SavinMucoPath - Novel therapeutic and prophylactic strategies to control mucosal infections by South American bacterial strains

EC contribution: : € 1.699.908
Duration: : 36 months
Starting date: : 01/10/2006
Funding scheme: : Specific Targeted Research Project
Keywords: : innate immunity, mucosal adjuvant, virulence factors, screening processes
Contract/Grant agreement number: : INCO-CT-2006-032266
Project web-site: : http://www.lille.inserm.fr/site/avenir_sirard/page.asp?page=557

Background:

Enteric and respiratory diseases remain a major cause of mortality during neonate life and childhood within developing countries. The SavinMucoPath project is focusing on bacteria that enter through or colonise enteric and respiratory mucosa, i.e. Streptococcus pneumoniae, Salmonella enterica serovar Enteritidis, and Bordetella pertussis. The selected bacterial pathogens are associated with important rates of morbidity and mortality in South America, especially in young children and those in the low socioeconomic bracket. Moreover, the strains and serotypes that cause infections are unique to the developing countries in this area and consequently, basic research and development of therapies and vaccines tailored to these local strains have been deserted by the European and North American scientific communities. The objectives of our concerted efforts are to gain in our understanding of the host-pathogen interaction in order to define novel strategies of interventions. For this purpose, we will study on the one hand, virulence mechanisms of bacterial pathogens and on the other hand, the early innate immune response of the host. This will allow to identify molecules from these bacteria that (1) can be targeted by novel antibiotics (strain-specific virulence factors) and (2) activate specifically protective mucosal innate immunity (conserved pathogen-associated molecular patterns, PAMP) in order to block the infections at the port of entry of bacteria.

Problem:

Mucosal tissues represent the major sites of infection by pathogenic microbes and the study of mucosal pathogens is therefore relevant for combating infection and reinforcing immunity. Thus, enteric and respiratory diseases remain a leading cause of mortality worldwide. This proposal focus on mucosal bacterial pathogens that are of main importance for public health in Latin America. The strategic objective is to confront the emergency caused by specific strains of Streptococcus pneumoniae, Salmonella spp, and Bordetella pertussis - through the improvement of knowledge on molecular pathogenesis and the development of novel therapeutic and prophylactic interventions. The control of these neglected communicable diseases is essential to improve the health and decrease the morbidity and mortality that they cause within the Latin American population, especially in children and communities with the lowest socio-economic status.
The existing strategies to treat bacterial diseases are based on antibiotic therapies and vaccines. However, these interventions have a limited effect on the diseases caused by the 3 pathogens that we have chosen. Indeed, there is no vaccine to prevent infections mediated by S. Enteritidis and available vaccines for B. pertussis and S. pneumoniae present several drawbacks when applied in Latin American countries. Strains of pathogens currently used to produce these vaccines are the most prevalent in Europe and North America but are different from the strains encountered in Latin America. In addition, there is a significant increase of antibiotic resistance among these bacterial strains thereby limiting the use of common low-cost antibiotics. A major issue about treatments is the route of administration and bio-distribution. Therapeutics delivered by systemic routes do not provide the optimal availability of drugs at mucosal sites. Most vaccines are formulated for systemic injections and do not generate appropriate levels of mucosal responses.

Aim:

The main objectives are to fuel understanding of the host-pathogen interaction and to develop novel mucosa-specific therapeutics and vaccines to control bacterial infections. Our strategies are based on the exploitation of innate defence mechanisms triggered by pathogen conserved molecules and pathogen-specific factors.
Experimental mucosal infection animal model will be used to (1) characterize the mucosal response to the pathogens with a particular emphasis on innate responses. As simultaneous mucosal infections are the norm rather than the exception, the influence of co-infections with unrelated pathogens on this response will also be analysed, (2) identify specific molecules produced by these pathogens to be used for therapeutic and prophylactic mucosal treatments in order to block the infection at the port of entry. These molecules include pathogen-associated molecular patterns (PAMP) and virulence factors. PAMPs stimulate natural mucosal immune defences through pattern-recognition receptors (PRR); these molecules could be used as adjuvants for vaccine formulation or as direct therapeutic agent to enhance the protective mucosal immune responses. Virulence factors are essential for mucosal colonization, inflammation and subversion of mucosal immunity; novel drugs could specifically target them and have antibiotic activity, (3) evaluate the efficacy of innovative approaches that enhance pathogen-specific response or prevent excessive inflammatory response.

Expected and obtained results:

The consortium expects to identify molecules from the selected bacteria that activate specifically protective mucosal innate immunity so as to block infections at the port of entry of bacteria and stimulate antigen-specific responses through mucosal cells.
We will develop cell and rodent models for high throughput screening of pathogen components to ultimately bring candidate experimental immuno-interventions against enteric and respiratory infections to clinical trials within the next FP

Potential applications:

SavinMucoPath should contribute to the development of appropriate treatment of the corresponding diseases, especially during childhood. The project will have a major impact in the field of development of mucosal immuno-stimulators - adjuvants that specifically control mucosal infections.
It will contribute to the development of screening assays to detect bacterial compounds that induce mucosal immunity. The assays based on luciferase and fluorescent reporters in human cell lines and mice strains, will allow high throughput screening. Such technology will not only be instrumental for the development of the proposed research activities but for further vaccine studies.
As application, the consortium will also attempt to deliver scaling-up processes in order to evaluate the potential use of selected bacteria components as vaccine components in large-scale production.
This effort may have a "transdisease" impact on anti-microbial treatments and vaccine strategies for different infectious diseases. If successful, the screened molecules may have an impact on the overall existing vaccines and antibiotherapy. A successful outcome of SavinMucoPath will substantially contribute to the further development of innovative and effective projects against any neglected mucosal infections.

Coordinator:

Dr Jean Claude Sirard
INSERM, U801
Institut Pasteur de Lille
Team of antimicrobial mucosal immunity
1 rue du Pr. Calmette
59021 Lille, France
Tel. +33 320871076
E-mail: jean-claude.sirard@ibl.fr

SavinMucoPath Documents:

SavinMucoPath Work Packages

Proof of concept that a proadrenomudullin N-terminal 20 peptide (PAMP) stimulates protective mucosal immunity

Salmonella enterocolitis: identification of the cell types initiating intestinal inflammation and role of innate immunity

Innate and adaptive immune responses to Streptococcus pneumoniae infection

Bordetella pertussis protective antigens against respiratory infections

Transcriptome signatures of protective mucosal innate responses

Production of bacterial lysates and PAMPs, quality control and evaluation of large-scale production

Generation of reporter epithelial cell lines

In vitro and in vivo screening of novel microbial components that activate mucosal immunity

Construction of transgenic animals reporter of bacterial enterocolitis

Influence of co-infections on immunity and pathology in the lung

Enhancing pathogen-specific immunity and preventing infection-associated immunopathology

Development of new S. pneumoniae vaccines based on killed whole bacteria preparations

Subversion of dendritic cell by Salmonella enterica serovars Typhimurium and Enteritidis

In vitro modelling of mucosal immune responses

European Commission