Verpoest Sara, Cay Brigitte, Favoreel Herman, De Regge Nick
Operational Direction Viral Diseases, CODA-CERVA, Ukkel, Belgium.
Department of Virology, Immunology and Parasitology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
J Virol. 2017 Jan 3;91(2). doi: 10.1128/JVI.02058-16. Print 2017 Jan 15.
The severity of clinical symptoms induced by pseudorabies virus (PRV) infection of its natural host is inversely related to the age of the pig. During this study, 2- and 15-week-old pigs were inoculated with PRV strain NIA3. This resulted in important clinical disease, although the associated morbidity and mortality were lower in older pigs. Quantitative PCR analysis of viral DNA in different organs confirmed the general knowledge on PRV pathogenesis. Several new findings and potential explanations for the observed age-dependent differences in virulence, however, were determined from the study of viral and cytokine mRNA expression at important sites of neuropathogenesis. First, only limited viral and cytokine mRNA expression was detected in the nasal mucosa, suggesting that other sites may serve as the primary replication site. Second, PRV reached the trigeminal ganglion (TG) and brain stem rapidly upon infection but, compared to 2-week-old pigs, viral replication was less pronounced in 15-week-old pigs, and the decrease in viral mRNA expression was not preceded by or associated with an increased cytokine expression. Third, extensive viral replication associated with a robust expression of cytokine mRNA was detected in the olfactory bulbs of pigs from both age categories and correlated with the observed neurological disease. Our results suggest that age-dependent differences in PRV-induced clinical signs are probably due to enhanced viral replication and associated immunopathology in immature TG and the central nervous system neurons of 2-week-old pigs and that neurological disease is related with extensive viral replication and an associated immune response in the olfactory bulb.
It is well known that alphaherpesvirus infections of humans and animals result in more severe clinical disease in newborns than in older individuals and that this is probably related to differences in neuropathogenesis. The underlying mechanisms, however, remain unclear. Pseudorabies virus infection of its natural host, the pig, provides a suitable infection model to study this more profoundly. We show here that the severe neurological disease observed in 2-week-old pigs does not appear to be related to a hampered innate immune response but is more likely to reflect the immature development state of the trigeminal ganglia (TG) and central nervous system (CNS) neurons, resulting in an inefficient suppression of viral replication. In 15-week-old pigs, viral replication was efficiently suppressed in the TG and CNS without induction of an extensive immune response. Furthermore, our results provide evidence that neurological disease could, at least in part, be related to viral replication and associated immunopathology in the olfactory bulb.
伪狂犬病病毒（PRV）感染其自然宿主所引发的临床症状严重程度与猪的年龄呈负相关。在本研究中，对2周龄和15周龄的猪接种PRV NIA3毒株。这引发了严重的临床疾病，尽管老龄猪的发病率和死亡率较低。对不同器官中病毒DNA的定量PCR分析证实了关于PRV发病机制的一般认知。然而，通过对神经发病重要部位的病毒和细胞因子mRNA表达进行研究，确定了一些关于观察到的毒力年龄依赖性差异的新发现及潜在解释。首先，在鼻黏膜中仅检测到有限的病毒和细胞因子mRNA表达，这表明其他部位可能是主要的复制位点。其次，感染后PRV迅速到达三叉神经节（TG）和脑干，但与2周龄的猪相比，15周龄猪的病毒复制不那么明显，且病毒mRNA表达的下降并非先于细胞因子表达增加或与之相关。第三，在两个年龄组猪的嗅球中均检测到与细胞因子mRNA强烈表达相关的广泛病毒复制，且这与观察到的神经疾病相关。我们的结果表明，PRV诱导的临床体征的年龄依赖性差异可能是由于2周龄猪未成熟的TG和中枢神经系统神经元中病毒复制增强及相关免疫病理学所致，并且神经疾病与嗅球中广泛的病毒复制及相关免疫反应有关。
众所周知，人类和动物的α疱疹病毒感染在新生儿中导致的临床疾病比在年长个体中更严重，这可能与神经发病机制的差异有关。然而，潜在机制仍不清楚。PRV感染其自然宿主猪为更深入研究此问题提供了合适的感染模型。我们在此表明，在2周龄猪中观察到的严重神经疾病似乎与先天性免疫反应受阻无关，而更可能反映三叉神经节（TG）和中枢神经系统（CNS）神经元的未成熟发育状态，导致对病毒复制的抑制效率低下。在15周龄猪中，TG和CNS中的病毒复制被有效抑制，且未诱导广泛的免疫反应。此外，我们的结果提供了证据表明神经疾病至少部分可能与嗅球中的病毒复制及相关免疫病理学有关。
