Intraspecies Transmission and Infectivity of Insectivore-Borne Hantaviruses

描述(申请人提供)：一组曾经鲜为人知的啮齿动物传播的病毒，已知引起肾综合征出血热(HFRS)，在1993年春天，当一种快速发展的心肺疾病在美国西南部的四角地区爆发时，立即臭名昭著。十年前被确认为水库宿主的一种新生的啮齿动物物种携带的汉坦病毒，会导致这种经常致命的呼吸道疾病，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像HFRS和HPS这样临床上不同的疾病，这增加了最近在地鼠身上检测到的汉坦病毒类似地导致广泛疾病的可能性。对新近从韩国新近分离到的伊姆津病毒(Imjin Virus，MJNV)的传播动力学和传染性的深入研究，可能会为其致病性提供线索，并为更快地诊断新发现的由新出现的汉坦病毒引起的疾病的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。我们的中心假设是，MJNV是一大类由鼠媒传播的汉坦病毒的原型，这些病毒与它们的宿主共同进化，能够在人类中引起感染，甚至可能导致疾病。我们的实验计划使用了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，并用于演示人类感染。具体目的1.确定MJNV与其他汉坦病毒之间的抗原性、遗传学和系统发育关系。明确MJNV感染的宿主范围、时间发生和空间分布。具体目的3.确定MJNV在人类中的传染性和致病潜力。这项拟议的研究具有创新性，因为它挑战了长期以来的教条，即啮齿动物是汉坦病毒的唯一宿主。关于MJNV进化起源、宿主范围和疾病潜在性的新发现将为深入了解汉坦病毒复杂的共同进化史和宿主-寄生虫关系提供线索，最终可能导致识别汉坦病毒致病和组织靶向的分子决定因素。汉坦病毒是一种重要的医学病毒，在世界各地许多种类的啮齿动物中都具有公共卫生相关性，它会导致人类两种截然不同的疾病。一种是欧洲和亚洲发生的伴有肾衰竭的出血热，另一种是美洲发生的一种进展迅速、往往致命的呼吸道疾病。最近，在地鼠身上发现了一组新的汉坦病毒。由于它们与致病的汉坦病毒有关，拟议的研究旨在确定这些新发现的汉坦病毒是否会导致人类感染和疾病。关于由泼妇传播的汉坦病毒的新知识将使我们更好地为诊断未来爆发的汉坦病毒疾病做好准备。

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.