Viral Infection in Lactobacilli: An Animal BV Model

这项申请是对NIH RFA(AI-02-008)标题为“微生物相互作用对传染病的影响”的响应。具体地说，我们将研究在动物实验性细菌性阴道病(BV)发展过程中病毒(噬菌体)和阴道乳杆菌之间的相互作用。BV是影响全球女性的最常见的阴道疾病。由于原因不明，目前还没有预防BV的方法。虽然BV本身只有轻微的不适，如排泄物和鱼腥味，但BV与妇女的两大健康风险有关：早产和感染艾滋病毒的易感性增加。这两起事件每年都会导致数百万新生儿和成年人死亡。因此，迫切需要研究BV的病因，因为发现其病因将是开发更有效的预防和治疗疾病的方法的关键一步。 在健康女性中，乳杆菌主导着阴道微生物生态。在BV期间，微生物的优势地位发生了变化--乳杆菌减少，而阴道加德纳氏菌和厌氧菌增加，但尚不清楚是什么触发了阴道生态的变化，从而导致了BV。我们已经分离出感染阴道乳杆菌的噬菌体。因为这些噬菌体可以潜在地改变阴道微生物的优势，它们被认为是BV的潜在原因。我们推测，BV可能发生在噬菌体感染阴道乳杆菌之后。我们将根据科赫的假设来检验这一假设。也就是说，从乳酸菌中分离出的病毒将被接种到动物体内，以引起动物的BV。我们将实现两个具体目标： 1)噬菌体与猴阴道乳酸菌的体外相互作用研究。 2)用乳杆菌噬菌体改变阴道生态建立猴BV模型。 研究完成后，我们希望在科赫的基础上开发出一种BV动物模型 假设，BV可以是一种传染病，感染性病原体是乳杆菌噬菌体。我们将对BV的病因有一个更好的理解。这将是实现我们的长期目标的第一步：开发更好的治疗和预防BV的方法。

This application is in response to the NIH RFA (AI-02-008) entitled "Impact of Microbial Interactions on Infectious Diseases." Specifically we will study the interaction between viruses (phages) and vaginal lactobacilli during the development of experimental bacterial vaginosis (BV) in animals. BV is the most common vaginal disorder affecting women worldwide. Because the cause is unknown, no methods are available to prevent BV. Although BV itself only has mild discomfort, such as discharge and fishy smell, BV is associated with two major health risks in women: preterm delivery and increased susceptibility to contract HIV. Both incidences kill millions of newborns and adults annually. Therefore, it is urgent to study the cause of BV, because discovering its cause will be a key step in developing more effective ways to prevent and cure the disease. In healthy women, lactobacilli dominate the vaginal microbial ecology. During BV, a shift in microbial dominance occurs-lactobacilli decrease while Gardnerrella vaginalis and anaerobic bacteria increase It is unknown, however, what triggers the shift in vaginal ecology to cause BV. We have isolated phages that infect vaginal lactobacilli. Because these phages can potentially shift vaginal microbial dominance, they are implicated as an underlying cause for BV. We hypothesize that BV may occur after phages infect vaginal lactobacilli. We will test this hypothesis according to Koch's postulates. Namely, a virus isolated from lactobacilli will be inoculated into an animal to cause BV in the animal. We will achieve two specific aims: 1) Study in vitro interactions between phages and monkey vaginal lactobacilli. 2) Establish a monkey BV model by shifting vaginal ecology with a Lactobacillus phage. Upon completion of the study, we expect to have developed a BV animal model based on Koch's postulates, documented that BV can be an infectious disease and that the infectious pathogen is the Lactobacillus phage. We will have an improved understanding of the BV etiology. This will be the first step in attaining our long-term goal: developing better methods to treat and prevent BV.