Department of Physics and Mathematics, Aoyama Gakuin University, Kanagawa 252-5258, Japan.
Faculty of Advanced Life Science, Hokkaido University, Sapporo, Hokkaido, 060-0810, Japan; PRESTO, Japan Science and Technology Agency, Saitama, 332-0012, Japan.
J Theor Biol. 2019 Jun 7;470:50-63. doi: 10.1016/j.jtbi.2019.03.010. Epub 2019 Mar 13.
Dengue infection results in a significant number of deaths, mostly in the tropical and subtropical regions across the world. Yet, despite the seriousness of this disease, vaccine, and antiviral drugs that could be employed in dengue treatment remain elusive. The desire to establish the factors determining the disease severity and the growing need for efficient drugs has prompted extensive research interest in within-host viral dynamics. However, very few mathematical models of within-host dengue dynamics pertaining to secondary dengue infection with another serotype are presently available. To address this gap in the pertinent literature, in this work, a secondary dengue infection model with T-cell mediated adaptive immunity and antibody-dependent enhancement was developed by considering the memory cell and heterogeneous antibody as the main factor. In particular, the explicit role of cytokines is considered for both virus and infected cell clearance, along with both extrinsic and intrinsic mechanisms for antibody-dependent enhancement. In case of secondary dengue infection, both the virus and homogeneous antibody production are enhanced due to the influence of memory cells remaining from the previous (primary) dengue infection. Owing to the high model sensitivity, it was possible to establish that, among antibody-dependent enhancement mechanisms, the increased virus replication inside the infected cell, which increases the overall virus burst size, exerts the maximum effect on disease severity during secondary infection. Moreover, the role of initial memory cell concentrations and half-saturation constant in the secretion of memory cell in the disease severity was studied. The obtained results concur with the clinical observations and may be helpful in further research on antibody-dependent enhancements aimed at producing schemes relevant for the dengue vaccine design and development.
登革热感染导致大量死亡，主要发生在世界范围内的热带和亚热带地区。然而，尽管这种疾病很严重，但用于登革热治疗的疫苗和抗病毒药物仍然难以捉摸。为了确定决定疾病严重程度的因素，并满足对高效药物的日益增长的需求，人们对宿主内病毒动力学进行了广泛的研究。然而，目前很少有关于继发感染另一种血清型的登革热的宿主内病毒动力学的数学模型。为了解决相关文献中的这一空白，在这项工作中，通过考虑记忆细胞和异质性抗体作为主要因素，开发了一个具有 T 细胞介导的适应性免疫和抗体依赖性增强的继发登革热感染模型。特别是，考虑到细胞因子对病毒和感染细胞清除的明确作用，以及抗体依赖性增强的外在和内在机制。在继发登革热感染的情况下，由于前一次（原发性）登革热感染后残留的记忆细胞的影响，病毒和同型抗体的产生都增加了。由于模型的高敏感性，可以确定在抗体依赖性增强机制中，感染细胞内病毒复制的增加，这会增加总病毒爆发规模，对继发感染期间的疾病严重程度产生最大影响。此外，还研究了初始记忆细胞浓度和半饱和常数在疾病严重程度中记忆细胞分泌中的作用。所得结果与临床观察一致，可能有助于进一步研究旨在产生与登革热疫苗设计和开发相关方案的抗体依赖性增强。
