Intraspecies Transmission and Infectivity of Insectivore-Borne Hantaviruses

描述（由申请人提供）：一种曾经不为人知的啮齿动物传播的病毒群，已知会引起肾综合征出血热（HFRS），在1993年春天，当美国西南部四角地区爆发了一种迅速发展的心肺疾病时，这种病毒立即臭名昭著。十年前，一种被认定为宿主的新生啮齿类动物携带的汉坦病毒，会导致这种经常致命的呼吸系统疾病，现在被称为汉坦病毒肺综合征（HPS），这超出了临床医生、流行病学家和医学病毒学家的集体想象。认识到啮齿动物传播的汉坦病毒能够引起临床不同的疾病，如HFRS和HPS，提高了最近在鼩鼱中检测到的汉坦病毒同样会引起广泛疾病的可能性。最近从韩国乌苏鼩（Crocidura lasiura）中分离到的Imjin病毒（MJNV）的传播动力学和传染性的深入研究可能为其致病性提供线索，以及为更快速地诊断新出现的汉坦病毒引起的新发现疾病的未来爆发提供有用的试剂。拟议研究的主要目标是确定MJNV的种内传播，并确定其对人类健康和疾病的重要性。我们的主要假设是，MJNV是鼩鼱传播的汉坦病毒的一个大分支的原型，该分支与其宿主共同进化，能够引起人类感染，并可能引起疾病。我们的实验计划采用血清学和分子生物学技术来检测和表征这种新的汉坦病毒，并证明人类感染。具体目标确定MJNV与其他汉坦病毒的抗原、遗传和系统发育关系。具体目标2。确定MJNV感染的宿主范围、时间发生和空间分布。具体目标3。确定MJNV在人体内的传染性和致病潜力。这项拟议中的研究具有创新性，因为它挑战了长期以来认为啮齿动物是汉坦病毒唯一宿主的教条。关于MJNV的进化起源、宿主范围和疾病潜力的新发现将为汉坦病毒复杂的共同进化历史和宿主-寄生虫关系提供见解，这可能最终导致确定汉坦病毒致病性和组织靶向性的分子决定因素。汉坦病毒由世界各地许多啮齿类动物携带，是医学上重要的病毒，它在人类中引起两种不同的疾病。一种是发生在欧洲和亚洲的伴有肾衰竭的出血热，另一种是发生在美洲的迅速进展的、经常致命的呼吸系统疾病。最近，在鼩鼱中发现了一组新的汉坦病毒。由于它们与致病汉坦病毒的相关性，拟议的研究旨在确定这些新发现的汉坦病毒是否会引起人类感染和疾病。关于鼩鼱传播的汉坦病毒的新知识将使我们更好地为诊断汉坦病毒病的未来爆发做好准备。

DESCRIPTION (provided by applicant): A once-obscure group of rodent-borne viruses, known to cause hemorrhagic fever with renal syndrome (HFRS), gained immediate notoriety in the spring of 1993, when an outbreak of a rapidly progressive cardiopulmonary disease erupted in the Four Corners region of the southwestern United States. That a hantavirus, harbored by a neotomine rodent species identified as a reservoir host a decade earlier, would be responsible for this frequently fatal respiratory disease, now known as hantavirus pulmonary syndrome (HPS), was beyond the collective imagination of clinicians, epidemiologists and medical virologists. The realization that rodent-borne hantaviruses are capable of causing diseases as clinically disparate as HFRS and HPS raises the probability that hantaviruses recently detected in shrews would similarly cause a wide spectrum of disease. In-depth studies on the transmission dynamics and infectivity of Imjin virus (MJNV), recently isolated from the Ussuri shrew (Crocidura lasiura) in South Korea, may provide clues about its pathogenicity, as well as useful reagents to more rapidly diagnose future outbreaks of newly recognized diseases caused by emerging hantaviruses. The primary objectives of the proposed research are to determine the intraspecies transmission of MJNV and to ascertain its importance to human health and disease. Our central hypothesis is that MJNV is the prototype of a large clade of shrew-borne hantaviruses, which have co-evolved with their reservoir hosts and which are capable of causing infection, and possibly disease, in humans. Our experimental plan employs serological and molecular biological techniques for the detection and characterization of this new hantavirus and for the demonstration of human infection. Specific Aim 1. To determine the antigenic, genetic and phylogenetic relationships between MJNV and other hantaviruses. Specific Aim 2. To determine the host range, temporal occurrence and spatial distribution of MJNV infection. Specific Aim 3. To determine the infectivity and disease potential of MJNV in humans. The proposed research is innovative in that it challenges the long-held dogma that rodents are the sole reservoir hosts of hantaviruses. Newfound information about the evolutionary origin, host range and disease potential of MJNV will provide insights into the complex co-evolutionary history and host-parasite relationship of hantaviruses, which may lead ultimately to identifying the molecular determinants of hantavirus pathogenicity and tissue targeting. PUBLIC HEALTH RELEVANCE Carried by many species of rodents worldwide, hantaviruses are medically important viruses, which cause two distinct diseases in humans. One is a type of hemorrhagic fever with associated kidney failure occurring in Europe and Asia and the other is a rapidly progressive, frequently fatal respiratory disease occurring in the Americas. Recently, a new group of hantaviruses have been discovered in shrews. Because of their relatedness to disease-causing hantaviruses, the proposed research aims to determine if these newly identified hantaviruses cause infection and disease in humans. New knowledge about the shrew-borne hantaviruses will better prepare us to diagnose future outbreaks of hantavirus diseases.