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

Final Report Summary - SAVINMUCOPATH (Novel Therapeutic and Prophylactic Strategies to Control Mucosal Infections by South American bacterial strains)

Among the communicable diseases that affect the public health in developing countries there are infectious and respiratory diseases, diarrhoea and food-borne diseases. The project chose to study bacterial pathogens that cause such diseases and have an impact on health in South America, namely Streptococcus pneumoniae, Salmonella enterica serovar Enteritidis, and Bordetella pertussis. A common feature for these diseases is that they are caused by pathogens entering by and colonising mucosa. Therefore, understanding host-pathogen interactions at the mucosal sites is essential for development of effective immuno-intervention measures.

The strategic objective is to confront the emergency caused by mucosal pathogens, 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. Respiratory and enteric infections are among the most prevalent cause of diseases in the childhood. The third leading cause of death worldwide is respiratory tract infections and, thereby, a World Health Organization (WHO) priority for vaccine development.

Thirty four articles and review articles have been published during the three-years period of activity. And the project plans for another 8-10 articles within the next year. In addition, national and international conferences have been attended by all partners. Similarly, we will continue to communicate the results achieved within the consortium to meetings in 2010 and later on. We have organised in 2007 in Argentina (at La Plata) a course of 'Mucosal Innate and Adaptive Immunity' involving most PIs from our consortium as teachers. This course targeted more than 50 Latin American PhD students and post-doctoral fellows. In 2008, we organised in Uruguay (Montevideo) a course of 'Transcriptomic analysis of immune responses to pathogens' involving most PIs, PhD students and post-doctoral fellows from our consortium.

Their major achievements can be listed as follows:
1. We have selected isolates specific for Latin American countries including Streptococcus pneumoniae serotype 1, Salmonella enterica serovar Enteritidis, and Bordetella pertussis. These pathogens are locally associated with important rates of morbidity and mortality.
2. We set up or delivered the infection and co-infection models in laboratory animals by mucosal route for all bacterial pathogens (+ influenza virus) described above.
3. We performed the transcriptional analysis of mucosal protective responses to all bacterial pathogens described above.
4. We developed animal and cell models for screening bacterial compounds that induce mucosal immunity (CCL20-luc, CXCL1-luc, and CXCL2-luc).
5. We dissected the protective mechanisms and pathogenic processes altering innate responses for Streptococcus and Salmonella.
6. We delivered the proof of concept that a PAMP can be used for therapeutic and prophylactic purposes
7. We further demonstrated that pre-existing challenge can modify the outcome of therapeutic or prophylactic treatments in lungs.
8. We defined new intervention strategies to improve mucosal immunity and dampen mucosal inflammation.

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.

This effort may have a 'transdisease' impact on anti-microbial treatments and vaccine strategies for different infectious diseases. The screened molecules may have an impact on the overall existing vaccines and antibiotherapy. SAVINMUCOPATH will substantially contribute to the further development of innovative and effective projects against any neglected mucosal infections.