Collaborative Research: Tradeoffs between specialist and generalist strategies for host immune evasion in a vector-borne bacterium

这项研究解决了环境如何通过塑造自然界中的细菌群落来影响人类和动物健康的一个独特例子。引起人类或动物疾病的微生物可以感染的宿主数量不同；有些专门针对一种动物/植物，有些则能够感染广泛的范围。特殊的生物也许能更好地逃脱宿主的免疫系统，从而存活下来，但如果宿主变得稀有，它们就有灭绝的危险。宿主范围广的病原体往往更容易“跳到”新的宿主身上，从而引发流行病。该奖项将研究导致莱姆病的伯氏疏螺旋体（Borrelia burgdorferi）如何逃脱其天然宿主免疫系统的杀死，以及这种细菌的不同遗传类型是否在自然界中独特地适应于哺乳动物和鸟类。该奖项还将研究伯氏疏螺旋体的多样性是通过对不同宿主的适应来解释的，还是通过宿主抗体靶向最常见的菌株，从而允许罕见菌株共存来解释的。疏螺旋体的多样性直接影响人类健康，因为菌株导致不同的疾病严重程度。该奖项将增加人们对生态学和进化微生物如何影响人类健康的认识。它将编写教育材料，并就环境与人类健康之间的联系向社区扩大宣传。此外，它还将在疾病生态学、分子生态学和生态流行病学领域的所有教育级别提供广泛的跨学科培训。该奖项将确定不同生态环境下伯氏疏螺旋体菌株之间的专业化程度和免疫介导的竞争，并验证这些表型性状是伯氏疏螺旋体多样性、群落结构和宿主专业化进化的重要驱动因素的假设。虽然有证据表明伯氏疏螺旋体宿主的差异关联可以驱动遗传多态性（“多生态位多态性”），但其他研究声称，作用于一个或多个伯氏疏螺旋体外表面蛋白的免疫介导的平衡选择可以维持观察到的多态性，而不调用定向过程（“负频率依赖选择”）。该奖项将通过对简化寄主群落的6年研究数据进行深度扩增子测序，评估菌株在多种寄主物种中的流行程度，从而阐明多种机制对伯氏疏螺旋体多样性的贡献。通过评估伯氏疏螺旋体菌株暴露于不同宿主血清免疫成分后的体外存活情况，探讨宿主特异性的生理基础。宿主特异性相关适应度和菌株之间免疫介导的竞争将通过体内传播实验进行评估。宿主专业化和免疫介导的竞争在不同生态环境下决定菌株多样性和进化的过程将使用新的数学模型进行研究。这项研究将为伯氏疏螺旋体适应其自然宿主免疫系统的性质提供强有力的证据。它将确定这些适应性是否具有物种特异性，并确定宿主特异性对伯氏疏螺旋体菌株群落结构和多样性的影响。该奖项将为研究生提供多学科培训，包括未被充分代表的少数民族，以及疾病生态学和建模方面的博士后。为了扩大这项工作的影响，研究人员将利用与当地环保组织的联系，在当地社区开展外展活动。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This research addresses a unique example of how the environment can impact human and animal health by shaping bacterial communities in nature. Microbes causing human or animal disease differ in the number of hosts they can infect; while some specialize on a single animal/plant, others are able to infect a wide range. Specialist organisms may be better able to escape the host immune system and thus survive, but they risk becoming extinct if the host becomes rare. Pathogens with wide host ranges are often better able to 'jump' to new hosts, driving epidemics. This award will investigate how Borrelia burgdorferi - the bacterium that causes Lyme disease - escapes killing by the immune system of its natural host and whether different genetic types of this bacterium are uniquely adapted to mammals versus birds in nature. This award will also investigate whether Borrelia diversity is explained by adaptation to different hosts or, alternatively, by the targeting of the most common strains by host antibodies, allowing coexistence of rarer strains. Borrelia diversity directly impacts human health because strains cause differential disease severity. This award will increase knowledge about how ecology and evolution of microbes impacts human health. It will develop educational materials and expand outreach into communities about the links between the environment and human health. In addition, it will provide extensive and interdisciplinary training, at all educational levels, in the fields of disease ecology, molecular ecology and eco-epidemiology.This award will determine the extent of specialization and immune-mediated competition among strains of B. burgdorferi in different ecological contexts and test the hypothesis that these phenotypic traits are important drivers of B. burgdorferi diversity, community structure and host specialization evolution. While there is evidence of differential B. burgdorferi host association which could drive genetic polymorphisms ('multiple niche polymorphism'), other studies claim that immune-mediated balancing selection acting on one or more B. burgdorferi outer surface proteins can maintain the observed polymorphisms without invoking directional processes ('negative frequency-dependent selection'). This award will disentangle the contribution of multiple mechanisms to B. burgdorferi diversity by assessing strain prevalence in multiple host species by applying deep amplicon sequencing to data from a 6-year-long study in a simplified host community. The physiological basis of host specificity will be explored by evaluating in vitro survival of B. burgdorferi strains when exposed to immune components in serum of different local hosts. Host-specificity related fitness and immune-mediated competition between strains will be assessed with in vivo transmission experiments. The processes by which host specialization and immune-mediated competition determine strain diversity and evolution in different ecological contexts will be examined using novel mathematical models. This study will provide strong evidence of the nature of B. burgdorferi adaptations to avoid the immune system of its natural hosts. It will determine whether these adaptations are species-specific and identify the consequences of host specificity on the structure and diversity of B. burgdorferi strain community. The award will provide multi-disciplinary training to graduate students, including under-represented minorities, and postdoctoral fellows in disease ecology and modeling. To broaden the impact of the work, researchers will leverage contacts with local environmental groups to conduct outreach within the local community.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.