Identifying Potential Therapeutic Targets of Methicillin-resistant Staphylococcus aureus Through in Vivo Proteomic Analysis

Diep, Binh An; Phung, Qui; Date, Shailesh V.; Arnott, David; Bakalarski, Corey E.; Xu, Min; Nakamura, Gerald; Swem, Danielle L.; Alexander, Mary Kate; Le, Hoan N.; Thuy, Thi; Tan, Man‐Wah; Brown, Eric J.; Nishiyama, Mireille

doi:10.1093/infdis/jit662

Cited by 38 publications

(44 citation statements)

References 50 publications

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“…In addition, vaccination of cattle with heat‐killed bacteria elicited antibodies against two lipoproteins, NWMN_0601 (MntC) and NWMN_0364. In contrast, only a slight MntC‐specific humoral or cellular immune response was detectable in humans naturally exposed to S. aureus in this study as well as that by Diep and co‐workers . Possibly, heat treatment disrupts the bacterial cell wall, thus facilitating lipoprotein release or exposure, which might explain the difference in the MntC‐directed antibody response between naturally S. aureus ‐exposed humans and vaccinated cattle.…”

Section: Discussioncontrasting

confidence: 62%

Adaptive immune response to lipoproteins of Staphylococcus aureus in healthy subjects

Kolata

Stentzel

et al. 2016

Proteomics

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Staphylococcus aureus is a frequent commensal but also a dangerous pathogen, causing many forms of infection ranging from mild to life‐threatening conditions. Among its virulence factors are lipoproteins, which are anchored in the bacterial cell membrane. Lipoproteins perform various functions in colonization, immune evasion, and immunomodulation. These proteins are potent activators of innate immune receptors termed Toll‐like receptors 2 and 6. This study addressed the specific B‐cell and T‐cell responses directed to lipoproteins in human S. aureus carriers and non‐carriers. 2D immune proteomics and ELISA approaches revealed that titers of antibodies (IgG) binding to S. aureus lipoproteins were very low. Proliferation assays and cytokine profiling data showed only subtle responses of T cells; some lipoproteins did not elicit proliferation. Hence, the robust activation of the innate immune system by S. aureus lipoproteins does not translate into a strong adaptive immune response. Reasons for this may include inaccessibility of lipoproteins for B cells as well as ineffective processing and presentation of the antigens to T cells.

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Section: Discussioncontrasting

confidence: 62%

Adaptive immune response to lipoproteins of Staphylococcus aureus in healthy subjects

Kolata

Stentzel

et al. 2016

Proteomics

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“…This is in stark contrast to many other Gram-positive pathogens that have been shown to employ both types of transporters. For example, in Staphylococcus aureus , which encodes both a Mn 2+ -ABC permease ( mntABC ) and NRAMP ( mntH ), loss of one or both Mn 2+ transporters has been reported to impact virulence of the pathogen, albeit to different extents (Diep et al 2014; Horsburgh et al 2002a; Kehl-Fie et al 2013). By contrast, lack of the Mn 2+ -specific ABC permease in streptococci invariably comprises their capacity for mediating disease in animal models (Crump et al 2014; Janulczyk et al 2003; McAllister et al 2004; Wichgers Schreur et al 2011).…”

Section: Manganese Acquisition Pathwaysmentioning

confidence: 99%

Manganese uptake and streptococcal virulence

2015

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Streptococcal solute-binding proteins (SBPs) associated with ATP-binding cassette transporters gained widespread attention first as ostensible adhesins, next as virulence determinants, and finally as metal ion transporters. In this mini-review, we will examine our current understanding of the cellular roles of these proteins, their contribution to metal ion homeostasis, and their crucial involvement in mediating streptococcal virulence. There are now more than 35 studies that have collected structural, biochemical and/or physiological data on the functions of SBPs across a broad range of bacteria. This offers a wealth of data to clarify the formerly puzzling and contentious findings regarding the metal specificity amongst this group of essential bacterial transporters. In particular we will focus on recent findings related to biological roles for manganese in streptococci. These advances will inform efforts aimed at exploiting the importance of manganese and manganese acquisition for the design of new approaches to combat serious streptococcal diseases.

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“…aureus , MntH is constitutively expressed, while MntABC is induced by Mn limitation [13, 31]. High-affinity Mn acquisition systems play a critical role in resisting Mn starvation during infection, and staphylococcal mutants lacking these systems are attenuated in several models of infection [13, 31, 36]. The virulence defect of a staphylococcal mutant lacking both Mn importers is reversed in CP-deficient mice, indicating that these systems specifically contribute to resisting host-imposed Mn starvation [13].…”

Section: Introductionmentioning

confidence: 99%

The Two-Component System ArlRS and Alterations in Metabolism Enable Staphylococcus aureus to Resist Calprotectin-Induced Manganese Starvation

Radin¹,

Kelliher²,

Solórzano³

et al. 2016

PLoS Pathog

114

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During infection the host imposes manganese and zinc starvation on invading pathogens. Despite this, Staphylococcus aureus and other successful pathogens remain capable of causing devastating disease. However, how these invaders adapt to host-imposed metal starvation and overcome nutritional immunity remains unknown. We report that ArlRS, a global staphylococcal virulence regulator, enhances the ability of S. aureus to grow in the presence of the manganese-and zinc-binding innate immune effector calprotectin. Utilization of calprotectin variants with altered metal binding properties revealed that strains lacking ArlRS are specifically more sensitive to manganese starvation. Loss of ArlRS did not alter the expression of manganese importers or prevent S. aureus from acquiring metals. It did, however, alter staphylococcal metabolism and impair the ability of S. aureus to grow on amino acids. Further studies suggested that relative to consuming glucose, the preferred carbon source of S. aureus, utilizing amino acids reduced the cellular demand for manganese. When forced to use glucose as the sole carbon source S. aureus became more sensitive to calprotectin compared to when amino acids are provided. Infection experiments utilizing wild type and calprotectin-deficient mice, which have defects in manganese sequestration, revealed that ArlRS is important for disease when manganese availability is restricted but not when this essential nutrient is freely available. In total, these results indicate that altering cellular metabolism contributes to the ability of pathogens to resist manganese starvation and that ArlRS enables S. aureus to overcome nutritional immunity by facilitating this adaptation.

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Identifying Potential Therapeutic Targets of Methicillin-resistant Staphylococcus aureus Through in Vivo Proteomic Analysis

Abstract: Besides providing experimental evidence that MntABC might be a potential therapeutic target for the development of antibiotics, our in vivo proteomics data will serve as a valuable basis for defining potential antigen combinations for multicomponent vaccines.

Cited by 38 publications

References 50 publications

Adaptive immune response to lipoproteins of Staphylococcus aureus in healthy subjects

Adaptive immune response to lipoproteins of Staphylococcus aureus in healthy subjects

Manganese uptake and streptococcal virulence

The Two-Component System ArlRS and Alterations in Metabolism Enable Staphylococcus aureus to Resist Calprotectin-Induced Manganese Starvation

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