Where does a Staphylococcus aureus vaccine stand?

Fowler, Vance G.; Proctor, Richard A.

doi:10.1111/1469-0691.12570

Cited by 209 publications

(187 citation statements)

References 94 publications

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“…The precise immune responses that protect against S. aureus skin infections are unclear, as nearly half of individuals with an S. aureus skin infection suffer a recurrence (2), despite the generation of high titers of specific antibodies and memory CD4 + T cells (3,4). Moreover, all prior S. aureus vaccines in humans that targeted antibody-mediated phagocytosis have lacked efficacy or resulted in increased mortality (5). Therefore, a greater understanding of the adaptive immune 1 0 2 8 jci.org Volume 128 Number 3 March 2018…”

Section: Introductionmentioning

confidence: 99%

Clonally expanded γδ T cells protect against Staphylococcus aureus skin reinfection

Dillen

Pinsker

Marusina³

et al. 2018

Journal of Clinical Investigation

112

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Section: Introductionmentioning

confidence: 99%

Clonally expanded γδ T cells protect against Staphylococcus aureus skin reinfection

Dillen

Pinsker

Marusina³

et al. 2018

Journal of Clinical Investigation

112

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“…An estimated 20% of the world's population are persistent carriers. The worldwide distribution of S. aureus coupled with its asymptomatic carriage have precluded any effective eradication strategy (8,9).…”

mentioning

confidence: 99%

Rifampin Resistance rpoB Alleles or Multicopy Thioredoxin/Thioredoxin Reductase Suppresses the Lethality of Disruption of the Global Stress Regulator spx in Staphylococcus aureus

et al. 2016

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Staphylococcus aureus is capable of causing a remarkable spectrum of disease, ranging from mild skin eruptions to life-threatening infections. The survival and pathogenic potential of S. aureus depend partly on its ability to sense and respond to changes in its environment. Spx is a thiol/oxidative stress sensor that interacts with the C-terminal domain of the RNA polymerase RpoA subunit, leading to changes in gene expression that help sustain viability under various conditions. Using genetic and deep-sequencing methods, we show that spx is essential in S. aureus and that a previously reported ⌬spx strain harbored suppressor mutations that allowed it to grow without spx. One of these mutations is a single missense mutation in rpoB (a P-to-L change at position 519 encoded by rpoB [rpoB-P519L]) that conferred high-level resistance to rifampin. This mutation alone was found to be sufficient to bypass the requirement for spx. The generation of rifampin resistance libraries led to the discovery of an additional rpoB mutation, R484H, which supported strains with the spx disruption. Other rifampin resistance mutations either failed to support the ⌬spx mutant or were recovered at unexpectedly low frequencies in genetic transduction experiments. The amino acid residues encoded by rpoB-P519L and -R484H map in close spatial proximity and comprise a highly conserved region of RpoB. We also discovered that multicopy expression of either trxA (encoding thioredoxin) or trxB (encoding thioredoxin reductase) supports strains with the deletion of spx. Our results reveal intriguing properties, especially of RNA polymerase, that compensate for the loss of an essential gene that is a key mediator of diverse processes in S. aureus, including redox and thiol homeostasis, antibiotic resistance, growth, and metabolism. IMPORTANCEThe survival and pathogenicity of S. aureus depend on complex genetic programs. An objective for combating this insidious organism entails dissecting genetic regulatory circuits and discovering promising new targets for therapeutic intervention. In this study, we discovered that Spx, an RNA polymerase-interacting stress regulator implicated in many stress responses in S. aureus, including responses to oxidative and cell wall antibiotics, is essential. We describe two mechanisms that suppress the lethality of spx disruption. One mechanism highlights how only certain rifampin resistance-encoding alleles of RpoB confer new properties on RNA polymerase, with important mechanistic implications. We describe additional stress conditions where the loss of spx is deleterious, thereby highlighting Spx as a multifaceted regulator and attractive drug discovery target. Staphylococcus aureus is a major human pathogen that causes a diversity of disease ranging from relatively minor to invasive and systemic disease with significant morbidity and mortality (1-7). S. aureus is common both in the community and in hospital environments and has the ability to transiently colonize the skin and mucous membranes of most humans,...

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“…none has successfully reached regulatory approval for S. aureus (24)(25)(26)(27). By combining the S. aureus-specific carbohydrate binding activity of selected autolysins and lysins with the Fc effector functions of human antibodies, we created three lysibodies specific to S. aureus.…”

Section: Significancementioning

confidence: 99%

Lysibodies are IgG Fc fusions with lysin binding domains targetingStaphylococcus aureuswall carbohydrates for effective phagocytosis

Raz

Serrano

Lawson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The cell wall of Gram-positive bacteria contains abundant surfaceexposed carbohydrate molecules that are highly conserved within and often across species. The potential therapeutic usefulness of high-affinity antibodies to cell wall carbohydrates is unquestioned, however obtaining such antibodies is challenging due to the poor overall immunogenicity of these bacterial targets. Autolysins and phage lysins are peptidoglycan hydrolases, enzymes that have evolved over a billion years to degrade bacterial cell wall. Such wall hydrolases are modular enzymes, composed of discrete domains for high-affinity binding to cell wall carbohydrates and cleavage activity. In this study, we demonstrate that binding domains from autolysins and lysins can be fused to the Fc region of human IgG, creating a fully functional homodimer (or "lysibody") with high-affinity binding and specificity for carbohydrate determinants on the bacterial surface. Furthermore, we demonstrate that this process is reproducible with three different binding domains specific to methicillin-resistant Staphylococcus aureus (MRSA). Cell-bound lysibodies induced the fixation of complement on the bacterial surface, promoted phagocytosis by macrophages and neutrophils, and protected mice from MRSA infection in two model systems. The lysibody approach could be used to target a range of difficult-to-treat pathogenic bacteria, given that cell wall hydrolases are ubiquitous in nature.immunotherapy | antibody | vaccine | monoclonal | peptidoglycan hydrolase

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Where does a Staphylococcus aureus vaccine stand?

Cited by 209 publications

References 94 publications

Clonally expanded γδ T cells protect against Staphylococcus aureus skin reinfection

Clonally expanded γδ T cells protect against Staphylococcus aureus skin reinfection

Rifampin Resistance rpoB Alleles or Multicopy Thioredoxin/Thioredoxin Reductase Suppresses the Lethality of Disruption of the Global Stress Regulator spx in Staphylococcus aureus

Lysibodies are IgG Fc fusions with lysin binding domains targetingStaphylococcus aureuswall carbohydrates for effective phagocytosis

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