دانلود رایگان مقاله ارزیابی آنتی بادی ضد ویروس کوکساکی A6 با مدل نوزادان موش

Abstract Coxsackievirus A6 (CA6) can induce atypical hand, foot, and mouth disease, which is characterized by severe rash, onychomadesis and a higher rate of infection in adults. Increasing epidemiological data indicated that outbreaks of CA6-associated hand, foot, and mouth disease have markedly increased worldwide in recent years. However, the current body of knowledge on the infection, pathogenic mechanism, and immunogenicity of CA6 is still very limited. In this study, we established the first neonatal mouse model for the evaluation of antibodies and vaccines against CA6. The CA6 strain CA6/141 could infect a one-day-old BALB/c mouse through intraperitoneal and intracerebral routes. The infected mice developed clinical symptoms, such as inactivity, wasting, hind-limb paralysis and even death. Pathological examination indicated that CA6 showed special tropism to skeletal muscles and skin, but not to nervous system or cardiac muscles. Infections with CA6 could induce vesicles in the dermis without a rash in mice, and the CA6 antigen was mainly localized in hair follicles. The strong tropism of CA6 to the skin may be related to its severe clinical features in infants. This mouse model was further applied to evaluate the efficacy of a therapeutic antibody and an experimental vaccine against CA6. A potential mAb 1D5 could fully protect mice from a lethal CA6 infection and also showed good therapeutic effects in the CA6-infected mice. In addition, an inactivated CA6 vaccine was evaluated through maternal immunization and showed 100% protection of neonatal mice from lethal CA6 challenge. Collectively, these results indicate that this infection model will be a useful tool in future studies on vaccines and antiviral reagents against CA6.

4. Discussion

The evaluation of the efficacy of experimental vaccines and antiviral reagents depends on a valid animal model. Thanks to the animal models of EV71 and CA16, vaccines against these two viruses progressed well, and EV71 vaccines were recently approved by the China Food and Drug Administration (CFDA) (Mao et al., 2016). Because the neonatal mouse model is sensitive, stable, easily acquired and low-cost, it has been widely used in study of HFMD-related enteroviruses (Liu et al., 2014; Wang and Yu, 2014). The outbreaks of CA6-associated HFMD boosted the demand for vaccines against CA6 and related animal models. CA6 is typically isolated and cultured in neonatal mice, while it is difficult to isolate or culture with cells susceptible to most enteroviruses (Bian et al., 2015; Liu et al., 2015; Schmidt et al., 1975). In a previous study, we reported that an isolated CA6 strain CA6/141 could grow in RD cells with high titers and showed high virulence in one-day-old neonatal mice (Yang et al., 2015). The CA6/141 strain belongs to lineage E, which is the predominant strain associated with HFMD worldwide (Bian et al., 2015). The high virulence of the CA6/141 strain makes it possible for us to develop a potential animal model of CA6 infection