巴西米纳斯吉拉斯州南部分离的登革病毒1型的系统发育分析

摘要(中文译文)

登革热是一个全球性的重大公共卫生问题，尤其是在世界热带和亚热带地区。初次感染单一登革病毒血清型会引起一种轻微、自限性的发热性疾病，称为登革热。然而，一部分经历不同血清型二次感染的患者可能进展为更严重的疾病形式，称为登革出血热。四种登革病毒血清型（1-4）在抗原性和遗传性上各不相同，每种血清型由多个基因型组成。在本研究中，我们从巴西米纳斯吉拉斯州南部阿尔费纳斯市一名登革出血热患者中分离出一株登革病毒1型血清型，命名为BR/Alfenas/2012，并基于NS5基因分析进行了分子鉴定。用该分离株感染瑞士小鼠，以验证其诱导登革热特征性组织病理学改变的能力。感染动物的肝脏组织病理学分析显示存在炎性浸润、肝脂肪变性，以及水肿、出血和局灶性坏死。基于包膜基因的系统发育和进化分析提供证据表明，分离株BR/Alfenas/2012属于基因型V、谱系I，并且可能来源于巴西里约热内卢的分离株。与同一基因型/谱系的其他巴西分离株相比，分离株BR/Alfenas/2012显示出两个独特的氨基酸替换（SER222THRE和PHE306SER）。构建了包膜蛋白的分子模型，表明氨基酸改变PHE306SER可能导致位于结构域III内该区域的不同折叠。使用BR/Alfenas/2012及属于同一谱系/基因型的其他分离株进行进一步的遗传学和动物模型研究，可能有助于确定这些遗传改变与易感人群中登革出血热的关系。

Abstract

Dengue is a major worldwide public health problem, especially in the tropical and subtropical regions of the world. Primary infection with a single Dengue virus serotype causes a mild, self-limiting febrile illness called dengue fever. However, a subset of patients who experience secondary infection with a different serotype can progress to a more severe form of the disease, called dengue hemorrhagic fever. The four Dengue virus serotypes (1-4) are antigenically and genetically distinct and each serotype is composed of multiple genotypes. In this study we isolated one Dengue virus 1 serotype, named BR/Alfenas/2012, from a patient with dengue hemorrhagic fever in Alfenas, South Minas Gerais, Brazil and molecular identification was performed based on the analysis of NS5 gene. Swiss mice were infected with this isolate to verify its potential to induce histopathological alterations characteristic of dengue. Liver histopathological analysis of infected animals showed the presence of inflammatory infiltrates, hepatic steatosis, as well as edema, hemorrhage and necrosis focal points. Phylogenetic and evolutionary analyses based on the envelope gene provided evidence that the isolate BR/Alfenas/2012 belongs to genotype V, lineage I and it is probably derived from isolates of Rio de Janeiro, Brazil. The isolate BR/Alfenas/2012 showed two unique amino acids substitutions (SER222THRE and PHE306SER) when compared to other Brazilian isolates from the same genotype/lineage. Molecular models were generated for the envelope protein indicating that the amino acid alteration PHE 306 SER could contribute to a different folding in this region located within the domain III. Further genetic and animal model studies using BR/Alfenas/2012 and other isolates belonging to the same lineage/genotype could help determine the relation of these genetic alterations and dengue hemorrhagic fever in a susceptible population.

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