Go Natacha, Touzeau Suzanne, Islam Zeenath, Belloc Catherine, Doeschl-Wilson Andrea
BIOEPAR, INRA, Oniris, Route de Gachet, CS 40706, Nantes, France.
BIOCORE, Inria, INRA, CNRS, UPMC Univ Paris 06, Université Côte d'Azur, 2004 route des Lucioles, BP 93, Sophia Antipolis, France.
BMC Syst Biol. 2019 Jan 29;13(1):15. doi: 10.1186/s12918-018-0666-7.
Understanding what determines the between-host variability in infection dynamics is a key issue to better control the infection spread. In particular, pathogen clearance is desirable over rebounds for the health of the infected individual and its contact group. In this context, the Porcine Respiratory and Reproductive Syndrome virus (PRRSv) is of particular interest. Numerous studies have shown that pigs similarly infected with this highly ubiquitous virus elicit diverse response profiles. Whilst some manage to clear the virus within a few weeks, others experience prolonged infection with a rebound. Despite much speculation, the underlying mechanisms responsible for this undesirable rebound phenomenon remain unclear.
We aimed at identifying immune mechanisms that can reproduce and explain the rebound patterns observed in PRRSv infection using a mathematical modelling approach of the within-host dynamics. As diverse mechanisms were found to influence PRRSv infection, we established a model that details the major mechanisms and their regulations at the between-cell scale. We developed an ABC-like optimisation method to fit our model to an extensive set of experimental data, consisting of non-rebounder and rebounder viremia profiles. We compared, between both profiles, the estimated parameter values, the resulting immune dynamics and the efficacies of the underlying immune mechanisms. Exploring the influence of these mechanisms, we showed that rebound was promoted by high apoptosis, high cell infection and low cytolysis by Cytotoxic T Lymphocytes, while increasing neutralisation was very efficient to prevent rebounds.
Our paper provides an original model of the immune response and an appropriate systematic fitting method, whose interest extends beyond PRRS infection. It gives the first mechanistic explanation for emergence of rebounds during PRRSv infection. Moreover, results suggest that vaccines or genetic selection promoting strong neutralising and cytolytic responses, ideally associated with low apoptotic activity and cell permissiveness, would prevent rebound.
了解决定宿主间感染动态变化的因素是更好地控制感染传播的关键问题。特别是，为了感染个体及其接触群体的健康，病原体清除优于复发。在这种情况下，猪繁殖与呼吸综合征病毒（PRRSv）尤为引人关注。大量研究表明，感染这种高度普遍存在病毒的猪会引发不同的反应模式。虽然有些猪能在几周内清除病毒，但其他猪会经历长时间感染并复发。尽管有诸多猜测，但导致这种不良复发现象的潜在机制仍不清楚。
我们旨在通过宿主内动态的数学建模方法，确定能够重现和解释PRRSv感染中观察到的复发模式的免疫机制。由于发现多种机制会影响PRRSv感染，我们建立了一个在细胞间尺度详细描述主要机制及其调控的模型。我们开发了一种类似ABC的优化方法，使我们的模型与由非复发者和复发者病毒血症谱组成的大量实验数据相拟合。我们比较了两种谱之间的估计参数值、由此产生的免疫动态以及潜在免疫机制的效力。通过探究这些机制的影响，我们发现高凋亡、高细胞感染和细胞毒性T淋巴细胞的低细胞溶解促进了复发，而增加中和作用对预防复发非常有效。
我们的论文提供了一个免疫反应的原始模型和一种合适的系统拟合方法，其意义超出了PRRS感染。它首次对PRRSv感染期间复发的出现给出了机制性解释。此外，结果表明，促进强烈中和和细胞溶解反应、理想情况下与低凋亡活性和细胞易感性相关的疫苗或基因选择将预防复发。
