Recombinant ESAT-6-Like Proteins Provoke Protective Immune Responses against Invasive Staphylococcus aureus Disease in a Murine Model

Abstract

bStaphylococcus aureus is a common pathogen found in the community and in hospitals. Most notably, methicillin-resistant S. aureus is resistant to many antibiotics, which is a growing public health concern. The emergence of drug-resistant strains has prompted the search for alternative treatments, such as immunotherapeutic approaches. To date, most clinical trials of vaccines or of passive immunization against S. aureus have ended in failure. In this study, we investigated two ESAT-6-like proteins secreted by S. aureus, S. aureus EsxA (SaEsxA) and SaEsxB, as possible targets for a vaccine. Mice vaccinated with these purified proteins elicited high titers of anti-SaEsxA and anti-SaEsxB antibodies, but these antibodies could not prevent S. aureus infection. On the other hand, recombinant SaEsxA (rSaEsxA) and rSaEsxB could induce Th1-and Th17-biased immune responses in mice. Mice immunized with rSaEsxA and rSaEsxB had significantly improved survival rates when challenged with S. aureus compared with the controls. These findings indicate that SaEsxA and SaEsxB are two promising Th1 and Th17 candidate antigens which could be developed into multivalent and serotype-independent vaccines against S. aureus infection.

Immunotherapy Targeting Adenosine Synthase A Decreases Severity of Staphylococcus aureus Infection in Mouse Model

“…Active (10 days after second immunization) or passive immunized BALB/C mice were challenged by intravenous injection of S. aureus [ 17 , 28 ]. Mice were infected with 5 × 10 7 CFU of S. aureus and monitored daily for 14 days.…”

“…At least 13 secreted proteins and 24 surface adhesion proteins from S. aureus have been implicated in the bacterial immune evasion, many of which have been evaluated as potential antigens [ 7–16 ]. Current and past S. aureus vaccines or therapeutic antibody strategies have mainly focused on virulence factors, capsular polysaccharide (CPS) and iron-regulated proteins, including ess extracellular A (EsxA) and ess extracellular B (EsxB) [ 17 ], alpha toxin (nontoxic derivative of H35L) [ 8 , 18 ], clumping factor A (ClfA) [ 19 ], fibronectin binding protein (FnBPA or FnBPB) [ 13 ], Panton-Valentine leukocidin (PVL) [ 20 ], and protein A [ 12 ]. Iron-regulated proteins have also been investigated as another possible target for vaccines against S. aureus , such as Merck V710, which is based on the iron-regulated surface determinant B (IsdB) [ 7 , 21 ].…”

One Dose of Staphylococcus aureus 4C-Staph Vaccine Formulated with a Novel TLR7-Dependent Adjuvant Rapidly Protects Mice through Antibodies, Effector CD4+ T Cells, and IL-17A

“…aureus infection, suggesting that additional antigens are required for an efficacious vaccine [ 9 ]. EsxAB is a fusion of the two ESAT-6-like secreted virulence factors EsxA and EsxB associated to abscess formation, which may facilitate persistence and spread of the pathogen in the infected host [ 11 – 13 ]. FhuD2 is a lipoprotein involved in iron uptake and in early stages of invasive S .…”

MF59- and Al(OH)3-Adjuvanted Staphylococcus aureus (4C-Staph) Vaccines Induce Sustained Protective Humoral and Cellular Immune Responses, with a Critical Role for Effector CD4 T Cells at Low Antibody Titers

“…Hla plays a role in the early stages of invasive and skin infections ( 15 ), and was shown to confer protection in several mouse infection models of S. aureus , including pneumonia ( 16 , 17 ), peritonitis ( 10 , 18 ), and dermonecrosis ( 15 , 19 ). EsxA and EsxB are secreted through the ESAT-6 secretion system, which are involved in abscess formation ( 20 – 22 ). To be exploited as vaccine antigens, Hla was detoxified with a histidine to leucine substitution at position 35 (Hla H35L ) ( 23 ), while EsxA and EsxB were fused together (EsxAB) ( 10 ).…”