Publication: Nuevas estrategias profilácticas y terapéuticas frente a la infección por Streptococcus pneumoniae
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2017-07-18
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Universidad Complutense de Madrid
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Abstract
Streptococcus pneumoniae es uno de los principales agentes etiológicos causantes de neumonía adquirida en la comunidad y enfermedades más severas, como sepsis y meningitis bacteriana, que afectan principalmente a la población infantil y a los mayores de 65 años (Koedel et al., 2002; van der Poll y Opal, 2009). Se estima que más del 25% de los 57 millones de muertes anuales en todo el mundo, están directamente relacionadas con las enfermedades infecciosas. En concreto, las infecciones respiratorias son responsables de la muerte de 4 millones de personas cada año. Según la organización mundial de la Salud (OMS) la prevalencia de sepsis o neumonía en neonatos, así como de neumonía en niños algo mayores representan el 29% de las 10.6 millones de muertes anuales registradas en niños menores de 5 años (10% y 19%, respectivamente), siendo Streptococcus pneumoniae la causa más común de neumonía severa en niños y adultos en Europa y Estados Unidos (O'Brien et al., 2009). En general, la tasa de infecciones neumocócicas es mayor que la causada por cualquier otra bacteria patogénica. Como consecuencia, la OMS y las organizaciones como Wellcome Trust y Bill & Melinda Gates Foundation consideran las enfermedades neumocócicas como un problema mundial. La prevención de la enfermedad neumocócica invasiva (ENI) es una de las prioridades en salud pública debido a las altas tasas mundiales de morbilidad y mortalidad, especialmente en niños en países en vías de desarrollo (O'Brien et al., 2009). La inmunización es una propuesta segura y altamente eficiente para prevenir ENI. La activación de las cascadas del complemento por anticuerpos específicos conduce a la formación del componente clave C3b, el cual juega un papel crucial en la defensa del hospedador frente a neumococo, recubriendo los microorganismos y estimulando la fagocitosis. Actualmente, con el fin de obtener protección frente a los niños, las medidas profilácticas frente a la infección neumocócica están basadas en vacunas que contienen polisacáridos capsulares que pueden estar conjugadas con proteínas transportadoras (O'Brien y Levine, 2006). Sin embargo, una de las mayores desventajas de estas vacunas polisacarídica se debe a la amplia variabilidad neumocócica, con hasta 96 diferentes polisacáridos capsulares (CPS) descritos hasta la fecha (Park et al., 2015). Una limitación adicional es el intercambio capsular que se ha observado tras la introducción de las vacunas neumocócicas conjugadas (PCVs), lo cual resulta preocupante dado que estas cepas pueden emerger evitando la inmunidad inducida por la vacunación debido a la adquisición de genes capsulares de serotipos no vacunales (Aguinagalde et al., 2015; Brueggemann et al., 2007; Golubchik et al., 2012). Para evitar estos problemas, los esfuerzos en investigación se centran en nuevas proteínas de S. pneumoniae candidatas a vacunas, que puede proteger frente a los diferentes serotipos existentes. Uno de los objetivos principales de esta Tesis ha sido caracterizar la hidrolasa de la pared celular LytB de S. pneumoniae como potencial candidata a vacuna. LytB se localiza en sitios cercanos a los extremos polares y está expuesta a la superficie. Esta enzima tiene actividad Nacetilglucosaminidasa y desempeña un papel esencial en la separación de células hijas (De las Rivas et al., 2002; García et al., 1999). En términos de patogénesis, LytB participa en la formación de biofilm, unión de células epiteliales humanas y contribuye a la sepsis y neumonía, incrementando la capacidad de LytC para evitar la inmunidad mediada por el complemento y fagocitosis (Bai et al., 2014; Moscoso et al., 2006; Ramos-Sevillano et al., 2011). Desde la perspectiva profiláctica, LytB puede ser una diana prometedora para desarrollar una vacuna universal antineumocócica dado que el antisuero anti-LytB protege significativamente a ratones tras ser infectados con dosis letales de diferentes serotipos de neumococo (Wizemann et al., 2001)...
Streptococcus pneumoniae is one of the leading etiologic agents of communityacquired pneumonia, sepsis and bacterial meningitis particularly affecting children and elderly adults (Koedel et al., 2002; van der Poll y Opal, 2009). More than 25% of the 57 million annual deaths worldwide are estimated to be directly related to infectious diseases. Particularly, respiratory infections are responsible of the death of 4 million people every year. According to World Health Organization (WHO) estimates of sepsis or pneumonia in neonates and pneumonia in older children accounted for 29% of the 10.6 million yearly deaths in children younger than 5 years (10% and 19%, respectively), being Streptococcus pneumoniae the most common cause of severe pneumonia among children in developing countries as well as in children and adults in Europe and the United States (O'Brien et al., 2009). Overall, the mortality rate of pneumococcal infections is higher than that originated by any other pathogenic bacteria. As a consequence, WHO and organizations such as the Wellcome Trust and the Bill & Melinda Gates Foundation consider the pneumococcal disease as a global burden. Prevention of invasive pneumococcal disease (IPD) is one of the leading priorities in public health due to the high morbidity and mortality rates worldwide, especially in children in developing countries (O'Brien et al., 2009). Immunization is a safe and highly efficient approach for preventing IPD. Activation of complement cascades by specific antibodies, leads to the formation of the key component C3b that is crucial in host defence against pneumococcus by coating the microorganism and stimulating phagocytosis. Current prophylactic measures against pneumococcal infection are based on polysaccharide-containing vaccines that may be conjugated to a carrier protein in order to elicit protection in children (O'Brien y Levine, 2006). However, one of the major disadvantages of these polysaccharide vaccines is the extensive variability among the pneumococcal population with up to 96 different capsular polysaccharides (CPS) described to date (Park et al., 2015). An additional limitation is that capsular switching appeared after the introduction of pneumococcal conjugate vaccines (PCVs), which results in a serious concern because these strains may emerge by avoiding vaccine-induced immunity due to acquisition of capsula genes from non-vaccine serotypes (Aguinagalde et al., 2015; Brueggemann et al., 2007; Golubchik et al., 2012). To circumvent these problems, efforts are being made to investigate S. pneumoniae protein-based candidate vaccines that may protect against different serotypes. One of the major goals of this Thesis was to characterize the cell wall hydrolase LytB of S. pneumoniae as a potential vaccine candidate. LytB is located at sites close to the polar ends of the cell and is surface exposed. This enzyme has Nacetylglucosaminidase activity and plays an essential role in daughter cell separation (De las Rivas et al., 2002; García et al., 1999). In terms of pathogenesis, LytB participates in biofilm formation, attachment to human epithelial cells and contributes to sepsis and pneumonia by increasing the ability of LytC to avoid complement-mediated immunity and phagocytosis (Bai et al., 2014; Moscoso et al., 2006; Ramos-Sevillano et al., 2011). From the prophylactic perspective, LytB might be a promising target for the development of a universal pneumococcal vaccine because an anti-LytB antiserum significantly protected mice from a lethal challenge with different pneumococcal strains (Wizemann et al., 2001)...
Streptococcus pneumoniae is one of the leading etiologic agents of communityacquired pneumonia, sepsis and bacterial meningitis particularly affecting children and elderly adults (Koedel et al., 2002; van der Poll y Opal, 2009). More than 25% of the 57 million annual deaths worldwide are estimated to be directly related to infectious diseases. Particularly, respiratory infections are responsible of the death of 4 million people every year. According to World Health Organization (WHO) estimates of sepsis or pneumonia in neonates and pneumonia in older children accounted for 29% of the 10.6 million yearly deaths in children younger than 5 years (10% and 19%, respectively), being Streptococcus pneumoniae the most common cause of severe pneumonia among children in developing countries as well as in children and adults in Europe and the United States (O'Brien et al., 2009). Overall, the mortality rate of pneumococcal infections is higher than that originated by any other pathogenic bacteria. As a consequence, WHO and organizations such as the Wellcome Trust and the Bill & Melinda Gates Foundation consider the pneumococcal disease as a global burden. Prevention of invasive pneumococcal disease (IPD) is one of the leading priorities in public health due to the high morbidity and mortality rates worldwide, especially in children in developing countries (O'Brien et al., 2009). Immunization is a safe and highly efficient approach for preventing IPD. Activation of complement cascades by specific antibodies, leads to the formation of the key component C3b that is crucial in host defence against pneumococcus by coating the microorganism and stimulating phagocytosis. Current prophylactic measures against pneumococcal infection are based on polysaccharide-containing vaccines that may be conjugated to a carrier protein in order to elicit protection in children (O'Brien y Levine, 2006). However, one of the major disadvantages of these polysaccharide vaccines is the extensive variability among the pneumococcal population with up to 96 different capsular polysaccharides (CPS) described to date (Park et al., 2015). An additional limitation is that capsular switching appeared after the introduction of pneumococcal conjugate vaccines (PCVs), which results in a serious concern because these strains may emerge by avoiding vaccine-induced immunity due to acquisition of capsula genes from non-vaccine serotypes (Aguinagalde et al., 2015; Brueggemann et al., 2007; Golubchik et al., 2012). To circumvent these problems, efforts are being made to investigate S. pneumoniae protein-based candidate vaccines that may protect against different serotypes. One of the major goals of this Thesis was to characterize the cell wall hydrolase LytB of S. pneumoniae as a potential vaccine candidate. LytB is located at sites close to the polar ends of the cell and is surface exposed. This enzyme has Nacetylglucosaminidase activity and plays an essential role in daughter cell separation (De las Rivas et al., 2002; García et al., 1999). In terms of pathogenesis, LytB participates in biofilm formation, attachment to human epithelial cells and contributes to sepsis and pneumonia by increasing the ability of LytC to avoid complement-mediated immunity and phagocytosis (Bai et al., 2014; Moscoso et al., 2006; Ramos-Sevillano et al., 2011). From the prophylactic perspective, LytB might be a promising target for the development of a universal pneumococcal vaccine because an anti-LytB antiserum significantly protected mice from a lethal challenge with different pneumococcal strains (Wizemann et al., 2001)...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Farmacia, Departamento de Microbiología II, leída el 20/01/2017