scholarly journals The Pro-Inflammatory Effect of Staphylokinase Contributes to Community-Associated Staphylococcus Aureus Pneumonia

2021 ◽  
Author(s):  
Yanan Wang ◽  
Na Zhao ◽  
Ying Jian ◽  
Yao Liu ◽  
Lin Zhao ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Lung Infection ◽  
Innate Immune ◽  
High Morbidity ◽  
Host Immune System ◽  
Wild Type ◽  
Lung Infections ◽  
Staphylococcus Aureus Pneumonia ◽  
Highly Virulent ◽  
Inflammatory Effect

Abstract Pneumonia caused by community-associated Staphylococcus aureus (CA-SA) has high morbidity and mortality. Pathogens can express a variety of virulence factors to promote infection. The game between the host immune system and pathogens determines the degree of infection and tissue damage, but its mechanism has not been well explored. In this study, we found that staphylokinase (SAK) is highly expressed in CA-SA lineage ST398 and promotes lung infection in both wild-type and cathelicidins-related antimicrobial peptide CRAMP knockout (CRAMP−/−) mice. Furthermore, our results showed that SAK can activate the host's innate immune inflammatory response. Importantly, SAK can promote the activation of NLRP3 inflammasome by increasing the production of ROS. This may be one of the important mechanisms of SAK aggravating CA-SA pneumonia after excluding its function of promoting fibrinolysis and neutralizing CRAMP. Our results emphasize the importance of controlling inflammation in acute lung infections, and also provides new insights into the pathogenesis of highly virulent CA-SA.

Staphylococci in a Mental Hospital

1964 ◽  
Vol 110 (465) ◽  
pp. 240-243
Author(s):  
S. S. Reza
Keyword(s):  
Staphylococcus Aureus ◽  
Mental Hospital ◽  
Lung Infection ◽  
Skin Lesions ◽  
Carrier Rate ◽  
Bacteriological Study ◽  
Nasal Carrier ◽  
Lung Infections ◽  
Institutionalized Patients

The present study on the acquisition of Staphylococcus aureus by patients during their stay in a mental hospital, and the nasal carrier rate in the institutionalized patients, was prompted by the fact that in 1959 and 1960 193 out of a total of 407 deaths in Napsbury Hospital were due to lung infection, and that a bacteriological study of 45 unselected cases at necropsy in 1960 had suggested that the fatal lung infections were predominantly staphylococcal (Table I). The incidence of staphylococcal skin lesions, however, remained low, and only 147 cases of this kind were reported during 1959 and 1960 (4 per cent. per annum of the population) (Table II).

scholarly journals Innate Immune Memory Contributes to Host Defense against Recurrent Skin and Skin Structure Infections Caused by Methicillin-Resistant Staphylococcus aureus

2016 ◽  
Vol 85 (2) ◽  
Author(s):  
Liana C. Chan ◽  
Siyang Chaili ◽  
Scott G. Filler ◽  
Lloyd S. Miller ◽  
Norma V. Solis ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Host Defense ◽  
Protective Efficacy ◽  
Innate Immune ◽  
Immune Memory ◽  
Wild Type ◽  
Methicillin Resistant ◽  
Content Type ◽  
Skin Structure ◽  
Mrsa Infection

ABSTRACT Staphylococcus aureus is the leading cause of skin and skin structure infections (SSSI). The high frequency of recurring SSSI due to S. aureus, including methicillin-resistant S. aureus (MRSA) strains, despite high titers of specific antibodies and circulating T cells, implies that traditional adaptive immunity imparts incomplete protection. We hypothesized that innate immune memory contributes to the protective host defense against recurring MRSA infection. To test this hypothesis, SSSI was induced in wild-type and rag1 −/− mice in the BALB/c and C57BL/6 backgrounds. Prior infection (priming) of wild-type and rag1 −/− mice of either background afforded protection against repeat infection, as evidenced by reduced abscess severities and decreased CFU densities compared to those in naive controls. Interestingly, protection was greater on the previously infected flank than on the naive flank for wild-type and rag1 −/− mice. For wild-type mice, protective efficacy corresponded to increased infiltration of neutrophils (polymorphonuclear leukocytes [PMN]), macrophages (MΦ), Langerin+ dendritic cells (LDC), and natural killer (NK) cells. Protection was associated with the induction of interleukin-17A (IL-17A), IL-22, and gamma interferon (IFN-γ) as well as the antimicrobial peptides CRAMP and mβD-3. Priming also protected rag1 −/− mice against recurring SSSI, with increased MΦ and LDC infiltration and induction of IL-22, CRAMP, and mβD-3. These findings suggest that innate immune memory, mediated by specific cellular and molecular programs, likely contributes to the localized host defense in recurrent MRSA SSSI. These insights support the development of targeted immunotherapeutic strategies to address the challenge of MRSA infection.

scholarly journals IL-21/type I interferon interplay regulates neutrophil-dependent innate immune responses to Staphylococcus aureus

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Rosanne Spolski ◽  
Erin E West ◽  
Peng Li ◽  
Sharon Veenbergen ◽  
Sunny Yung ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Type I Interferon ◽  
Human Peripheral Blood ◽  
Granzyme B ◽  
Gene Signature ◽  
Innate Immune ◽  
Type I ◽  
Innate Immune Responses ◽  
Wild Type ◽  
Blood Neutrophils

Methicillin-resistant Staphylococcus aureus (MRSA) is a major hospital- and community-acquired pathogen, but the mechanisms underlying host-defense to MRSA remain poorly understood. Here, we investigated the role of IL-21 in this process. When administered intra-tracheally into wild-type mice, IL-21 induced granzymes and augmented clearance of pulmonary MRSA but not when neutrophils were depleted or a granzyme B inhibitor was added. Correspondingly, IL-21 induced MRSA killing by human peripheral blood neutrophils. Unexpectedly, however, basal MRSA clearance was also enhanced when IL-21 signaling was blocked, both in Il21r KO mice and in wild-type mice injected with IL-21R-Fc fusion-protein. This correlated with increased type I interferon and an IFN-related gene signature, and indeed anti-IFNAR1 treatment diminished MRSA clearance in these animals. Moreover, we found that IFNβ induced granzyme B and promoted MRSA clearance in a granzyme B-dependent fashion. These results reveal an interplay between IL-21 and type I IFN in the innate immune response to MRSA.

scholarly journals Prevention and Treatment of Staphylococcus aureus Pneumonia with a β-Cyclodextrin Derivative

2009 ◽  
Vol 54 (1) ◽  
pp. 298-304 ◽  
Author(s):  
Brook E. Ragle ◽  
Vladimir A. Karginov ◽  
Juliane Bubeck Wardenburg
Keyword(s):  
Staphylococcus Aureus ◽  
Alveolar Epithelial Cells ◽  
Lethal Challenge ◽  
Alveolar Epithelial ◽  
Alpha Hemolysin ◽  
Life Threatening ◽  
Novel Strategy ◽  
Staphylococcus Aureus Pneumonia ◽  
Favorable Safety ◽  
Highly Virulent

ABSTRACT Staphylococcus aureus pneumonia is a common, potentially life-threatening infection caused by this human pathogen. The only therapies available to treat S. aureus pneumonia are antibiotics, a modality that is jeopardized by the organism's remarkable ability to acquire antimicrobial resistance. S. aureus alpha-hemolysin is a pore-forming cytotoxin that is essential for the pathogenesis of pneumonia. Strains lacking this cytotoxin are avirulent in a murine model of pneumonia; likewise, vaccine-based strategies that antagonize the toxin afford protection against lethal disease. Disruption of the function of this toxin therefore provides a potent mechanism to prevent and/or treat S. aureus pneumonia. β-Cyclodextrin derivatives are small molecules with a sevenfold symmetry that mirrors the heptameric alpha-hemolysin. These compounds block the assembled alpha-hemolysin pore, compromising toxin function. We report that a modified β-cyclodextrin compound, IB201, prevents alpha-hemolysin-induced lysis of human alveolar epithelial cells. This protective effect does not result from the ability of the β-cyclodextrin to impair formation of the oligomeric alpha-hemolysin on the cell surface, supporting a role for this molecule in blockade of the lytic pore. An examination of IB201 in murine S. aureus pneumonia demonstrated that administration of this compound prevents and treats disease, protecting against mortality. Consistent with the vital importance of alpha-hemolysin in pneumonia caused by methicillin-sensitive and highly virulent methicillin-resistant S. aureus strains, IB201 protects against lethal challenge with both types of isolates. These observations, coupled with a favorable safety profile of β-cyclodextrin compounds, provide a novel strategy that may be developed to combat S. aureus pneumonia.

scholarly journals The Surface Protein Pls of Methicillin-Resistant Staphylococcus aureus Is a Virulence Factor in Septic Arthritis

2005 ◽  
Vol 73 (5) ◽  
pp. 2812-2817 ◽  
Author(s):  
Elisabet Josefsson ◽  
Katri Juuti ◽  
Maria Bokarewa ◽  
Pentti Kuusela
Keyword(s):  
Staphylococcus Aureus ◽  
Septic Arthritis ◽  
Virulence Factor ◽  
Solid Phase ◽  
Bacterial Load ◽  
Surface Protein ◽  
Wild Type ◽  
Knockout Mutant ◽  
Methicillin Resistant ◽  
Inflammatory Effect

ABSTRACT Pls, a surface protein of certain methicillin-resistant Staphylococcus aureus strains, is associated with poor bacterial adherence to solid-phase fibronectin and immunoglobulin G, as well as with reduced invasion of cultured epithelial cells. Here the importance of Pls for the development of septic arthritis and sepsis was investigated by using a mouse model. Mice inoculated with a pls knockout mutant developed a much milder arthritis and showed less grave weight reduction than mice infected with the wild-type Pls+ clinical isolate. Also, the pls mutant induced a significantly lower frequency of mortality than the wild-type strain. The bacterial load of the kidneys was larger in mice infected with the Pls+ strain than in animals challenged with the pls mutant. However, there was no evident inflammatory effect due to the Pls molecule alone, as indicated by knee injection of purified Pls. In conclusion, the results show that Pls is a virulence factor for septic arthritis and sepsis.

scholarly journals Repair of Global Regulators in Staphylococcus aureus 8325 and Comparative Analysis with Other Clinical Isolates

2010 ◽  
Vol 78 (6) ◽  
pp. 2877-2889 ◽  
Author(s):  
Silvia Herbert ◽  
Anne-Kathrin Ziebandt ◽  
Knut Ohlsen ◽  
Tina Schäfer ◽  
Michael Hecker ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Hemolytic Activity ◽  
Protein Pattern ◽  
Protein A ◽  
Wild Type ◽  
Global Regulators ◽  
Regulatory Functions ◽  
Highly Virulent ◽  
Model Strain ◽  
Regulatory Phenotype

ABSTRACT The pathogenicity of Staphylococcus aureus strains varies tremendously (as seen with animals). It is largely dependent on global regulators, which control the production of toxins, virulence, and fitness factors. Despite the vast knowledge of staphylococcal molecular genetics, there is still widespread dispute over what factors must come together to make a strain highly virulent. S. aureus NCTC8325 (RN1 and derivatives) is a widely used model strain for which an incomparable wealth of knowledge has accumulated in the almost 50 years since its isolation. Although RN1 has functional agr, sarA, and sae global regulators, it is defective in two regulatory genes, rsbU (a positive activator of SigB) and tcaR (an activator of protein A transcription), and is therefore considered by many to be a poor model for studies of regulation and virulence. Here, we repaired these genes and compared the resulting RN1 derivatives with other widely used strains, Newman, USA300, UAMS-1, and COL, plus the parental RN1, with respect to growth, extracellular protein pattern, hemolytic activity, protein A production, pigmentation, biofilm formation, and mouse lethality. The tcaR-repaired strain, showed little alteration in these properties. However, the rsbU-repaired strain was profoundly altered. Hemolytic activity was largely decreased, the exoprotein pattern became much more similar to that of typical wild-type (wt) S. aureus, and there was a surprising increase in mouse lethality. We note that each of the strains tested has a mutational alteration in one or more other regulatory functions, and we conclude that the repaired RN1 is a good model strain for studies of staphylococcal regulation and pathobiology; although strain Newman has been used extensively for such studies in recent years, it has a missense mutation in saeS, the histidine kinase component of the sae signaling module, which profoundly alters its regulatory phenotype. If this mutation were repaired, Newman would be considerably improved as a model strain.

scholarly journals Immune evasion by Staphylococcus aureus conferred by iron-regulated surface determinant protein IsdH

Microbiology ◽  
2009 ◽  
Vol 155 (3) ◽  
pp. 667-679 ◽  
Author(s):  
Livia Visai ◽  
Naoko Yanagisawa ◽  
Elisabet Josefsson ◽  
Andrej Tarkowski ◽  
Ilaria Pezzali ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Immune Responses ◽  
Innate Immune ◽  
Human Neutrophils ◽  
Protective Mechanism ◽  
Innate Immune Responses ◽  
Null Mutant ◽  
Wild Type ◽  
Accelerated Degradation ◽  
Associated Proteins

The ability of Staphylococcus aureus to avoid innate immune responses including neutrophil-mediated phagocytosis is crucial for the organism to cause infection. This multifactorial process involves several secreted and cell-surface-associated proteins. In this paper we report a novel mechanism of combating neutrophils that involves iron-regulated surface determinant protein H (IsdH). The IsdH protein is part of a complex that is only expressed under iron-restricted conditions in order to bind haemoglobin and extract and transport haem into the cytoplasm. A null mutant defective in expression of IsdH, and mutants expressing variants of IsdH with substitutions in residues predicted to be involved in ligand binding, were generated from S. aureus 8325-4. The IsdH-defective mutants were shown by several measures to have reduced virulence compared with the wild-type. The mutant was engulfed more rapidly by human neutrophils in the presence of serum opsonins, survived poorly in fresh whole human blood and was less virulent in a mouse model of sepsis. The protective mechanism seems to stem from an accelerated degradation of the serum opsonin C3b.

scholarly journals Evidence for Establishing the Clinical Breakpoint of Cefquinome against Haemophilus Parasuis in China

Pathogens ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 105
Author(s):  
Kun Mi ◽  
Da Sun ◽  
Mei Li ◽  
Haihong Hao ◽  
Kaixiang Zhou ◽  
...  
Keyword(s):  
Monte Carlo Simulation ◽  
Antibacterial Activity ◽  
Inhibitory Concentration ◽  
High Morbidity ◽  
Haemophilus Parasuis ◽  
Wild Type ◽  
Time Curve ◽  
Resistance Change ◽  
Concentration Time ◽  
Clinical Experiments

Haemophilus parasuis can cause high morbidity and mortality in swine. Cefquinome possesses excellent antibacterial activity against pathogens causing diseases of the respiratory tract. This study aimed to establish the clinical breakpoint (CBP) of cefquinome against H. parasuis and to monitor the resistance change. Referring to the minimum inhibitory concentration (MIC) distribution of cefquinome against 131 H. parasuis isolates, the MIC50 and MIC90 were determined to be 0.125 and 1 μg/mL, respectively. And the epidemiological cutoff (ECOFF) value was 1 μg/mL. HPS42 was selected as a representative strain for the pharmacodynamic (PD) experiment, pharmacokinetic (PK) experiment and clinical experiments. The PK/PD index values, area under concentration-time curve (AUC)/MIC, of the bacteriostatic, bactericidal, and bacterial elimination effects were 23, 41, and 51 h, respectively. The PK/PD cutoff was calculated as 0.125 μg/mL by Monte Carlo simulation (MCS), and the clinical cutoff was 0.25−4 μg/mL by WindoW. Combing these three values, the CBP of cefquinome against H. parasuis was found to be 1 μg/mL. In conclusion, this was the first study to integrate various cutoffs to establish the CBP in the laboratory. It is helpful to distinguish wild type H. parasuis and reduce the probability of treatment failure.

Association between a rapid diagnostic test to detect methicillin-resistant Staphylococcus Aureus pneumonia and decreased vancomycin use in a medical intensive care unit over a 30-month period

2021 ◽  
pp. 1-3
Author(s):  
Chiagozie I. Pickens ◽  
Chao Qi ◽  
Michael Postelnick ◽  
Joseph Paonessa ◽  
Helen K. Donnelly ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Staphylococcus Aureus ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Medical Intensive Care Unit ◽  
Pcr Assay ◽  
Days Of Therapy ◽  
Medical Intensive Care ◽  
Staphylococcus Aureus Pneumonia ◽  
Few Data ◽  
Rule Out

Abstract Vancomycin overuse is common, yet few data are available regarding how to improve stewardship of this antibiotic. We identify an association between use of a PCR assay to rule out MRSA pneumonia and a significant, sustained decrease in average vancomycin days of therapy over a 30-month period.

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