The development of invasive pneumococcal disease is frequently preceded by the establishment of the “carrier state”, this is, the colonization of the human nasopharynx by Streptococcus pneumoniae (pneumococcus). Pneumococcal carriage takes place through the establishment of a still largely unknown, host-pathogen interplay as well as by interactions with other bacteria colonizing the same habitat, such as non-typeable pneumococci, other streptococci of the mitis group, or pathogens like Haemophilus influenzae. Most of these interactions involve bacterial surface proteins on one hand, and cellular receptors and host defense mechanisms on the other. The surface-located, chain-dispersing S. pneumoniae enzyme LytB is involved in pathogenesis. LytB is needed both for attachment/colonization as well as for complement evasion but the structural requirements are essentially unknown. Another relevant example of surface protein is the main pneumococcal autolysin (LytA) that is also required for biofilm formation and that is thought to play an important role in pathogenesis by releasing cell wall fragments that are markedly pro-inflammatory. Moreover, autolysis allows the liberation of the toxin pneumolysin (Ply), which is partially responsible for immune response evasion. The role(s) in colonization of LytA and pneumolysin will be studied using biofilms (either mono or multispecies), cell cultures, and a mouse model of nasopharyngeal colonization. Besides, the impact of risky behaviors like smoking that facilitates bacterial colonization of the lungs and that contributes to the acute exacerbations in patients with chronic obstructive pulmonary disease, will also be examined in this project. Finally, one of the main aims of the present project is to develop prophylactic and therapeutic approaches to fight pneumococcal colonization. This will be performed using peptidoglycan hydrolases (enzybiotics) like Cpl-7 (a phage-coded enzyme of great antibacterial potential), and novel drugs including several choline analogs and ceragenins. As for other objectives of this project, the efficacy of enzybiotics and novel drugs will be tested first in vitro (planktonic as well as biofilm cultures) and then in animal models of infection.
Key words: Streptococcus pneumoniae, virulence, immunity, complement system, carrier state, choline-binding proteins, biofilms, enzybiotics, bacteriophages, structure-function.
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— MCyT, BMC2000-1002 (2000-2003).
— Fundación Ramón Areces (2000-2003).
— BIO2000-0009-P4-04 (2001-2005).
— MCyT, BMC2003-00074 (2003-2006).
— Ministerio de Sanidad y Consumo, Redes G03/103 y C03/104.
— MCyT, SAF2006-00390 (2006-2009)
— Member of the CIBER of Respiratory Diseases (Instituto de Salud Carlos III)
– CAM, COMBACT Program, S-BIO-0260/2006 (2007-2010)
– MICINN, SAF2009-10824 (2010-2012)
– MICINN, IPT-2011-1337-010000
- MINECO, SAF2012-39444-C02-01 (2013-2015)
International DropSens Award to the best research work in Applied Electroanalytical Chemistry. Malmö (Sweden). June 2014.