scholarly journals Bacteriophages encoding human immune evasion factors adapt to livestock-associated MRSA through rounds of integration and excision

2021 ◽  
Author(s):  
Helena Leinweber ◽  
Raphael Sieber ◽  
Jesper Larsen ◽  
Marc Stegger ◽  
Hanne Ingmer
Keyword(s):  
Staphylococcus Aureus ◽  
Immune Evasion ◽  
Attachment Site ◽  
Bacterial Attachment ◽  
Adaptive Mutations ◽  
Integration Sites ◽  
Human Immune ◽  
Bacterial Viruses ◽  
Human Infections ◽  
Model Strain

AbstractIn recent years there has been an increase in human infections with methicillin-resistant Staphylococcus aureus (MRSA) originating from livestock and strains carrying bacterial viruses of the Sa3int-family have disseminated into the community. Sa3int phages express immune evasion factors and are common in human staphylococcal strains. As the bacterial attachment site (attB) for Sa3int phages is mutated in livestock-associated strains, the integration frequency is low and a key question is how the phages are established. Here we show that Sa3int phages adapt to alternative bacterial integration sites by mutating the phage attachment sequence, attP, leading to enhanced integration at these sites. Using a model strain carrying the mutated attBLA of livestock-associated strains we find that once established, the Sa3int phage, Φ13 is inducible with release of heterogenous phage populations carrying mutations in attP that in part increase homology to alternative integration sites or attBLA. Compared to the original phage, the adaptive mutations increase phage integration in new rounds of infection. Also, Sa3int phages induced from livestock-associated outbreak strains reveal mutated attP sequences. We suspect that promiscuity of the phage-encoded recombinase allows this adaptation and propose it may explain how phages mediate “host jumps” that are regularly observed for staphylococcal lineages.

scholarly journals Prevalence and Genetic Characteristics of Staphylococcus aureus CC398 Isolates From Invasive Infections in Spanish Hospitals, Focusing on the Livestock-Independent CC398-MSSA Clade

2021 ◽  
Vol 12 ◽  
Author(s):  
Olouwafemi Mistourath Mama ◽  
Carmen Aspiroz ◽  
Laura Ruiz-Ripa ◽  
Sara Ceballos ◽  
Maria Iñiguez-Barrio ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Immune Evasion ◽  
Statistical Significance ◽  
Blood Cultures ◽  
Human Adaptation ◽  
Genetic Characteristics ◽  
Invasive Infections ◽  
Human Immune ◽  
Epidemiological Characteristics ◽  
Immune Evasion Cluster

BackgroundLivestock-associated (LA)-CC398-MRSA is closely related to pigs, being unfrequently detected in human invasive infections. CC398-MSSA is emerging in human invasive infections in some countries, but genetic and epidemiological characteristics are still scarcely reported.ObjectivesTo determine the prevalence of Staphylococcus aureus (SA) CC398, both MRSA and MSSA, among blood cultures SA isolates recovered in Spanish hospitals located in regions with different pig-farming densities (PD) and characterize the recovered isolates.MethodsOne thousand twenty-two SA isolates (761 MSSA, 261 MRSA) recovered from blood cultures during 6–12 months in 17 Spanish hospitals (2018–2019) were studied. CC398 lineage identification, detection of spa-types, and antibiotic resistance, virulence and human immune evasion cluster (IEC) genes were analyzed by PCR/sequencing.ResultsForty-four CC398-MSSA isolates (4.3% of SA; 5.8% of MSSA) and 10 CC398-MRSA isolates (1% of SA; 3.8% of MRSA) were detected. Eleven spa-types were found among the CC398-MSSA isolates with t571 and t1451 the most frequent spa-types detected (75%). Most of CC398-MSSA isolates were Immune-Evasion-Cluster (IEC)-positive (88.6%), tetracycline-susceptible (95.5%) and erythromycin/clindamycin–inducible-resistant/erm(T)-positive (75%). No statistical significance was detected when the CC398-MSSA/MSSA rate was correlated to PD (pigs/km2) (p = 0.108). On the contrary, CC398-MRSA isolates were all IEC-negative, predominately spa-t011 (70%), and the CC398-MRSA/MRSA rate was significantly associated to PD (p < 0.005).ConclusionCC398-MSSA is an emerging clade in invasive infections in Spanish hospitals. CC398-MRSA (mostly t011) and CC398-MSSA (mostly t571 and t1451) show important differences, possibly suggesting divergent steps in host-adaptation evolutionary processes. While CC398-MRSA is livestock-associated (lacking IEC-system), CC398-MSSA seems to be mostly livestock-independent, carrying human-adaptation markers.

scholarly journals Staphylococcus aureus uses the ArlRS and MgrA cascade to regulate immune evasion during skin infection

Cell Reports ◽  
2021 ◽  
Vol 36 (4) ◽  
pp. 109462
Author(s):  
Jakub M. Kwiecinski ◽  
Rachel M. Kratofil ◽  
Corey P. Parlet ◽  
Bas G.J. Surewaard ◽  
Paul Kubes ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Immune Evasion ◽  
Skin Infection

scholarly journals ε2-Phages Are Naturally Bred and Have a Vastly Improved Host Range in Staphylococcus aureus over Wild Type Phages

2021 ◽  
Vol 14 (4) ◽  
pp. 325
Author(s):  
David Sáez Moreno ◽  
Zehra Visram ◽  
Michele Mutti ◽  
Marcela Restrepo-Córdoba ◽  
Susana Hartmann ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibiotic Resistance ◽  
Detection Limit ◽  
Host Range ◽  
Alternative Treatment ◽  
Standard Of Care ◽  
Wild Type ◽  
Rapid Spread ◽  
Pharmaceutical Properties ◽  
Human Infections

Due to the rapid spread of antibiotic resistance, and the difficulties of treating biofilm-associated infections, alternative treatments for S. aureus infections are urgently needed. We tested the lytic activity of several wild type phages against a panel of 110 S. aureus strains (MRSA/MSSA) composed to reflect the prevalence of S. aureus clonal complexes in human infections. The plaquing host ranges (PHR) of the wild type phages were in the range of 51% to 60%. We also measured what we called the kinetic host range (KHR), i.e., the percentage of strains for which growth in suspension was suppressed for 24 h. The KHR of the wild type phages ranged from 2% to 49%, substantially lower than the PHRs. To improve the KHR and other key pharmaceutical properties, we bred the phages by mixing and propagating cocktails on a subset of S. aureus strains. These bred phages, which we termed evolution-squared (ε2) phages, have broader KHRs up to 64% and increased virulence compared to the ancestors. The ε2-phages with the broadest KHR have genomes intercrossed from up to three different ancestors. We composed a cocktail of three ε2-phages with an overall KHR of 92% and PHR of 96% on 110 S. aureus strains and called it PM-399. PM-399 has a lower propensity to resistance formation than the standard of care antibiotics vancomycin, rifampicin, or their combination, and no resistance was observed in laboratory settings (detection limit: 1 cell in 1011). In summary, ε2-phages and, in particular PM-399, are promising candidates for an alternative treatment of S. aureus infections.

Immune Evasion by Staphylococcus aureus

2019 ◽  
Vol 7 (2) ◽  
Author(s):  
Nienke W. M. de Jong ◽  
Kok P. M. van Kessel ◽  
Jos A. G. van Strijp
Keyword(s):  
Staphylococcus Aureus ◽  
Immune Evasion

scholarly journals Role of Staphylococcal Phage and SaPI Integrase in Intra- and Interspecies SaPI Transfer

2007 ◽  
Vol 189 (15) ◽  
pp. 5608-5616 ◽  
Author(s):  
Elisa Maiques ◽  
Carles Úbeda ◽  
María Ángeles Tormo ◽  
María Desamparados Ferrer ◽  
Íñigo Lasa ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Special Reference ◽  
Attachment Site ◽  
Pathogenicity Islands ◽  
Specific Attachment ◽  
Generalized Transduction

ABSTRACT SaPIbov2 is a member of the SaPI family of staphylococcal pathogenicity islands and is very closely related to SaPIbov1. Typically, certain temperate phages can induce excision and replication of one or more of these islands and can package them into special small phage-like particles commensurate with their genome sizes (referred to as the excision-replication-packaging [ERP] cycle). We have studied the phage-SaPI interaction in some depth using SaPIbov2, with special reference to the role of its integrase. We demonstrate here that SaPIbov2 can be induced to replicate by different staphylococcal phages. After replication, SaPIbov2 is efficiently encapsidated and transferred to recipient organisms, including different non-Staphylococcus aureus staphylococci, where it integrates at a SaPI-specific attachment site, attC , by means of a self-coded integrase (Int). Phages that cannot induce the SaPIbov2 ERP cycle can transfer the island by recA-dependent classical generalized transduction and can also transfer it by a novel mechanism that requires the expression of SaPIbov2 int in the recipient but not in the donor. It is suggested that this mechanism involves the encapsidation of standard transducing fragments containing the intact island followed by int-mediated excision, circularization, and integration in the recipient.

scholarly journals Activity of Debio1452, a FabI Inhibitor with Potent Activity against Staphylococcus aureus and Coagulase-Negative Staphylococcus spp., Including Multidrug-Resistant Strains

2015 ◽  
Vol 59 (5) ◽  
pp. 2583-2587 ◽  
Author(s):  
Robert K. Flamm ◽  
Paul R. Rhomberg ◽  
Nachum Kaplan ◽  
Ronald N. Jones ◽  
David J. Farrell
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Agents ◽  
Fatty Acid Biosynthesis ◽  
Multidrug Resistant ◽  
Coagulase Negative Staphylococcus ◽  
Significant Activity ◽  
Coagulase Negative Staphylococci ◽  
Content Type ◽  
Mrsa Strains ◽  
Human Infections

ABSTRACTStaphylococcus aureusand coagulase-negative staphylococci (CoNS) are responsible for a wide variety of human infections. The investigational antibacterial Debio1450 (previously AFN-1720), a prodrug of Debio1452 (previously AFN-1252), specifically targets staphylococci without significant activity against other Gram-positive or Gram-negative species. Debio1452 inhibits FabI, an enzyme critical to fatty acid biosynthesis in staphylococci. The activity of Debio1452 against CoNS, methicillin-susceptibleS. aureus(MSSA), and methicillin-resistantS. aureus(MRSA), including significant clones, was determined. A globally diverse collection of 574 patient isolates from 35 countries was tested that included CoNS (6 species, 103 strains), MSSA (154 strains), MRSA (163 strains), and molecularly characterized strains (includingspa-typed MRSA clones; 154 strains). The isolates were tested for susceptibility by CLSI broth microdilution methods against Debio1452 and 10 comparators. The susceptibility rates for the comparators were determined using CLSI and EUCAST breakpoint criteria. AllS. aureusand CoNS strains were inhibited by Debio1452 concentrations of ≤0.12 and ≤0.5 μg/ml, respectively. The MIC50s for MSSA, MRSA, and molecularly characterized MRSA strains were 0.004 μg/ml, and the MIC90s ranged from 0.008 to 0.03 μg/ml. The MICs were higher for the CoNS isolates (MIC50/90, 0.015/0.12 μg/ml). AmongS. aureusstrains, resistance was common for erythromycin (61.6%), levofloxacin (49.0%), clindamycin (27.6%), tetracycline (15.7%), and trimethoprim-sulfamethoxazole (7.0%). Debio1452 demonstrated potent activity against MSSA, MRSA, and CoNS. Debio1452 showed significantly greater activity overall (MIC50, 0.004 μg/ml) than the other agents tested against these staphylococcal species, which included dominant MRSA clones and strains resistant to currently utilized antimicrobial agents.

Presence of Immune Evasion Cluster and Molecular Typing of Methicillin-Susceptible Staphylococcus aureus Isolated from Food Handlers

2016 ◽  
Vol 79 (4) ◽  
pp. 682-686 ◽  
Author(s):  
LÍVIA G. BAPTISTÃO ◽  
NATHALIA C. C. SILVA ◽  
ERIKA C. R. BONSAGLIA ◽  
BRUNA F. ROSSI ◽  
IVANA G. CASTILHO ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Immune Evasion ◽  
Close Contact ◽  
Meca Gene ◽  
Low Frequency ◽  
Food Handlers ◽  
Spa Typing ◽  
Typing Method ◽  
Spa Types ◽  
Immune Evasion Cluster

ABSTRACT The hands and noses of food handlers colonized by Staphylococcus aureus are an important source of food contamination in restaurants and food processing. Several virulence factors can be carried by mobile elements in strains of S. aureus, including the immune evasion cluster (IEC). This gene cluster improves the capacity of S. aureus to evade the human immune response. Many studies have reported the transmission of strains between animals and humans, such as farm workers that have close contact with livestock. However, there are few studies on the transmission between food and food handlers. The aim of this study was to detect the IEC and the mecA gene in strains isolated from food handlers and to type these strains using the spa typing method. Thirty-five strains of S. aureus isolated from the noses and hands of food handlers in three different kitchens were analyzed for the presence of the mecA gene and IEC and by spa typing. All strains were negative for the mecA gene, and the presence of IEC was observed in 10 (28.6%) strains. Fifteen different spa types were observed, with the most frequent being t127 (42.85%) and t002 (11.42%). Strains from the two most prevalent spa types and a novel spa type were typed by multilocus sequence typing. spa types t127, t002, and t13335 were determined to be multilocus sequence types (ST) ST-30, ST-5, and ST-45, respectively. The food handlers may have been contaminated by these strains of S. aureus through food, which is suggested by the low frequency of IEC and by ST that are observed more commonly in animals.

scholarly journals Identification, Cloning, and Characterization ofStaphylococcus pseudintermediusCoagulase

2018 ◽  
Vol 86 (8) ◽  
Author(s):  
Alaa H. Sewid ◽  
M. Nabil Hassan ◽  
A. M. Ammar ◽  
David A. Bemis ◽  
Stephen A. Kania
Keyword(s):  
Staphylococcus Aureus ◽  
Recombinant Protein ◽  
Immune Evasion ◽  
Complement C3 ◽  
Fibrin Deposition ◽  
Staphylococcus Pseudintermedius ◽  
Content Type ◽  
Chromogenic Assay ◽  
Prothrombin Activation ◽  
Multifunctional Properties

ABSTRACTCoagulase activation of prothrombin by staphylococcus induces the formation of fibrin deposition that facilitates the establishment of infection byStaphylococcusspecies. Coagulase activity is a key characteristic ofStaphylococcus pseudintermedius; however, no coagulase gene or associated protein has been studied to characterize this activity. We report a recombinant protein sharing 40% similarity toStaphylococcus aureuscoagulase produced from a putativeS. pseudintermediuscoagulase gene. Prothrombin activation by the protein was measured with a chromogenic assay using thrombin tripeptide substrate. Stronger interaction with bovine prothrombin than with human prothrombin was observed. TheS. pseudintermediuscoagulase protein also bound complement C3 and immunoglobulin. Recombinant coagulase facilitated the escape ofS. pseudintermediusfrom phagocytosis, presumably by forming a bridge between opsonizing antibody, complement, and fibrinogen. Evidence from this work suggests thatS. pseudintermediuscoagulase has multifunctional properties that contribute to immune evasion that likely plays an important role in virulence.

An Alanine-Rich Peptide Attenuates Quorum Sensing-Regulated Virulence and Biofilm Formation in Staphylococcus aureus

2019 ◽  
Vol 102 (4) ◽  
pp. 1228-1234 ◽  
Author(s):  
Raid Al Akeel ◽  
Ayesha Mateen ◽  
Rabbani Syed
Keyword(s):  
Gene Expression ◽  
Staphylococcus Aureus ◽  
Quorum Sensing ◽  
Biofilm Formation ◽  
Bacterial Attachment ◽  
The Body ◽  
Dependent Manner ◽  
Virulence Determinants ◽  
Microarray Gene Expression ◽  
Concentration Dependent Manner

Abstract Background: Alanine-rich proteins/peptides (ARP), with bioactivity of up to 20 amino acid residues, can be observed by the body easily during gastrointestinal digestion. Objective: Populus trichocarpa extract’s capability to attenuate quorum sensing-regulated virulence and biofilm formation in Staphylococcus aureus is described. Methods: PT13, an ARP obtained from P. trichocarpa, was tested for its activity against S. aureus using the broth microdilution test; a crystal-violet biofilm assay was performed under a scanning electron microscope. The production of various virulence factors was estimated with PT13 treatment. Microarray gene expression profiling of PT13-treated S. aureus was conducted and compared with an untreated control. Exopolysaccharides (EPS) was estimated to observe the PT13 inhibition activity. Results: PT13 was antimicrobial toward S. aureus at different concentrations and showed a similar growth rate in the presence and absence of PT13 at concentrations ≤8 μg/mL. Biofilm production was interrupted even at low concentrations, and biofilm-related genes were down-regulated when exposed to PT13. The genes encoding cell adhesion and bacterial attachment protein were the major genes suppressed by PT13. In addition, hemolysins, clumping activity, and EPS production of S. aureus decreased after treatment in a concentration-dependent manner. Conclusions: A long-chain PT13 with effective actions that, even at low concentration levels, not only regulated the gene expression in the producer organism but also blocked the virulence gene expression in this Gram-positive human pathogen is described. Highlights: We identified a PT13 as a potential antivirulence agent that regulated production of bacterial virulence determinants (e.g., toxins, enzymes and biofilm), downwards and it may be a promising anti-virulence agent to be further developed as an anti-infective agent.

scholarly journals Light Modulates Important Pathogenic Determinants and Virulence in Acinetobacter baumannii, Pseudomonas aeruginosa and Staphylococcus aureus ESKAPE Pathogens

2020 ◽  
Author(s):  
M. R. Tuttobene ◽  
J. F. Pérez ◽  
E. Pavesi ◽  
B. Perez Mora ◽  
D. Biancotti ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Acinetobacter Baumannii ◽  
Pathogenic Bacteria ◽  
Bacterial Pathogens ◽  
General Concept ◽  
Infection Model ◽  
Type Vi Secretion System ◽  
Sense And Respond ◽  
Human Infections

Light sensing has been extensively characterized in the human pathogen Acinetobacter baumannii at environmental temperatures. However, the influence of light on the physiology and pathogenicity of human bacterial pathogens at temperatures found in warm-blooded hosts is still poorly understand. In this work, we show that ESKAPE priority pathogens, such as Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter spp., which have been recognized by the WHO and the CDC as critical, can also sense and respond to light at temperatures found in human hosts. Most interestingly, in these pathogens light modulates important pathogenicity determinants as well as virulence in an epithelial infection model, which could have implications in human infections. In fact, we found that alpha-toxin-dependent hemolysis, motility and growth under iron deprived conditions are modulated by light in S. aureus. Light also regulates persistence, metabolism and the ability to kill competitors, in some of these microorganisms. Finally, light exerts a profound effect on the virulence of these pathogens in an epithelial infection model, though the response is not the same in the different species: virulence was enhanced by light in A. baumannii and S. aureus, while in A. nosocomialis and P. aeruginosa it was reduced. Neither the BlsA photoreceptor nor the type VI secretion system (T6SS) are involved in virulence modulation by light in A. baumannii. Overall, this fundamental knowledge highlights the potential use of light to control pathogen's virulence, either directly or by manipulating the light regulatory switch toward the lowest virulence/persistence configuration. IMPORTANCE Pathogenic bacteria are microorganisms capable of producing disease. Dangerous bacterial pathogens such as Staphylococcus aureus, Pseudomonas aeruginosa and Acinetobacter baumannii are responsible for serious intrahospital and community infections in humans. Therapeutics is often complicated due to resistance to multiple antibiotics, rendering them ineffective. In this work, we show that these pathogens sense natural light and respond to it by modulating aspects related to their ability to cause disease: in the presence of light some of them become more aggressive while others show an opposite response. Overall, we provide new understanding on the behavior of these pathogens, which could contribute to control infections caused by them. Since the response is distributed in diverse pathogens, this notion could prove a general concept.

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