COMPSTAPH

Exploiting innate immune evasion strategies of Staphylococcus aureus for the design of novel antibody-based therapeutic agents for the treatment of bacteremia

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 Obiettivo del progetto (Objective)

'Staphylococcus aureus is a widely disseminated human pathogen whose virulence is associated with a broad range of severe and potentially fatal health complications. It has been shown to produce a series of immunomodulators that promote virulence by affecting both arms of the host immune response. Complement (C’) represents a key innate immune effector that protects against infection, and S. aureus has evolved several strategies to evade C’ neutralization. C’ proteins are essential for the propagation of host inflammatory reactions to bacterial infection and serve as attractive targets for the dampening of this response by pathogens. Indeed, several S. aureus-secreted proteins have been described to have C’ inhibitory activity. To this date, no systematic research effort has been placed on the development of complement-based antimicrobial therapeutics that might exploit immune evasion mechanisms of S. aureus. The current proposal focuses on dissecting critical interactions of S. aureus immune evasion molecules with key components of the innate immune response (complement and cytokine networks) by means of antibody-targeted studies on virulence and inflammation. Our research aims to: 1. Characterize antibodies from S. aureus-exposed individuals that recognize key microbial evasion targets and can attenuate inflammation in a whole blood model of S. aureus-induced bacteremia. Studies will also focus on dissecting the neutralizing capacity of these antibodies on a broad spectrum of inflammatory mediators triggered by bacterial infection. 2. Develop single-chain antibodies against S. aureus proteins identified in Aim 1 as being targets for pathogen neutralization by phage library approaches. The therapeutic efficacy of these library-generated antibodies will be evaluated in in vitro models of inflammation and in vivo mouse models of sepsis. These studies are anticipated to provide a framework for the design of novel antibody-based therapeutics for infectious diseases'

Introduzione (Teaser)

A European research team developed antibody-based therapeutics against Staphylococcus aureus. This novel approach should improve the outcome of patients with S. aureus infections.

Descrizione progetto (Article)

S. aureus is an important human pathogen associated with hospital and community-acquired infections. It can cause severe and potentially fatal health complications, such as endocarditis or septicaemia, as well as infect implanted medical devices.

Injudicious use of antibiotics has led to the emergence of methicillin resistant S. aureus (MRSA). MRSA shows low susceptibility even to broad-spectrum antibiotics and has a diverse repertoire of immune evasion strategies. As such, there is an urgent need to develop novel therapeutic interventions.

The administration of combinatorial monoclonal antibodies is gaining ground as an alternative treatment. The EU-funded COMPSTAPH project set out to generate such human antibodies to neutralise the virulence of S. aureus. Project activities concentrated on the immune-evasion and virulence-promoting extracellular fibrinogen-binding (Efb) protein.

To validate the mechanism of action of Efb, researchers developed an ex vivo model of blood S. aureus infection (bacteraemia) which recapitulates the human condition. They found that addition of Efb increased pathogen survival by rendering the pathogen 'invisible' to the immune system.

Human antibodies against Efb were isolated following a thorough screening of an antibody library. To identify which antibodies blocked Efb binding with the complement protein C3d, scientists set up a competition ELISA assay. The most effective antibody candidates were tested in the bacteraemia model to identify lead molecules with therapeutic efficacy.

To evaluate if these antibodies could be used as a multivalent vaccine, the consortium screened their efficacy in an in vivo model of kidney infection. Treatment of mice with just a single dose of blocking antibodies significantly lowered bacterial burden in infected kidneys and reduced inflammation. These antibodies remained in circulation and were functional for at least 36 hours, supporting their further exploitation in other disease models.

Collectively, the findings of the COMPSTAPH study support the validity of passive immunisation through the delivery of antibodies as an effective strategy against S. aureus infection. Considering the dismal outcome of S. aureus infections, a therapeutic vaccine is long overdue.