scholarly journals Human Keratinocyte Response to Superantigens

mSphere ◽  
2020 ◽  
Vol 5 (5) ◽  
Author(s):  
Patrick M. Schlievert ◽  
Francoise A. Gourronc ◽  
Donald Y. M. Leung ◽  
Aloysius J. Klingelhutz
Keyword(s):  
Staphylococcus Aureus ◽  
Streptococcus Pyogenes ◽  
Skin Barrier ◽  
Human Keratinocytes ◽  
Human Diseases ◽  
Human Pathogens ◽  
Chemokine Production ◽  
Content Type ◽  
Human Keratinocyte ◽  
Stimulation Of

ABSTRACT Staphylococcus aureus and Streptococcus pyogenes are significant human pathogens, causing infections at multiple body sites, including across the skin. Both are organisms that cause human diseases and secrete superantigens, including toxic shock syndrome toxin-1 (TSST-1), staphylococcal enterotoxins (SEs), and streptococcal pyrogenic exotoxins (SPEs). On the skin, human keratinocytes represent the first cell type to encounter these superantigens. We employed transcriptome sequencing (RNA-seq) to evaluate the human primary keratinocyte response to both TSST-1 and staphylococcal enterotoxin B (SEB) in triplicate analyses. Both superantigens caused large numbers of genes to be up- and downregulated. The genes that exhibited 2-fold differential gene expression compared to vehicle-treated cells, whether up- or downregulated, totaled 5,773 for TSST-1 and 4,320 for SEB. Of these, 4,482 were significantly upregulated by exposure of keratinocytes to TSST-1, whereas 1,291 were downregulated. For SEB, expression levels of 3,785 genes were upregulated, whereas those of 535 were downregulated. There was the expected high overlap in both upregulation (3,412 genes) and downregulation (400 genes). Significantly upregulated genes included those associated with chemokine production, with the possibility of stimulation of inflammation. We also tested an immortalized human keratinocyte line, from a different donor, for chemokine response to four superantigens. TSST-1 and SEB caused production of interleukin-8 (IL-8), MIP-3α, and IL-33. SPEA and SPEC were evaluated for stimulation of expression of IL-8 as a representative chemokine; both stimulated production of IL-8. IMPORTANCE Staphylococcus aureus and Streptococcus pyogenes are common human pathogens, causing infections that include the skin. Both pathogens produce a family of secreted toxins called superantigens, which have been shown to be important in human diseases. The first cell types encountered by superantigens on skin are keratinocytes. Our studies demonstrated, that the human keratinocyte pathway, among other pathways, responds to superantigens with production of chemokines, setting off inflammation. This inflammatory response may be harmful, facilitating opening of the skin barrier.

scholarly journals The Streptococcal Protease SpeB Antagonizes the Biofilms of the Human Pathogen Staphylococcus aureus USA300 through Cleavage of the Staphylococcal SdrC Protein

2020 ◽  
Vol 202 (11) ◽  
Author(s):  
Katelyn E. Carothers ◽  
Zhong Liang ◽  
Jeffrey Mayfield ◽  
Deborah L. Donahue ◽  
Mijoon Lee ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Proteolytic Activity ◽  
Streptococcus Pyogenes ◽  
Human Pathogen ◽  
Content Type ◽  
Functional Studies ◽  
Human Proteins ◽  
Group A ◽  
Biofilm Disruption

ABSTRACT Streptococcus pyogenes, or group A Streptococcus (GAS), is both a pathogen and an asymptomatic colonizer of human hosts and produces a large number of surface-expressed and secreted factors that contribute to a variety of infection outcomes. The GAS-secreted cysteine protease SpeB has been well studied for its effects on the human host; however, despite its broad proteolytic activity, studies on how this factor is utilized in polymicrobial environments are lacking. Here, we utilized various forms of SpeB protease to evaluate its antimicrobial and antibiofilm properties against the clinically important human colonizer Staphylococcus aureus, which occupies niches similar to those of GAS. For our investigation, we used a skin-tropic GAS strain, AP53CovS+, and its isogenic ΔspeB mutant to compare the production and activity of native SpeB protease. We also generated active and inactive forms of recombinant purified SpeB for functional studies. We demonstrate that SpeB exhibits potent biofilm disruption activity at multiple stages of S. aureus biofilm formation. We hypothesized that the surface-expressed adhesin SdrC in S. aureus was cleaved by SpeB, which contributed to the observed biofilm disruption. Indeed, we found that SpeB cleaved recombinant SdrC in vitro and in the context of the full S. aureus biofilm. Our results suggest an understudied role for the broadly proteolytic SpeB as an important factor for GAS colonization and competition with other microorganisms in its niche. IMPORTANCE Streptococcus pyogenes (GAS) causes a range of diseases in humans, ranging from mild to severe, and produces many virulence factors in order to be a successful pathogen. One factor produced by many GAS strains is the protease SpeB, which has been studied for its ability to cleave and degrade human proteins, an important factor in GAS pathogenesis. An understudied aspect of SpeB is the manner in which its broad proteolytic activity affects other microorganisms that co-occupy niches similar to that of GAS. The significance of the research reported herein is the demonstration that SpeB can degrade the biofilms of the human pathogen Staphylococcus aureus, which has important implications for how SpeB may be utilized by GAS to successfully compete in a polymicrobial environment.

scholarly journals A Phenome-Wide Association Study Uncovers a Pathological Role of Coagulation Factor X duringAcinetobacter baumanniiInfection

2019 ◽  
Vol 87 (5) ◽  
Author(s):  
Jacob E. Choby ◽  
Andrew J. Monteith ◽  
Lauren E. Himmel ◽  
Paris Margaritis ◽  
Jana K. Shirey-Rice ◽  
...  
Keyword(s):  
Immune Response ◽  
Association Study ◽  
Immune Cell ◽  
Coagulation Factor ◽  
Factor X ◽  
Human Pathogens ◽  
Chemokine Production ◽  
Content Type ◽  
Factor X Deficiency ◽  
Deficient Mice

ABSTRACTCoagulation and inflammation are interconnected, suggesting that coagulation plays a key role in the inflammatory response to pathogens. A phenome-wide association study (PheWAS) was used to identify clinical phenotypes of patients with a polymorphism in coagulation factor X. Patients with this single nucleotide polymorphism (SNP) were more likely to be hospitalized with hemostatic and infection-related disorders, suggesting that factor X contributes to the immune response to infection. To investigate this, we modeled infections by human pathogens in a mouse model of factor X deficiency. Factor X-deficient mice were protected from systemicAcinetobacter baumanniiinfection, suggesting that factor X plays a role in the immune response toA. baumannii. Factor X deficiency was associated with reduced cytokine and chemokine production and alterations in immune cell population during infection: factor X-deficient mice demonstrated increased abundance of neutrophils, macrophages, and effector T cells. Together, these results suggest that factor X activity is associated with an inefficient immune response and contributes to the pathology ofA. baumanniiinfection.

Decadron in the treatment of cerebral abscess

1976 ◽  
Vol 45 (3) ◽  
pp. 301-310 ◽  
Author(s):  
Gilbert R. C. Quartey ◽  
Jane Anne Johnston ◽  
Bohdan Rozdilsky
Keyword(s):  
Staphylococcus Aureus ◽  
Inflammatory Response ◽  
Streptococcus Pyogenes ◽  
Granulation Tissue ◽  
Medical Literature ◽  
Control Group ◽  
Normal Brain ◽  
Content Type ◽  
Antibiotic Group ◽  
Fine Print

✓ Forty rabbits were inoculated with Streptococcus pyogenes or Staphylococcus aureus to produce cerebral abscesses. One-third of the rabbits received no treatment and served as controls. One-third received dexamethasone (Decadron) plus an appropriate antibiotic. One-third received only the appropriate antibiotic in the same dosage. The animals were sacrificed 10 days after inoculation and the brains examined. In the control group, an abscess at the stage of granulation tissue encapsulation containing the inoculated organisms was found. The surrounding brain showed a marked inflammatory response. In the Decadron plus antibiotic group, necrotic lesions were found containing the inoculated organisms and surrounded by relatively normal brain. In the group treated with antibiotic alone, healed glial scars were found in relatively normal brain. Our findings are discussed with reference to the medical literature regarding the influence of glucocorticoids on the inflammatory response and the efficacy of antibiotics when this response is suppressed.

scholarly journals Livestock Origin for a Human Pandemic Clone of Community-Associated Methicillin-Resistant Staphylococcus aureus

mBio ◽  
2013 ◽  
Vol 4 (4) ◽  
Author(s):  
Laura E. Spoor ◽  
Paul R. McAdam ◽  
Lucy A. Weinert ◽  
Andrew Rambaut ◽  
Henrik Hasman ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Pathogenic Bacteria ◽  
Control Measures ◽  
Human Populations ◽  
Epidemic Spread ◽  
Human Pathogens ◽  
Methicillin Resistant ◽  
Content Type ◽  
Evolutionary Origins ◽  
Healthy Humans

ABSTRACTThe importance of livestock as a source of bacterial pathogens with the potential for epidemic spread in human populations is unclear. In recent years, there has been a global increase in community-associated methicillin-resistantStaphylococcus aureus(CA-MRSA) infections of healthy humans, but an understanding of the different evolutionary origins of CA-MRSA clones and the basis for their recent expansion is lacking. Here, using a high-resolution phylogenetic approach, we report the discovery of two emergent clones of human epidemic CA-MRSA which resulted from independent livestock-to-human host jumps by the major bovineS. aureuscomplex, CC97. Of note, one of the new clones was isolated from human infections on four continents, demonstrating its global dissemination since the host jump occurred over 40 years ago. The emergence of both humanS. aureusclones coincided with the independent acquisition of mobile genetic elements encoding antimicrobial resistance and human-specific mediators of immune evasion, consistent with an important role for these genetic events in the capacity to survive and transmit among human populations. In conclusion, we provide evidence that livestock represent a reservoir for the emergence of new human-pathogenicS. aureusclones with the capacity for pandemic spread. These findings have major public health implications highlighting the importance of surveillance for early identification of emergent clones and improved transmission control measures at the human-livestock interface.IMPORTANCEAnimals are the major source of new pathogens affecting humans. However, the potential for pathogenic bacteria that originally were found in animals to switch hosts and become widely established in human populations is not clear. Here, we report the discovery of emergent clones of methicillin-resistantStaphylococcus aureus(MRSA) that originated in livestock and switched to humans, followed by host-adaptive evolution and epidemic spread in global human populations. Our findings demonstrate that livestock can act as a reservoir for the emergence of new human bacterial clones with potential for pandemic spread, highlighting the potential role of surveillance and biosecurity measures in the agricultural setting for preventing the emergence of new human pathogens.

scholarly journals Complete Genome Sequences of Two Staphylococcus aureus Sequence Type 5 Isolates from California, USA

2017 ◽  
Vol 5 (13) ◽  
Author(s):  
Samantha J. Hau ◽  
Darrell O. Bayles ◽  
David P. Alt ◽  
Tracy L. Nicholson
Keyword(s):  
Staphylococcus Aureus ◽  
Complete Genome ◽  
Mobile Genetic Elements ◽  
Sequence Type ◽  
Human Diseases ◽  
Genome Sequences ◽  
Content Type ◽  
Genetic Elements

ABSTRACT Staphylococcus aureus causes a variety of human diseases ranging in severity. The pathogenicity of S. aureus can be partially attributed to the acquisition of mobile genetic elements. In this report, we provide two complete genome sequences from human clinical S. aureus isolates.

scholarly journals Internalization of Staphylococcus aureus by Human Keratinocytes

2004 ◽  
Vol 72 (10) ◽  
pp. 5668-5675 ◽  
Author(s):  
Sompid Kintarak ◽  
Simon A. Whawell ◽  
Paul M. Speight ◽  
Samantha Packer ◽  
Sean P. Nair
Keyword(s):  
Staphylococcus Aureus ◽  
Human Keratinocytes ◽  
Host Cells ◽  
Human Pathogens ◽  
Chronic Infections ◽  
Primary Keratinocytes ◽  
Bacterial Uptake ◽  
Fibronectin Binding ◽  
Isogenic Mutants ◽  
Systemic Infections

ABSTRACT Staphylococcus aureus is among the most important human pathogens and causes various superficial and systemic infections. The ability of S. aureus to be internalized by, and survive within, host cells, such as keratinocytes, may contribute to the development of persistent or chronic infections and may finally lead to deeper tissue infections or dissemination. To examine the mechanisms of internalization of S. aureus by keratinocytes, isogenic mutants lacking fibronectin-binding proteins (FnBPs), a recombinant protein consisting of the fibronectin-binding domain of S. aureus FnBPs, and an anti-α5β1 antibody were used in cocultures with immortalized keratinocytes and primary keratinocytes. We found that internalization of S. aureus by immortalized keratinocytes requires bacterial FnBPs and is mediated by the major fibronectin-binding integrin α5β1. In contrast to internalization by immortalized keratinocytes, internalization of S. aureus by primary keratinocytes could occur through FnBP-dependent and -independent pathways. S. aureus clumping factor B (ClfB), which was recently determined to bind to epithelial cells, was not involved in the uptake of this bacterium by keratinocytes. The identification of an alternate uptake pathway, which is independent of S. aureus FnBPs and host cell α5β1, has important implications for the design of therapies targeted to bacterial uptake by host cells.

scholarly journals Draft Genome Sequences of Staphylococcus sp. Strain CWZ226, of Unknown Origin, and Pseudomonas sp. Strain CVAP#3, Antagonistic to Strain CWZ226

2021 ◽  
Vol 10 (37) ◽  
Author(s):  
Brianna L. McCall ◽  
J. A. C. Vriezen
Keyword(s):  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Bioactive Compounds ◽  
Draft Genome ◽  
Unknown Origin ◽  
Pseudomonas Sp ◽  
Human Pathogens ◽  
Genome Sequences ◽  
Content Type

Many Staphylococcus and Pseudomonas species, such as Staphylococcus aureus and Pseudomonas aeruginosa , are opportunistic human pathogens. However, Pseudomonas species are also known to produce bioactive compounds. Here, we report on the genome sequences of a Pseudomonas isolate and a Staphylococcus species of unknown origin that it inhibits.

scholarly journals Novel Bacteriophage Lysin with Broad Lytic Activity Protects against Mixed Infection by Streptococcus pyogenes and Methicillin-Resistant Staphylococcus aureus

2013 ◽  
Vol 57 (6) ◽  
pp. 2743-2750 ◽  
Author(s):  
Daniel B. Gilmer ◽  
Jonathan E. Schmitz ◽  
Chad W. Euler ◽  
Vincent A. Fischetti
Keyword(s):  
Staphylococcus Aureus ◽  
Streptococcus Pyogenes ◽  
Catalytic Domain ◽  
Group A Streptococcus ◽  
Group B Streptococcus ◽  
Streptococcus Suis ◽  
Lytic Activity ◽  
Methicillin Resistant ◽  
Content Type

ABSTRACTMethicillin-resistantStaphylococcus aureus(MRSA) andStreptococcus pyogenes(group A streptococcus [GrAS]) cause serious and sometimes fatal human diseases. They are among the many Gram-positive pathogens for which resistance to leading antibiotics has emerged. As a result, alternative therapies need to be developed to combat these pathogens. We have identified a novel bacteriophage lysin (PlySs2), derived from aStreptococcus suisphage, with broad lytic activity against MRSA, vancomycin-intermediateS. aureus(VISA),Streptococcus suis,Listeria,Staphylococcus simulans,Staphylococcus epidermidis,Streptococcus equi,Streptococcus agalactiae(group B streptococcus [GBS]),S. pyogenes,Streptococcus sanguinis, group G streptococci (GGS), group E streptococci (GES), andStreptococcus pneumoniae. PlySs2 has an N-terminal cysteine-histidine aminopeptidase (CHAP) catalytic domain and a C-terminal SH3b binding domain. It is stable at 50°C for 30 min, 37°C for >24 h, 4°C for 15 days, and −80°C for >7 months; it maintained full activity after 10 freeze-thaw cycles. PlySs2 at 128 μg/mlin vitroreduced MRSA andS. pyogenesgrowth by 5 logs and 3 logs within 1 h, respectively, and exhibited a MIC of 16 μg/ml for MRSA. A single, 2-mg dose of PlySs2 protected 92% (22/24) of the mice in a bacteremia model of mixed MRSA andS. pyogenesinfection. Serially increasing exposure of MRSA andS. pyogenesto PlySs2 or mupirocin resulted in no observed resistance to PlySs2 and resistance to mupirocin. To date, no other lysin has shown such notable broad lytic activity, stability, and efficacy against multiple, leading, human bacterial pathogens; as such, PlySs2 has all the characteristics to be an effective therapeutic.

scholarly journals Methicillin-Resistant Staphylococcus aureus Sequence Type (ST) 5 Isolates from Health Care and Agricultural Sources Adhere Equivalently to Human Keratinocytes

2017 ◽  
Vol 84 (2) ◽  
Author(s):  
Samantha J. Hau ◽  
Steven Kellner ◽  
Kirsten C. Eberle ◽  
Ursula Waack ◽  
Susan L. Brockmeier ◽  
...  
Keyword(s):  
Public Health ◽  
Staphylococcus Aureus ◽  
Human Skin ◽  
Hospital Setting ◽  
Human Keratinocytes ◽  
The United States ◽  
Sequence Type ◽  
Methicillin Resistant ◽  
Content Type

ABSTRACT Staphylococcus aureus is part of the nasal microbiome of many humans and has become a significant public health burden due to infections with antibiotic-resistant strains, including methicillin-resistant S. aureus (MRSA) strains. Several lineages of S. aureus, including MRSA, are found in livestock species and can be acquired by humans through contact with animals. These livestock-associated MRSA (LA-MRSA) isolates raise public health concerns because of the potential for livestock to act as reservoirs for MRSA outside the hospital setting. In the United States, swine harbor a mixed population of LA-MRSA isolates, with the sequence type 398 (ST398), ST9, and ST5 lineages being detected. LA-MRSA ST5 isolates are particularly concerning to the public health community because, unlike the isolates in the ST398 and ST9 lineages, isolates in the ST5 lineage are a significant cause of human disease in both the hospital and community settings globally. The ability of swine-associated LA-MRSA ST5 isolates to adhere to human keratinocytes in vitro was investigated, and the adherence genes harbored by these isolates were evaluated and compared to those in clinical MRSA ST5 isolates from humans with no swine contact. The two subsets of isolates adhered equivalently to human keratinocytes in vitro and contained an indistinguishable complement of adherence genes that possessed a high degree of sequence identity. Collectively, our data indicate that, unlike LA-MRSA ST398 isolates, LA-MRSA ST5 isolates do not exhibit a reduced genotypic or phenotypic capacity to adhere to human keratinocytes. IMPORTANCE Our data indicate that swine-associated livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) ST5 isolates are as capable of adhering to human skin and have the same genetic potential to adhere as clinical MRSA ST5 isolates from humans. This suggests that humans in contact with livestock have the potential to become colonized with LA-MRSA ST5 isolates; however, the genes that contribute to the persistence of S. aureus on human skin were absent in LA-MRSA ST5 isolates. The data presented here are important evidence in evaluating the potential risks that LA-MRSA ST5 isolates pose to humans who come into contact with livestock.

scholarly journals Staphylococcus aureus Exploits the Host Apoptotic Pathway To Persist during Infection

mBio ◽  
2019 ◽  
Vol 10 (6) ◽  
Author(s):  
Volker Winstel ◽  
Olaf Schneewind ◽  
Dominique Missiakas
Keyword(s):  
Staphylococcus Aureus ◽  
Caspase 3 ◽  
Bloodstream Infections ◽  
Nucleotide Polymorphisms ◽  
Human Pathogens ◽  
Loss Of Function ◽  
Phagocytic Cells ◽  
Apoptotic Pathway ◽  
Single Nucleotide ◽  
Content Type

ABSTRACT Staphylococcus aureus is a deadly pathogen that causes fatal diseases in humans. During infection, S. aureus secretes nuclease (Nuc) and adenosine synthase A (AdsA) to generate cytotoxic deoxyadenosine (dAdo) from neutrophil extracellular traps which triggers noninflammatory apoptosis in macrophages. In this manner, replicating staphylococci escape phagocytic killing without alerting the immune system. Here, we show that mice lacking caspase-3 in immune cells exhibit increased resistance toward S. aureus. Caspase-3-deficient macrophages are resistant to staphylococcal dAdo and gain access to abscess lesions to promote bacterial clearance in infected animals. We identify specific single nucleotide polymorphisms in CASP3 as candidate human resistance alleles that protect macrophages from S. aureus-derived dAdo, raising the possibility that the allelic repertoire of caspase-3 may contribute to the outcome of S. aureus infections in humans. IMPORTANCE Caspase-3 controls the apoptotic pathway, a form of programmed cell death designed to be immunologically silent. Polymorphisms leading to reduced caspase-3 activity are associated with variable effects on tumorigenesis and yet arise frequently. Staphylococcus aureus is a human commensal and a frequent cause of soft tissue and bloodstream infections. Successful commensalism and virulence can be explained by the secretion of a plethora of immune evasion factors. One such factor, AdsA, destroys phagocytic cells by exploiting the apoptotic pathway. However, human CASP3 variants with loss-of-function alleles shield phagocytes from AdsA-mediated killing. This finding raises the possibility that some caspase-3 alleles may arise from exposure to S. aureus and other human pathogens that exploit the apoptotic pathway for infection.

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