Special Issue "Staphylococcus Aureus Infection"

A special issue of Pathogens (ISSN 2076-0817).

Deadline for manuscript submissions: closed (30 September 2015).

Special Issue Editor

Guest Editor
Prof. Dr. Rachel McLoughlin

School of Biochemistry and Immunology, Trinity College Dublin, Ireland
Website | E-Mail
Interests: T-cells in Staphylococcus aureus infection, S.aureus vaccine development, S.aureus evasion of phagocytes

Special Issue Information

Dear Colleagues,

The recent WHO report, ‘Antimicrobial resistance: global report on surveillance’ highlights the epidemic of antibiotic resistance in Staphylococcus aureus as a particular threat to society. Antibiotic resistance is a global crisis, which urgently requires alternative strategies to standard antibiotic therapy.  There is an immediate unmet clinical need for an anti-S. aureus vaccine. Despite major efforts and significant financial investment by drug companies, an anti-S. aureus vaccine still eludes us. One of the critical factors impeding progress towards an efficacious anti-S. aureus vaccine has been an insufficient understanding of how this organism interacts with the host and in particular a paucity of insight into S. aureus immune mechanisms in humans. Compounding matters is S. aureus propensity for immune evasion. Novel therapeutic strategies will be required to disarm these immune evasion strategies, thus, promoting host immunity against infection. To-date, all vaccine candidates have worked on the premise of inducing protective anti-S. aureus antibodies. However, recent studies have revealed the importance of T-cells in coordinating phagocytic cell function and promoting bacterial clearance. It is now widely accepted that protective immunity to S. aureus requires a contribution from both cellular and humoral immunity. It is clear that any future success towards realizing an efficacious anti-S. aureus vaccine or the development of alternative immunomodulatory therapies against S. aureus will require that we increase our understanding of how this organism interacts with the host. For this Special Issue of Pathogens we invite you to submit a review article/original research article related to S. aureus host-pathogen interactions, and look forward to your contribution.

Dr. Rachel McLoughlin
Guest Editor

Manuscript Submission Information

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Keywords

  • Staphylococcus aureus
  • innate immunity
  • adaptive immunity
  • T-cells
  • phagocytes
  • immune evasion

Published Papers (10 papers)

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Research

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Open AccessArticle
The T Cell Response to Staphylococcus aureus
Received: 11 January 2016 / Revised: 1 March 2016 / Accepted: 8 March 2016 / Published: 17 March 2016
Cited by 22 | PDF Full-text (647 KB) | HTML Full-text | XML Full-text
Abstract
Staphylococcus aureus (S. aureus) is a dangerous pathogen and a leading cause of both nosocomial and community acquired bacterial infection worldwide. However, on the other hand, we are all exposed to this bacterium, often within the first hours of life, and [...] Read more.
Staphylococcus aureus (S. aureus) is a dangerous pathogen and a leading cause of both nosocomial and community acquired bacterial infection worldwide. However, on the other hand, we are all exposed to this bacterium, often within the first hours of life, and usually manage to establish equilibrium and coexist with it. What does the adaptive immune system contribute toward lifelong control of S. aureus? Will it become possible to raise or enhance protective immune memory by vaccination? While in the past the S. aureus-specific antibody response has dominated this discussion, the research community is now coming to appreciate the role that the cellular arm of adaptive immunity, the T cells, plays. There are numerous T cell subsets, each with differing functions, which together have the ability to orchestrate the immune response to S. aureus and hence to tip the balance between protection and pathology. This review summarizes the state of the art in this dynamic field of research. Full article
(This article belongs to the Special Issue Staphylococcus Aureus Infection)
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Open AccessArticle
Importance of B Lymphocytes and the IgG-Binding Protein Sbi in Staphylococcus aureus Skin Infection
Received: 1 September 2015 / Revised: 19 January 2016 / Accepted: 21 January 2016 / Published: 27 January 2016
Cited by 2 | PDF Full-text (1241 KB) | HTML Full-text | XML Full-text
Abstract
Recurrent Staphylococcus aureus infections are common, suggesting that immunity elicited by these infections is not protective. We previously reported that S. aureus skin infection (SSTI) elicited antibody-mediated immunity against secondary SSTI in BALB/c mice. In this study, we investigated the role of humoral [...] Read more.
Recurrent Staphylococcus aureus infections are common, suggesting that immunity elicited by these infections is not protective. We previously reported that S. aureus skin infection (SSTI) elicited antibody-mediated immunity against secondary SSTI in BALB/c mice. In this study, we investigated the role of humoral immunity and the IgG-binding proteins Sbi and SpA in S. aureus SSTI. We found that B lymphocyte-deficient μMT mice were highly susceptible to infection, compared with congenic BALB/c mice. Importantly, transfer of immune serum protected μMT mice, demonstrating an appropriate response to protective antibody. We found that deletion of sbi, but not spa, impaired virulence, as assessed by skin lesion severity, and that Sbi-mediated virulence required B lymphocytes/antibody. Furthermore, neither Sbi nor SpA impaired the elicited antibody response or protection against secondary SSTI. Taken together, these findings highlight a B lymphocyte/antibody-dependent role of Sbi in the pathogenesis of S. aureus SSTI, and demonstrate that neither Sbi nor SpA interfered with elicited antibody-mediated immunity. Full article
(This article belongs to the Special Issue Staphylococcus Aureus Infection)
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Open AccessArticle
Differential Contributions of the Complement Anaphylotoxin Receptors C5aR1 and C5aR2 to the Early Innate Immune Response against Staphylococcus aureus Infection
Pathogens 2015, 4(4), 722-738; https://doi.org/10.3390/pathogens4040722
Received: 16 September 2015 / Revised: 19 October 2015 / Accepted: 20 October 2015 / Published: 23 October 2015
Cited by 5 | PDF Full-text (1424 KB) | HTML Full-text | XML Full-text
Abstract
The complement anaphylatoxin C5a contributes to host defense against Staphylococcus aureus. In this study, we investigated the functional role of the two known C5a receptors, C5aR1 and C5aR2, in the host response to S. aureus. We found that C5aR1−/ mice [...] Read more.
The complement anaphylatoxin C5a contributes to host defense against Staphylococcus aureus. In this study, we investigated the functional role of the two known C5a receptors, C5aR1 and C5aR2, in the host response to S. aureus. We found that C5aR1−/ mice exhibited greater susceptibility to S. aureus bloodstream infection than wild type and C5aR2−/ mice, as demonstrated by the significantly higher bacterial loads in the kidneys and heart at 24 h of infection, and by the higher levels of inflammatory IL-6 in serum. Histological and immunohistochemistry investigation of infected kidneys at 24 h after bacterial inoculation revealed a discrete infiltration of neutrophils in wild type mice but already well-developed abscesses consisting of bacterial clusters surrounded by a large number of neutrophils in both C5aR1−/ and C5aR2/ mice. Furthermore, blood neutrophils from C5aR1−/ mice were less efficient than those from wild type or C5aR2−/ mice at killing S. aureus. The requirement of C5aR1 for efficient killing of S. aureus was also demonstrated in human blood after disrupting C5a-C5aR1 signaling using specific inhibitors. These results demonstrated a role for C5aR1 in S. aureus clearance as well as a role for both C5aR1 and C5aR2 in the orchestration of the inflammatory response during infection. Full article
(This article belongs to the Special Issue Staphylococcus Aureus Infection)
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Open AccessArticle
Assessing the Surrogate Susceptibility of Oxacillin and Cefoxitin for Commonly Utilized Parenteral Agents against Methicillin-Susceptible Staphylococcus aureus: Focus on Ceftriaxone Discordance between Predictive Susceptibility and in Vivo Exposures
Pathogens 2015, 4(3), 599-605; https://doi.org/10.3390/pathogens4030599
Received: 3 July 2015 / Revised: 15 July 2015 / Accepted: 28 July 2015 / Published: 30 July 2015
Cited by 4 | PDF Full-text (192 KB) | HTML Full-text | XML Full-text
Abstract
Susceptibility testing with the use of surrogate agents is common among clinical microbiology laboratories. One such example is oxacillin and cefoxitin for β-lactams against methicillin-susceptible Staphylococcus aureus (MSSA). This study aimed to assess the surrogate predictive value (SPV) of oxacillin and cefoxitin for [...] Read more.
Susceptibility testing with the use of surrogate agents is common among clinical microbiology laboratories. One such example is oxacillin and cefoxitin for β-lactams against methicillin-susceptible Staphylococcus aureus (MSSA). This study aimed to assess the surrogate predictive value (SPV) of oxacillin and cefoxitin for the susceptibility of commonly utilized parenteral β-lactams against MSSA as well as to evaluate the concordance between predictive susceptibility testing and the in vivo exposures for ceftriaxone. Broth microdilution MICs were determined for cefazolin, cefoxitin, ceftaroline, ceftriaxone, nafcillin, and oxacillin against a national collection of 1238 MSSA from US hospitals. Pharmacodynamic profiling was utilized to establish a clinical breakpoint for commonly utilized doses of ceftriaxone. Oxacillin had good SPVs for all the β-lactams tested, whereas cefoxitin produced unacceptable major errors for all four agents and thus appears to be an unacceptable susceptibility surrogate. While oxacillin is an adequate surrogate based on the currently defined laboratory criteria, our data also suggest that caution should be exercised when incorporating this testing approach in the clinical setting in view of the fact that the MIC distribution of MSSA coupled with the commonly utilized low doses of ceftriaxone may result in inadequate in vivo exposures against this pathogen. Full article
(This article belongs to the Special Issue Staphylococcus Aureus Infection)

Review

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Open AccessReview
Evasion of Neutrophil Killing by Staphylococcus aureus
Received: 23 February 2016 / Revised: 11 March 2016 / Accepted: 14 March 2016 / Published: 17 March 2016
Cited by 23 | PDF Full-text (1968 KB) | HTML Full-text | XML Full-text
Abstract
Staphylococcus aureus causes many types of infections, ranging from self-resolving skin infections to severe or fatal pneumonia. Human innate immune cells, called polymorphonuclear leukocytes (PMNs or neutrophils), are essential for defense against S. aureus infections. Neutrophils are the most prominent cell type of [...] Read more.
Staphylococcus aureus causes many types of infections, ranging from self-resolving skin infections to severe or fatal pneumonia. Human innate immune cells, called polymorphonuclear leukocytes (PMNs or neutrophils), are essential for defense against S. aureus infections. Neutrophils are the most prominent cell type of the innate immune system and are capable of producing non-specific antimicrobial molecules that are effective at eliminating bacteria. Although significant progress has been made over the past few decades, our knowledge of S. aureus-host innate immune system interactions is incomplete. Most notably, S. aureus has the capacity to produce numerous molecules that are directed to protect the bacterium from neutrophils. Here we review in brief the role played by neutrophils in defense against S. aureus infection, and correspondingly, highlight selected S. aureus molecules that target key neutrophil functions. Full article
(This article belongs to the Special Issue Staphylococcus Aureus Infection)
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Open AccessReview
The Role of Staphylococcus aureus Virulence Factors in Skin Infection and Their Potential as Vaccine Antigens
Received: 18 December 2015 / Revised: 27 January 2016 / Accepted: 3 February 2016 / Published: 17 February 2016
Cited by 26 | PDF Full-text (710 KB) | HTML Full-text | XML Full-text
Abstract
Staphylococcus aureus (S. aureus) causes the vast majority of skin and soft tissue infections (SSTIs) in humans. S. aureus has become increasingly resistant to antibiotics and there is an urgent need for new strategies to tackle S. aureus infections. Vaccines offer [...] Read more.
Staphylococcus aureus (S. aureus) causes the vast majority of skin and soft tissue infections (SSTIs) in humans. S. aureus has become increasingly resistant to antibiotics and there is an urgent need for new strategies to tackle S. aureus infections. Vaccines offer a potential solution to this epidemic of antimicrobial resistance. However, the development of next generation efficacious anti-S. aureus vaccines necessitates a greater understanding of the protective immune response against S. aureus infection. In particular, it will be important to ascertain if distinct immune mechanisms are required to confer protection at distinct anatomical sites. Recent discoveries have highlighted that interleukin-17-producing T cells play a particularly important role in the immune response to S. aureus skin infection and suggest that vaccine strategies to specifically target these types of T cells may be beneficial in the treatment of S. aureus SSTIs. S. aureus expresses a large number of cell wall-anchored (CWA) proteins, which are covalently attached to the cell wall peptidoglycan. The virulence potential of many CWA proteins has been demonstrated in infection models; however, there is a paucity of information regarding their roles during SSTIs. In this review, we highlight potential candidate antigens for vaccines targeted at protection against SSTIs. Full article
(This article belongs to the Special Issue Staphylococcus Aureus Infection)
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Open AccessReview
Coordinated Molecular Cross-Talk between Staphylococcus aureus, Endothelial Cells and Platelets in Bloodstream Infection
Pathogens 2015, 4(4), 869-882; https://doi.org/10.3390/pathogens4040869
Received: 15 October 2015 / Accepted: 2 December 2015 / Published: 5 December 2015
Cited by 9 | PDF Full-text (211 KB) | HTML Full-text | XML Full-text
Abstract
Staphylococcus aureus is an opportunistic pathogen often carried asymptomatically on the human body. Upon entry to the otherwise sterile environment of the cardiovascular system, S. aureus can lead to serious complications resulting in organ failure and death. The success of S. aureus as [...] Read more.
Staphylococcus aureus is an opportunistic pathogen often carried asymptomatically on the human body. Upon entry to the otherwise sterile environment of the cardiovascular system, S. aureus can lead to serious complications resulting in organ failure and death. The success of S. aureus as a pathogen in the bloodstream is due to its ability to express a wide array of cell wall proteins on its surface that recognise host receptors, extracellular matrix proteins and plasma proteins. Endothelial cells and platelets are important cells in the cardiovascular system and are a major target of bloodstream infection. Endothelial cells form the inner lining of a blood vessel and provide an antithrombotic barrier between the vessel wall and blood. Platelets on the other hand travel throughout the cardiovascular system and respond by aggregating around the site of injury and initiating clot formation. Activation of either of these cells leads to functional dysregulation in the cardiovascular system. In this review, we will illustrate how S. aureus establish intimate interactions with both endothelial cells and platelets leading to cardiovascular dysregulation. Full article
(This article belongs to the Special Issue Staphylococcus Aureus Infection)
Open AccessReview
Antimicrobial Mechanisms of Macrophages and the Immune Evasion Strategies of Staphylococcus aureus
Pathogens 2015, 4(4), 826-868; https://doi.org/10.3390/pathogens4040826
Received: 30 October 2015 / Revised: 17 November 2015 / Accepted: 24 November 2015 / Published: 27 November 2015
Cited by 41 | PDF Full-text (1364 KB) | HTML Full-text | XML Full-text
Abstract
Habitually professional phagocytes, including macrophages, eradicate microbial invaders from the human body without overt signs of infection. Despite this, there exist select bacteria that are professional pathogens, causing significant morbidity and mortality across the globe and Staphylococcus aureus is no exception. S. aureus [...] Read more.
Habitually professional phagocytes, including macrophages, eradicate microbial invaders from the human body without overt signs of infection. Despite this, there exist select bacteria that are professional pathogens, causing significant morbidity and mortality across the globe and Staphylococcus aureus is no exception. S. aureus is a highly successful pathogen that can infect virtually every tissue that comprises the human body causing a broad spectrum of diseases. The profound pathogenic capacity of S. aureus can be attributed, in part, to its ability to elaborate a profusion of bacterial effectors that circumvent host immunity. Macrophages are important professional phagocytes that contribute to both the innate and adaptive immune response, however from in vitro and in vivo studies, it is evident that they fail to eradicate S. aureus. This review provides an overview of the antimicrobial mechanisms employed by macrophages to combat bacteria and describes the immune evasion strategies and some representative effectors that enable S. aureus to evade macrophage-mediated killing. Full article
(This article belongs to the Special Issue Staphylococcus Aureus Infection)
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Open AccessReview
Immunomodulation and Disease Tolerance to Staphylococcus aureus
Pathogens 2015, 4(4), 793-815; https://doi.org/10.3390/pathogens4040793
Received: 10 November 2015 / Accepted: 10 November 2015 / Published: 13 November 2015
Cited by 15 | PDF Full-text (542 KB) | HTML Full-text | XML Full-text
Abstract
The Gram-positive bacterium Staphylococcus aureus is one of the most frequent pathogens that causes severe morbidity and mortality throughout the world. S. aureus can infect skin and soft tissues or become invasive leading to diseases such as pneumonia, endocarditis, sepsis or toxic shock [...] Read more.
The Gram-positive bacterium Staphylococcus aureus is one of the most frequent pathogens that causes severe morbidity and mortality throughout the world. S. aureus can infect skin and soft tissues or become invasive leading to diseases such as pneumonia, endocarditis, sepsis or toxic shock syndrome. In contrast, S. aureus is also a common commensal microbe and is often part of the human nasal microbiome without causing any apparent disease. In this review, we explore the immunomodulation and disease tolerance mechanisms that promote commensalism to S. aureus. Full article
(This article belongs to the Special Issue Staphylococcus Aureus Infection)
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Other

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Open AccessBrief Report
Kinase Inhibitors that Increase the Sensitivity of Methicillin Resistant Staphylococcus aureus to β-Lactam Antibiotics
Pathogens 2015, 4(4), 708-721; https://doi.org/10.3390/pathogens4040708
Received: 24 August 2015 / Revised: 16 October 2015 / Accepted: 20 October 2015 / Published: 22 October 2015
Cited by 10 | PDF Full-text (1270 KB) | HTML Full-text | XML Full-text
Abstract
Staphylococcus aureus are Gram-positive bacteria that are the leading cause of recurrent infections in humans that include pneumonia, bacteremia, osteomyelitis, arthritis, endocarditis, and toxic shock syndrome. The emergence of methicillin resistant S. aureus strains (MRSA) has imposed a significant concern in sustained measures [...] Read more.
Staphylococcus aureus are Gram-positive bacteria that are the leading cause of recurrent infections in humans that include pneumonia, bacteremia, osteomyelitis, arthritis, endocarditis, and toxic shock syndrome. The emergence of methicillin resistant S. aureus strains (MRSA) has imposed a significant concern in sustained measures of treatment against these infections. Recently, MRSA strains deficient in expression of a serine/threonine kinase (Stk1 or PknB) were described to exhibit increased sensitivity to β-lactam antibiotics. In this study, we screened a library consisting of 280 drug-like, low-molecular-weight compounds with the ability to inhibit protein kinases for those that increased the sensitivity of wild-type MRSA to β-lactams and then evaluated their toxicity in mice. We report the identification of four kinase inhibitors, the sulfonamides ST085384, ST085404, ST085405, and ST085399 that increased sensitivity of WT MRSA to sub-lethal concentrations of β-lactams. Furthermore, these inhibitors lacked alerting structures commonly associated with toxic effects, and toxicity was not observed with ST085384 or ST085405 in vivo in a murine model. These results suggest that kinase inhibitors may be useful in therapeutic strategies against MRSA infections. Full article
(This article belongs to the Special Issue Staphylococcus Aureus Infection)
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