Staphylococcus aureus Vaccine Research and Development: The Past, Present and Future, Including Novel Therapeutic Strategies

Clegg, Jonah; Soldaini, Elisabetta; McLoughlin, Rachel M.; Rittenhouse, Stephen; Bagnoli, Fábio; Phogat, Sanjay

doi:10.3389/fimmu.2021.705360

Cited by 76 publications

(62 citation statements)

References 205 publications

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“…One strategy to combat antibiotic resistance, a top-10 threat to global health ( 21 ), is vaccination where specific bacterial antigens can be used for immunization ( 22 ). However, there is currently no vaccine against MRSA infections, and the search for suitable staphylococcal antigens for vaccination is still in progress ( 23 , 24 ). Importantly, the model protein IsaA employed in our present study to asses protein secretion by midi Bacillus is a potential target for innovative antistaphylococcal immunotherapy ( 25 – 27 ).…”

Section: Introductionmentioning

confidence: 99%

Redirected Stress Responses in a Genome-Minimized ‘midi Bacillus ’ Strain with Enhanced Capacity for Protein Secretion

et al. 2021

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Our present study showcases a genome-minimized nonpathogenic bacterium, the so-called midi Bacillus , as a chassis for the development of future industrial strains that serve in the production of high-value difficult-to-produce proteins. In particular, we explain how midi Bacillus , which lacks about one-third of the original genome, effectively secretes a protein of the major human pathogen Staphylococcus aureus that cannot be produced by the parental Bacillus subtilis strain.

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Section: Introductionmentioning

confidence: 99%

Redirected Stress Responses in a Genome-Minimized ‘midi Bacillus ’ Strain with Enhanced Capacity for Protein Secretion

et al. 2021

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“…(9)(10)(11) A deeper understanding of immune responses against S. aureus is essential for the development therapies and vaccines against this pathogen, as efforts to develop effective vaccines have failed. (12,13) A primary mechanism of immune defense against extracellular bacteria like S. aureus is phagocytosis and killing of microbes by innate immune cells-neutrophils and to a lesser extent macrophages. (14) Influx of neutrophils to sites of infection is mediated by inflammatory cytokines such as IL-1β and TNF, and by IL-17 family cytokines, that induce chemokine expression and endothelial activation.…”

Section: Introductionmentioning

confidence: 99%

Immune Response to Persistent Staphyloccocus Aureus Periprosthetic Joint Infection in a Mouse Tibial Implant Model

Sokhi

Xia

Sosa

et al. 2020

Journal of Bone and Mineral Research

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Staphyloccocus aureus is one of the major pathogens in orthopedic periprosthetic joint infection (PJI), a devastating complication of total joint arthroplasty that often results in chronic and persistent infections that are refractory to antibiotics and require surgical interventions. Biofilm formation has been extensively investigated as a reason for persistent infection. The cellular composition, activation status, cytokine profile, and role of the immune response during persistent S. aureus PJI are incompletely understood. In this study, we used histology, multiparametric flow cytometry, and gene expression analysis to characterize the immune response in a clinically relevant orthopedic PJI model. We tested the hypothesis that persistent S. aureus infection induces feedback mechanisms that suppress immune cell activation, thereby affecting the course of infection. Surprisingly, persistent infection was characterized by strikingly high cytokine gene expression indicative of robust activation of multiple components of innate and adaptive immunity, along with ongoing severe neutrophil-dominated inflammation, in infected joint and bone tissues. Activation and expansion of draining lymph nodes and a bone marrow stress granulopoiesis reaction were also maintained during late phase infection. In parallel, feedback mechanisms involving T-cell inhibitory receptors and exhaustion markers, suppressive cytokines, and regulatory T cells were activated and associated with decreased T-cell proliferation and tissue infiltration during the persistent phase of infection. These results identify the cellular and molecular components of the mouse immune response to persistent S. aureus PJI and indicate that neutrophil infiltration, inflammatory cytokine responses, and ongoing lymph node and bone marrow reactions are insufficient to clear infection and that immune effector mechanisms are suppressed by feedback inhibitory pathways. These immune-suppressive mechanisms are associated with diminished T-cell proliferation and tissue infiltration and can be targeted as part of adjuvant immunotherapeutic strategies in combination with debridement of biofilm, antibiotics, and other therapeutic modalities to promote eradication of infection.

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“…To date, S. aureus vaccine development is still a global challenge. The most common method has been the application of engineered bacteria to produce recombinant proteins or polysaccharide antigens 24 . There has been very little research into oral vaccination to prevent the S. aureus pathogen.…”

Section: Discussionmentioning

confidence: 99%

Generation of Bacillus subtilis displaying alpha-toxin HlaH35LH48L fused with CotB and CotG, and studying the immune response in mice

Nguyen¹,

Duong²,

Truong³

et al. 2021

Biomed. Res. Ther.

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Introduction:The Bacillus subtilis spore is considered to be a powerful vehicle for surface display and antigen delivery. Being safe and widely used for the purpose of oral bacteriotherapy in humans and animals, B. subtilis spore has potential in the domain of needle-free vaccine development. The spores themselves also behave as an adjuvant. This study aims to generate B. subtilis spores expressing mutant staphylococcal alpha-toxin Hla H35LH48L on the surface and to study their ability to evoke a specific immune response in mice. Methods: Vectors carrying the hla H35LH48L gene fused with the coding genes of anchor proteins, cotB and cotG, were cloned in E. coli before being transformed into B. subtilis. The generation of the B. subtilis new strains via chromosomal integration was confirmed by PCR. Sporulation was observed under the m icroscope. The expression of the target protein on the spore surface was determined by sporeELISA. The level of IgG in the serum and IgA in the feces of Swiss mice were analyzed using ELISA to learn about the immune response against the B. subtilis spore administrated via the oral route. Results: The PCR products of an expected size on agarose gel electrophoresis showed successful integration, resulting in the construction of new B. subtilis strains BsHT2331 and BsHT2334. sporeELISA analysis detected a significant Hla H35LH48L expression on the spore surface. The BsHT2331 spores (CotB-Hla H35LH48L ) triggered a constant increase in the IgG and IgA levels in mice after three doses as 5.5-fold and 2.5-fold higher than the pre-immunization, respectively (p-value < 0.0001). Meanwhile, the group of mice orally administrated with BsHT2334 (CotG-Hla H35LH48L ) showed a notable IgG titer but minor IgA response. Conclusion: The results concluded that the construction of two new strains BsHT2331 and BsHT2334 that used spore coat proteins CotB and CotG to display mutant alpha-toxin Hla H35LH48L on the B. subtilis spore surface was successful. It provided an assessment of the ability of B. subtilis spores to stimulate specific antibody production in mice.

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Staphylococcus aureus Vaccine Research and Development: The Past, Present and Future, Including Novel Therapeutic Strategies

Cited by 76 publications

References 205 publications

Redirected Stress Responses in a Genome-Minimized ‘midi Bacillus ’ Strain with Enhanced Capacity for Protein Secretion

Redirected Stress Responses in a Genome-Minimized ‘midi Bacillus ’ Strain with Enhanced Capacity for Protein Secretion

Immune Response to Persistent Staphyloccocus Aureus Periprosthetic Joint Infection in a Mouse Tibial Implant Model

Generation of Bacillus subtilis displaying alpha-toxin HlaH35LH48L fused with CotB and CotG, and studying the immune response in mice

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