RESUMEN
Mayaro virus (MAYV) is endemic in South American countries where it is responsible for sporadic outbreaks of acute febrile illness. The hallmark of MAYV infection is a highly debilitating and chronic arthralgia. Although MAYV emergence is a potential threat, there are no specific therapies or licensed vaccine. In this study, we developed a murine model of MAYV infection that emulates many of the most relevant clinical features of the infection in humans and tested a live-attenuated MAYV vaccine candidate (MAYV/IRES). Intraplantar inoculation of a WT strain of MAYV into immunocompetent mice induced persistent hypernociception, transient viral replication in target organs, systemic production of inflammatory cytokines, chemokines and specific humoral IgM and IgG responses. Inoculation of MAYV/IRES in BALB/c mice induced strong specific cellular and humoral responses. Moreover, MAYV/IRES vaccination of immunocompetent and interferon receptor-defective mice resulted in protection from disease induced by the virulent wt MAYV strain. Thus, this study describes a novel model of MAYV infection in immunocompetent mice and highlights the potential role of a live-attenuated MAYV vaccine candidate in host's protection from disease induced by a virulent MAYV strain.
Asunto(s)
Infecciones por Alphavirus/prevención & control , Alphavirus/inmunología , Anticuerpos Antivirales/inmunología , Modelos Animales de Enfermedad , Huésped Inmunocomprometido/inmunología , Vacunas Atenuadas/inmunología , Vacunas Virales/administración & dosificación , Infecciones por Alphavirus/inmunología , Infecciones por Alphavirus/virología , Animales , Citocinas , Masculino , Ratones , Ratones Endogámicos BALB C , América del Sur , Vacunas Virales/inmunología , Replicación ViralRESUMEN
INTRODUCTION: The timely resolution of inflammation is essential to restore tissue homeostasis and to avoid chronic inflammatory diseases. Resolution of inflammation is an active process modulated by various proresolving mediators, including annexin A1 (AnxA1) and specialized proresolving lipid mediators (SPMs), which counteract excessive inflammatory responses and stimulate proresolving mechanisms. Areas covered: The protective effects of AnxA1 and SPMs have been extensively explored in pre-clinical animal models. However, studies investigating the function of these molecules in human diseases are just emerging. This review highlights recent advances on the role of proresolving mediators, and pharmacological opportunities of promoting resolution pathways in preclinical models and patients with various human diseases. Expert opinion: Dysregulation or 'failure' in proresolving mechanisms might be involved in the pathogenesis of chronic inflammatory diseases. Altered levels of proresolving mediators were found in a wide range of human diseases. In some cases, AnxA1 and SPMs are up-regulated in human blood and tissues but fail to engage in proresolving signaling and, hence, to regulate excessive inflammation. Thus, the new concept of 'resolution pharmacology' could be applied to compensate deficiency of endogenous proresolving mediators' generation and/or possible failures in the engagement of resolution pathways observed in many chronic inflammatory diseases.
Asunto(s)
Anexina A1/metabolismo , Diseño de Fármacos , Inflamación/tratamiento farmacológico , Animales , Antiinflamatorios/farmacología , Humanos , Inflamación/patología , Mediadores de Inflamación/metabolismo , Metabolismo de los LípidosRESUMEN
Neutrophils (also named polymorphonuclear leukocytes or PMN) are essential components of the immune system, rapidly recruited to sites of inflammation, providing the first line of defense against invading pathogens. Since neutrophils can also cause tissue damage, their fine-tuned regulation at the inflammatory site is required for proper resolution of inflammation. Annexin A1 (AnxA1), also known as lipocortin-1, is an endogenous glucocorticoid-regulated protein, which is able to counterregulate the inflammatory events restoring homeostasis. AnxA1 and its mimetic peptides inhibit neutrophil tissue accumulation by reducing leukocyte infiltration and activating neutrophil apoptosis. AnxA1 also promotes monocyte recruitment and clearance of apoptotic leukocytes by macrophages. More recently, some evidence has suggested the ability of AnxA1 to induce macrophage reprogramming toward a resolving phenotype, resulting in reduced production of proinflammatory cytokines and increased release of immunosuppressive and proresolving molecules. The combination of these mechanisms results in an effective resolution of inflammation, pointing to AnxA1 as a promising tool for the development of new therapeutic strategies to treat inflammatory diseases.