Four-Component Staphylococcus aureus Vaccine 4C-Staph Enhances Fcγ Receptor Expression in Neutrophils and Monocytes and Mitigates S. aureus Infection in Neutropenic Mice

Torre, Antonina; Bacconi, Marta; Sammicheli, Chiara; Galletti, Bruno; Laera, Donatello; Fontana, Maria Rita; Grandi, Guido; Gregorio, Ennio De; Bagnoli, Fábio; Nuti, Sandra; Bertholet, Sylvie; Bensi, Giuliano

doi:10.1128/iai.00258-15

Cited by 27 publications

(30 citation statements)

References 37 publications

(39 reference statements)

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“…We have recently described a multi-protein vaccine formulation, 4C-Staph, which protects mice from S. aureus infection in different models212223. Since arthrosynovitis and OM are among the most severe S. aureus -dependent diseases in humans345, we wanted to test the efficacy of the vaccine formulation in a mouse model of knee joint infection and evaluate local and systemic host immune responses.…”

Section: Resultsmentioning

confidence: 99%

“…Antigen-specific antibodies were proven to play a central role in controlling S. aureus infection in different models2122. We therefore assessed IgG titers specific for each single component of the 4C-Staph formulation in knee joint washes of mock-immunized and 4C-Staph-immunized mice sacrificed 7 days after the infection with Newman.…”

Section: Resultsmentioning

confidence: 99%

“…This is also supported by the fact that the use of an effective vaccine against a major human pathogen responsible for SA, H. influenzae type B , resulted in the complete disappearance of this disease6. Although a vaccine against S. aureus is not yet available, we have recently demonstrated that immunization of mice with a multi-component protein-based vaccine (4C-Staph) was able to ameliorate the outcome of S. aureus infection in different in vivo models and that protection was dependent on both the humoral and cellular responses induced by vaccination21222324. We therefore set up a S. aureus infection model, resulting in a consistent bacterial infection of murine joints, in which we tested the ability of the proposed 4C-Staph formulation to reduce the burden of bacterial infection in the knees.…”

Section: Discussionmentioning

confidence: 99%

“…We have recently demonstrated that an adjuvanted protein combination vaccine, 4C-Staph, conferred significant protection against different S. aureus strains in multiple murine infection models, and that protection was dependent on both humoral and cellular immune responses21222324.…”

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confidence: 99%

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Staphylococcus aureus-dependent septic arthritis in murine knee joints: local immune response and beneficial effects of vaccination

Corrado

Donato

Maccari

et al. 2016

Sci Rep

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Staphylococcus aureus is the major cause of human septic arthritis and osteomyelitis, which deserve special attention due to their rapid evolution and resistance to treatment. The progression of the disease depends on both bacterial presence in situ and uncontrolled disruptive immune response, which is responsible for chronic disease. Articular and bone infections are often the result of blood bacteremia, with the knees and hips being the most frequently infected joints showing the worst clinical outcome. We report the development of a hematogenous model of septic arthritis in murine knees, which progresses from an acute to a chronic phase, similarly to what occurs in humans. Characterization of the local and systemic inflammatory and immune responses following bacterial infection brought to light specific signatures of disease. Immunization of mice with the vaccine formulation we have recently described (4C-Staph), induced a strong antibody response and specific CD4+ effector memory T cells, and resulted in reduced bacterial load in the knee joints, a milder general inflammatory state and protection against bacterial-mediated cellular toxicity. Possible correlates of protection are finally proposed, which might contribute to the development of an effective vaccine for human use.Staphylococcus aureus is a human pathogen responsible for a variety of diseases ranging from minor/mild skin infections to life threatening diseases 1 . It is a major cause of bacteremia, which frequently leads to severe complications like endocarditis, toxic shock syndrome, septic arthritis (SA) and osteomyelitis (OM) 2 . Among others, joint-related diseases deserve special attention because of their rapid evolution and serious clinical outcomes, such as intense pain and impairment due to bone erosion requiring urgent intervention [3][4][5] . Joint infections are frequently localized in the knees and hips, and monoarticular disease is more frequent and less severe than polyarticular infection 6,7 . The mortality rate associated with these infections is around 5-20% in the adult population 3 , but can reach 50% depending on delayed diagnosis, immunodeficiency, older age 3,4 and pre-existing underlying conditions, such as rheumatoid arthritis and diabetes 3,8,9 . Joint and bone disruption is caused by the activity of bacteria in the joints, as well as by uncontrolled activation of the host immune system sustaining a local destructive inflammatory state, which can eventually result in chronic disease [10][11][12][13] . OM is often not treatable with antibiotics, a problem that is presently more evident with the increasing emergence of antibiotic-resistant S. aureus strains [14][15][16][17][18][19] . On the other hand, early application of antibiotic treatment can be efficacious for SA, which however often requires surgical intervention 3,4,7,20 .Given these premises, the development of an efficacious vaccine able to prevent S. aureus-mediated SA and OM would be highly desirable. We have recently demonstrated that an adjuvanted protein comb...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Staphylococcus aureus-dependent septic arthritis in murine knee joints: local immune response and beneficial effects of vaccination

Corrado

Donato

Maccari

et al. 2016

Sci Rep

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“…We have recently described the use of multiple murine models of S. aureus infection, which were used to define a protective vaccine formulation and to study the possible immune mechanisms involved Torre et al 2015). In these models, groups of mice were observed for a limited time frame and killed at a defined time point when organs were taken and their bacterial burden determined.…”

Section: Introductionmentioning

confidence: 99%

A stable luciferase reporter plasmid for in vivo imaging in murine models of Staphylococcus aureus infections

Bacconi

Haag

Torre

et al. 2015

Appl Microbiol Biotechnol

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In vivo imaging of bioluminescent bacteria permits their visualization in infected mice, allowing spatial and temporal evaluation of infection progression. Most available bioluminescent strains were obtained by integration of the luciferase genes into the bacterial chromosome, a challenging and time-consuming approach. Recently, episomal plasmids were used, which were introduced in bacteria and expressed all genes required for bioluminescence emission. However, the plasmid was progressively lost in vitro and in vivo, if bacteria were not maintained under antibiotic selective pressure. Increased stability could be obtained inserting into the plasmid backbone sequences that assured plasmid partition between daughter bacterial cells, or caused death of bacteria that had lost the plasmid. So far, no detailed analysis was performed of either plasmid stability in vivo or contribution of different stabilizing sequence types. Here we report the construction of a plasmid, which includes the Photorhabdus luminescens lux cassette expressed under the control of a Staphylococcus aureus specific gene promoter, and toxin/antitoxin (T/A) and partition sequences (Par) conferring stability and transmissibility of the plasmid. Following infection of mice with S. aureus carrying this plasmid, we demonstrated that the promoter-lux fusion was functional in vivo, that the plasmid was retained by 70-100% of bacterial cells 7 days post-infection, and that both stabilizing sequence types were required to maximize plasmid retention. These data suggest that the plasmid can be a valuable tool to study gene expression and bacterial spread in small laboratory animals infected with S. aureus or possibly other Gram-positive human pathogens.

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Vaccine development to preventStaphylococcus aureussurgical-site infections

Mohamed

Wang

Huec³

et al. 2017

British Journal of Surgery

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Background: Staphylococcus aureus surgical-site infections (SSIs) are a major cause of poor health outcomes, including mortality, across surgical specialties. Despite current advances as a result of preventive interventions, the disease burden of S. aureus SSI remains high, and increasing antibiotic resistance continues to be a concern. Prophylactic S. aureus vaccines may represent an opportunity to prevent SSI.Methods: A review of SSI pathophysiology was undertaken in the context of evaluating new approaches to developing a prophylactic vaccine to prevent S. aureus SSI.Results: A prophylactic vaccine ideally would provide protective immunity at the time of the surgical incision to prevent initiation and progression of infection. Although the pathogenicity of S. aureus is attributed to many virulence factors, previous attempts to develop S. aureus vaccines targeted only a single virulence mechanism. The field has now moved towards multiple-antigen vaccine strategies, and promising results have been observed in early-phase clinical studies that supported the recent initiation of an efficacy trial to prevent SSI. Conclusion:There is an unmet medical need for novel S. aureus SSI prevention measures. Advances in understanding of S. aureus SSI pathophysiology could lead to the development of effective and safe prophylactic multiple-antigen vaccines to prevent S. aureus SSI.

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Four-Component Staphylococcus aureus Vaccine 4C-Staph Enhances Fcγ Receptor Expression in Neutrophils and Monocytes and Mitigates S. aureus Infection in Neutropenic Mice

Cited by 27 publications

References 37 publications

Staphylococcus aureus-dependent septic arthritis in murine knee joints: local immune response and beneficial effects of vaccination

Staphylococcus aureus-dependent septic arthritis in murine knee joints: local immune response and beneficial effects of vaccination

A stable luciferase reporter plasmid for in vivo imaging in murine models of Staphylococcus aureus infections

Vaccine development to preventStaphylococcus aureussurgical-site infections

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