Research

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Open AccessArticle

The T Cell Response to Staphylococcus aureus

by Barbara M. Bröker, Daniel Mrochen and Vincent Péton

Pathogens 2016, 5(1), 31; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens5010031 - 17 Mar 2016

Cited by 84 | Viewed by 11657

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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1241 KiB

Open AccessArticle

Importance of B Lymphocytes and the IgG-Binding Protein Sbi in Staphylococcus aureus Skin Infection

by Fan Zhao, Anita S. Chong and Christopher P. Montgomery

Pathogens 2016, 5(1), 12; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens5010012 - 27 Jan 2016

Cited by 8 | Viewed by 5058

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

by Sarah A. Horst, Andreas Itzek, Andreas Klos, Andreas Beineke and Eva Medina

Pathogens 2015, 4(4), 722-738; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens4040722 - 23 Oct 2015

Cited by 10 | Viewed by 5077

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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192 KiB

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

by Nayon Kang, Seth T. Housman and David P. Nicolau

Pathogens 2015, 4(3), 599-605; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens4030599 - 30 Jul 2015

Cited by 10 | Viewed by 5025

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

by Will A. McGuinness, Scott D. Kobayashi and Frank R. DeLeo

Pathogens 2016, 5(1), 32; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens5010032 - 17 Mar 2016

Cited by 57 | Viewed by 14385

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

by Keenan A. Lacey, Joan A. Geoghegan and Rachel M. McLoughlin

Pathogens 2016, 5(1), 22; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens5010022 - 17 Feb 2016

Cited by 92 | Viewed by 20823

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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211 KiB

Open AccessReview

Coordinated Molecular Cross-Talk between Staphylococcus aureus, Endothelial Cells and Platelets in Bloodstream Infection

by Carolina D. Garciarena, Tony M. McHale, Rebecca L. Watkin and Steven W. Kerrigan

Pathogens 2015, 4(4), 869-882; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens4040869 - 05 Dec 2015

Cited by 16 | Viewed by 4962

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)

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Open AccessReview

Antimicrobial Mechanisms of Macrophages and the Immune Evasion Strategies of Staphylococcus aureus

by Ronald S. Flannagan, Bryan Heit and David E. Heinrichs

Pathogens 2015, 4(4), 826-868; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens4040826 - 27 Nov 2015

Cited by 137 | Viewed by 15507

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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542 KiB

Open AccessReview

Immunomodulation and Disease Tolerance to Staphylococcus aureus

by Zhigang Li, Adam G. Peres, Andreea C. Damian and Joaquín Madrenas

Pathogens 2015, 4(4), 793-815; https://doi.org/10.3390/pathogens4040793 - 13 Nov 2015

Cited by 29 | Viewed by 8679

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

by Jay Vornhagen, Kellie Burnside, Christopher Whidbey, Jessica Berry, Xuan Qin and Lakshmi Rajagopal

Pathogens 2015, 4(4), 708-721; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens4040708 - 22 Oct 2015

Cited by 22 | Viewed by 5195

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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