RESUMO
In spite of several decades of research, an effective vaccine against schistosomiasis remains elusive. The radiation-attenuated (RA) cercarial vaccine is still the best model eliciting high protection levels, although the immune mechanisms have not yet been fully characterized. In order to identify genes and pathways underlying protection we investigated patterns of gene expression in PBMC and skin draining Lymph Nodes (LN) from mice using two exposure comparisons: vaccination with 500 attenuated cercariae versus infection with 500 normal cercariae; one versus three doses. Vaccinated mice were challenged with 120 normal parasites. Integration of PBMC and LN data from the infected group revealed early up-regulation of pathways associated with Th2 skewing and polarization of IgG antibody profiles. Additionally, hemostasis pathways were downregulated in infected mice, correlating with platelet reduction, potentially a mechanism to assist parasite migration through capillary beds. Conversely, up regulation of such mechanisms after vaccination may explain parasite blockade in the lungs. In contrast, a single exposure to attenuated parasites revealed early establishment of a Th1 bias (signaling of IL-1, IFN-γ; and Leishmania infection). Genes encoding chemokines and their receptors were more prominent in vaccinated mice, indicating an enhanced capacity for inflammation, potentially augmenting the inhibition of intravascular migration. Increasing the vaccinations from one to three did not dramatically elevate protection, but there was a clear shift towards antibody-mediated effectors. However, elements of the Th1 bias were still evident. Notable features after three vaccinations were markers of cytotoxicity (including IL-6 and NK cells) together with growth factors and their receptors (FGFR/VEGF/EGF) and the apoptosis pathway. Indeed, there is evidence for the development of anergy after three vaccinations, borne out by the limited responses detected in samples after challenge. We infer that persistence of a Th1 response puts a limit on expression of antibody-mediated mechanisms. This feature may explain the failure of multiple doses to drive protection towards sterile immunity. We suggest that the secretions of lung stage parasites would make a novel cohort of antigens for testing in protection experiments.
Assuntos
Hemostasia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Vacinas Protozoárias/administração & dosagem , Schistosoma mansoni/imunologia , Esquistossomose mansoni/prevenção & controle , Biologia de Sistemas , Animais , Cercárias/imunologia , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Hemostasia/genética , Interações Hospedeiro-Parasita , Peptídeos e Proteínas de Sinalização Intercelular/genética , Linfonodos/imunologia , Linfonodos/metabolismo , Linfonodos/parasitologia , Camundongos Endogâmicos C57BL , Análise em Microsséries , Vacinas Protozoárias/imunologia , Schistosoma mansoni/patogenicidade , Esquistossomose mansoni/imunologia , Esquistossomose mansoni/metabolismo , Esquistossomose mansoni/parasitologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th1/parasitologia , Equilíbrio Th1-Th2 , Células Th2/imunologia , Células Th2/metabolismo , Células Th2/parasitologia , Fatores de Tempo , Transcriptoma , Vacinação , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/imunologiaRESUMO
In spite of several decades of research, an effective vaccine against schistosomiasis remains elusive. The radiation-attenuated (RA) cercarial vaccine is still the best model eliciting high protection levels, although the immune mechanisms have not yet been fully characterized. In order to identify genes and pathways underlying protection we investigated patterns of gene expression in PBMC and skin draining Lymph Nodes (LN) from mice using two exposure comparisons: vaccination with 500 attenuated cercariae versus infection with 500 normal cercariae; one versus three doses. Vaccinated mice were challenged with 120 normal parasites. Integration of PBMC and LN data from the infected group revealed early up-regulation of pathways associated with Th2 skewing and polarization of IgG antibody profiles. Additionally, hemostasis pathways were downregulated in infected mice, correlating with platelet reduction, potentially a mechanism to assist parasite migration through capillary beds. Conversely, up regulation of such mechanisms after vaccination may explain parasite blockade in the lungs. In contrast, a single exposure to attenuated parasites revealed early establishment of a Th1 bias (signaling of IL-1, IFN-γ; and Leishmania infection). Genes encoding chemokines and their receptors were more prominent in vaccinated mice, indicating an enhanced capacity for inflammation, potentially augmenting the inhibition of intravascular migration. Increasing the vaccinations from one to three did not dramatically elevate protection, but there was a clear shift towards antibody-mediated effectors. However, elements of the Th1 bias were still evident. Notable features after three vaccinations were markers of cytotoxicity (including IL-6 and NK cells) together with growth factors and their receptors (FGFR/VEGF/EGF) and the apoptosis pathway. Indeed, there is evidence for the development of anergy after three vaccinations, borne out by the limited responses detected in samples after challenge. We infer that persistence of a Th1 response puts a limit on expression of antibody-mediated mechanisms. This feature may explain the failure of multiple doses to drive protection towards sterile immunity. We suggest that the secretions of lung stage parasites would make a novel cohort of antigens for testing in protection experiments.
RESUMO
La exposición a ruido no ocupacional y a la música a alto nivel sonoro, constituye un creciente factor de riesgo de pérdida auditiva en adolescentes. Estudios internacionales postulan que una función importante del Sistema Eferente Medial (SEM) es proteger el oído interno frente al ruido mediante un mecanismo reflejo y que puede ser evaluado a través de la Supresión Contralateral (SC) de las otoemisiones acústicas transitorias (TEOAEs). El mecanismo subyacente de este fenómeno no se conoce en su totalidad y los antecedentes sobre el tema son escasos. En esta investigación se analizó la relación entre la Exposición General a Música (EGM), el estado de la función auditiva y el mecanismo de protección coclear. Participaron 91 adolescentes con edades entre 14 y 15 años. Se evaluaron dos dimensiones (a) Psicosocial: se examinó la EGM con un cuestionario de actividades extraescolares y (b) auditiva o sea el funcionamiento del SEM mediante SC de las TEOAEs y los perfiles audiométricos con audiometrías. Los resultados mostraron que la SC no influyó estadísticamente en los perfiles audiométricos y categorías de exposición. Sin embargo, los resultados de la SC se orientan hacia la menor magnitud de efecto supresor, disminución en la respuesta total en relación al descenso de los umbrales auditivos y en relación con las categorías alta y baja de EGM. Es necesario promover trabajos destinados al comportamiento de riesgo auditivo conjuntamente con el mecanismo protector del SEM. De esta manera se podrá contribuir en la identificación temprana de la sensibilidad auditiva en adolescentes expuestos a ruido no ocupacional.
Non-occupational exposure to noise, such as loud music sound level is an increasing risk factor for hearing loss in adolescents. International studies propose that an important function of the medial efferent system (MES) is protect the inner ear against noise by a reflex mechanism and can be evaluated through Contralateral Suppression (CS) of transient otoacoustic emissions (TEOAEs) to analyzing the presence or absence of suppressive effect. The absence of suppressive effect is considered a possible alteration of the MES and the role it exerts on the regulation of the outer hair cells. The underlying mechanism of this phenomenon is not known totality and the background about this topic are limited. However, researches suggests that MES would have an important role in protection against acoustic overstimulation under the hypothesis that a hearing with the presence of suppressive effect would tend to be more protected against exposure to high noise levels while ears with no effect suppressor may be more vulnerable to noise exposure. In this research the relationship between the General Exposure to Music (MGE), the state of hearing function and cochlear protection mechanism were analyzed in 91 adolescents with 14/15 years old, with male predominance, of two technical schools of the city of Córdoba (Argentina). Were evaluated the following dimensions: (a) Psychosocial: MGE through an Out of School Activities Questionnaire to know in detail the participation in five recreational activities to finally analyze the MGE and (b) Audiological: assessment of audiometric profiles, as a subjective method, by audiometry in the conventional frequency ranges (250-8000) Hz and an extended high frequency audiometry (8000-16000) Hz; function of MES assessment, objective method, through CS of TEOAEs to determine the presence or absence of suppressive effect. The study CS of TEOAEs consisted of two steps: Step 1, application of TEOAEs of an ear in form ipsilateral without acoustic stimulation in the contralateral ear (CAS) and Step 2, application of TEOAEs in the ear ipsilateral while applying CAS. Was considered presence of suppressive effect when there was a reduction in the response after the CAS that is to say when the difference of values obtained in the total response with and without CAS was positive. At the same time, was considered absence of suppressive effect in cases of maintained or increased the response after the CAS, obtaining a value of zero or negative. The results of the research showed that in the group with presence of suppressive effect the most of ears is among moderate and high categories of MGE with a lower average magnitude of suppressive effect and a decreased amplitude of the total response in the high category of MGE than the media category. Regarding audiometry the ears with presence of suppressive effect showed higher magnitude in the group of normal hearing thresholds compared with the group of descended hearing thresholds. The results related to CS of the TEOAEs statistically did not influence in the audiometric profiles and the exposure categories. However the results of the CS were oriented towards the smaller magnitude of suppressive effect, decreased total response related with the descended hearing thresholds and high and low categories of MGE. It is necessary to promote and intensify researches in relation to the auditory risk behaviors together with the protection mechanism of MES. In this way, more researches can contribute to the early identification of hearing sensitivity in adolescents exposed to non-occupational noise. It is important to implement a Psycho-Auditory Screening to collaborate in the prevention and promotion of hearing health.