and efferocytose apoptotic neutrophils. Together, this work highlights the crucial impact that diet and hydration play in protecting against infection.
PMCID:11268424
PMID: 39047095
ISSN: 2375-2548
CID: 5696022

Proton-coupled transport mechanism of the efflux pump NorA

Li, Jianping; Li, Yan; Koide, Akiko; Kuang, Huihui; Torres, Victor J; Koide, Shohei; Wang, Da-Neng; Traaseth, Nathaniel J
Efflux pump antiporters confer drug resistance to bacteria by coupling proton import with the expulsion of antibiotics from the cytoplasm. Despite efforts there remains a lack of understanding as to how acid/base chemistry drives drug efflux. Here, we uncover the proton-coupling mechanism of the Staphylococcus aureus efflux pump NorA by elucidating structures in various protonation states of two essential acidic residues using cryo-EM. Protonation of Glu222 and Asp307 within the C-terminal domain stabilized the inward-occluded conformation by forming hydrogen bonds between the acidic residues and a single helix within the N-terminal domain responsible for occluding the substrate binding pocket. Remarkably, deprotonation of both Glu222 and Asp307 is needed to release interdomain tethering interactions, leading to opening of the pocket for antibiotic entry. Hence, the two acidic residues serve as a "belt and suspenders" protection mechanism to prevent simultaneous binding of protons and drug that enforce NorA coupling stoichiometry and confer antibiotic resistance.
PMCID:11130294
PMID: 38802368
ISSN: 2041-1723
CID: 5663352

Quorum-sensing agr system of Staphylococcus aureus primes gene expression for protection from lethal oxidative stress

Podkowik, Magdalena; Perault, Andrew I; Putzel, Gregory; Pountain, Andrew; Kim, Jisun; DuMont, Ashley L; Zwack, Erin E; Ulrich, Robert J; Karagounis, Theodora K; Zhou, Chunyi; Haag, Andreas F; Shenderovich, Julia; Wasserman, Gregory A; Kwon, Junbeom; Chen, John; Richardson, Anthony R; Weiser, Jeffrey N; Nowosad, Carla R; Lun, Desmond S; Parker, Dane; Pironti, Alejandro; Zhao, Xilin; Drlica, Karl; Yanai, Itai; Torres, Victor J; Shopsin, Bo
The agr quorum-sensing system links Staphylococcus aureus metabolism to virulence, in part by increasing bacterial survival during exposure to lethal concentrations of H2O2, a crucial host defense against S. aureus. We now report that protection by agr surprisingly extends beyond post-exponential growth to the exit from stationary phase when the agr system is no longer turned on. Thus, agr can be considered a constitutive protective factor. Deletion of agr resulted in decreased ATP levels and growth, despite increased rates of respiration or fermentation at appropriate oxygen tensions, suggesting that Δagr cells undergo a shift towards a hyperactive metabolic state in response to diminished metabolic efficiency. As expected from increased respiratory gene expression, reactive oxygen species (ROS) accumulated more in the agr mutant than in wild-type cells, thereby explaining elevated susceptibility of Δagr strains to lethal H2O2 doses. Increased survival of wild-type agr cells during H2O2 exposure required sodA, which detoxifies superoxide. Additionally, pretreatment of S. aureus with respiration-reducing menadione protected Δagr cells from killing by H2O2. Thus, genetic deletion and pharmacologic experiments indicate that agr helps control endogenous ROS, thereby providing resilience against exogenous ROS. The long-lived 'memory' of agr-mediated protection, which is uncoupled from agr activation kinetics, increased hematogenous dissemination to certain tissues during sepsis in ROS-producing, wild-type mice but not ROS-deficient (Cybb
PMID: 38687677
ISSN: 2050-084x
CID: 5729302

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

Impact of oral vancomycin treatment duration on rate of Clostridioides difficile recurrence in patients requiring concurrent systemic antibiotics

Kwiatkowski, Diana; Marsh, Kassandra; Katz, Alyson; Papadopoulos, John; So, Jonathan; Major, Vincent J; Sommer, Philip M; Hochman, Sarah; Dubrovskaya, Yanina; Arnouk, Serena
BACKGROUND:infection (CDI) in patients requiring concomitant systemic antibiotics. OBJECTIVES/OBJECTIVE:To evaluate prescribing practices of vancomycin for CDI in patients that required concurrent systemic antibiotics and to determine whether a prolonged duration of vancomycin (>14 days), compared to a standard duration (10-14 days), decreased CDI recurrence. METHODS:(VRE). RESULTS:= .083) were not significantly different between groups. Discontinuation of vancomycin prior to completion of antibiotics was an independent predictor of 8-week recurrence on multivariable logistic regression (OR, 4.8; 95% CI, 1.3-18.1). CONCLUSIONS:Oral vancomycin prescribing relative to the systemic antibiotic end date may affect CDI recurrence to a greater extent than total vancomycin duration alone. Further studies are needed to confirm these findings.
PMID: 38288606
ISSN: 1559-6834
CID: 5627432

TLR4 sensing of IsdB of Staphylococcus aureus induces a proinflammatory cytokine response via the NLRP3-caspase-1 inflammasome cascade

Gonzalez, Juan José Izquierdo; Hossain, Md Faruq; Neef, Jolanda; Zwack, Erin E; Tsai, Chih-Ming; Raafat, Dina; Fechtner, Kevin; Herzog, Luise; Kohler, Thomas P; Schlüter, Rabea; Reder, Alexander; Holtfreter, Silva; Liu, George Y; Hammerschmidt, Sven; Völker, Uwe; Torres, Victor J; van Dijl, Jan Maarten; Lillig, Christopher H; Bröker, Barbara M; Darisipudi, Murty N
The prevalence of multidrug-resistant Staphylococcus aureus is of global concern, and vaccines are urgently needed. The iron-regulated surface determinant protein B (IsdB) of S. aureus was investigated as a vaccine candidate because of its essential role in bacterial iron acquisition but failed in clinical trials despite strong immunogenicity. Here, we reveal an unexpected second function for IsdB in pathogen-host interaction: the bacterial fitness factor IsdB triggers a strong inflammatory response in innate immune cells via Toll-like receptor 4 and the inflammasome, thus acting as a novel pathogen-associated molecular pattern of S. aureus. Our discovery contributes to a better understanding of how S. aureus modulates the immune response, which is necessary for vaccine development against the sophisticated pathogen.
PMID: 38112465
ISSN: 2150-7511
CID: 5612322

SarS and Rot are necessary for the repression of lukED and lukSF-PV in Staphylococcus aureus

Anderson, Exene E; Ilmain, Juliana K; Torres, Victor J
The leukocidins play an important role in disarming the host immune system and promoting infection. While both SarS and Rot have been established as repressors of leukocidins, the importance of each repressor in infection is unclear. Here, we demonstrate that repression by SarS and Rot is not additive and show that in addition to upregulating expression of each other, they are also able to bind concurrently to the leukocidin promoters. These findings suggest that both repressors are necessary for maximal repression of lukED and lukSF-PV and illuminate another complex relationship among Staphylococcus aureus virulence regulators.
PMCID:10715151
PMID: 37800956
ISSN: 2165-0497
CID: 5613162

Unlatching of the stem domains in the Staphylococcus aureus pore-forming leukocidin LukAB influences toxin oligomerization

Ilmain, Juliana K; Perelman, Sofya S; Panepinto, Maria C; Irnov, Irnov; Coudray, Nicolas; Samhadaneh, Nora; Pironti, Alejandro; Ueberheide, Beatrix; Ekiert, Damian C; Bhabha, Gira; Torres, Victor J
Staphylococcus aureus (S. aureus) is a serious global pathogen that causes a diverse range of invasive diseases. S. aureus utilizes a family of pore-forming toxins, known as bi-component leukocidins, to evade the host immune response and promote infection. Among these is LukAB (leukocidin A/leukocidin B), a toxin that assembles into an octameric β-barrel pore in the target cell membrane, resulting in host cell death. The established cellular receptor for LukAB is CD11b of the Mac-1 complex. Here, we show that hydrogen voltage-gated channel 1 is also required for the cytotoxicity of all major LukAB variants. We demonstrate that while each receptor is sufficient to recruit LukAB to the plasma membrane, both receptors are required for maximal lytic activity. Why LukAB requires two receptors, and how each of these receptors contributes to pore-formation remains unknown. To begin to resolve this, we performed an alanine scanning mutagenesis screen to identify mutations that allow LukAB to maintain cytotoxicity without CD11b. We discovered 30 mutations primarily localized in the stem domains of LukA and LukB that enable LukAB to exhibit full cytotoxicity in the absence of CD11b. Using crosslinking, electron microscopy, and hydroxyl radical protein footprinting, we show these mutations increase the solvent accessibility of the stem domain, priming LukAB for oligomerization. Together, our data support a model in which CD11b binding unlatches the membrane penetrating stem domains of LukAB, and this change in flexibility promotes toxin oligomerization.
PMCID:10665946
PMID: 37802313
ISSN: 1083-351x
CID: 5614202