Berryhill Brandon A, Gil-Gil Teresa, Witzany Christopher, Goldberg David A, Vega Nic M, Regoes Roland R, Levin Bruce R
Department of Biology, Emory University; Atlanta, Georgia, 30322, USA.
Program in Microbiology and Molecular Genetics, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University; Atlanta, GA, 30322, USA.
bioRxiv. 2024 Aug 23:2024.08.23.609294. doi: 10.1101/2024.08.23.609294.
Critical to our understanding of infections and their treatment is the role the innate immune system plays in controlling bacterial pathogens. Nevertheless, many in vivo systems are made or modified such that they do not have an innate immune response. Use of these systems denies the opportunity to examine the synergy between the immune system and antimicrobial agents. In this study we demonstrate that the larva of is an effective in vivo model for the study of the population and evolutionary biology of bacterial infections and their treatment. To do this we test three hypotheses concerning the role of the innate immune system during infection. We show: i) sufficiently high densities of bacteria are capable of saturating the innate immune system, ii) bacteriostatic drugs and bacteriophages are as effective as bactericidal antibiotics in preventing mortality and controlling bacterial densities, and iii) minority populations of bacteria resistant to a treating antibiotic will not ascend. Using a highly virulent strain of and a mathematical computer-simulation model, we further explore how the dynamics of the infection within the short term determine the ultimate infection outcome. We find that excess immune activation in response to high densities of bacteria leads to a strong but short-lived immune response which ultimately results in a high degree of mortality. Overall, our findings illustrate the utility of the model system in conjunction with established in vivo models in studying infectious disease progression and treatment.
对于我们理解感染及其治疗而言，固有免疫系统在控制细菌病原体方面所起的作用至关重要。然而，许多体内系统被构建或修改后，不再具有固有免疫反应。使用这些系统剥夺了研究免疫系统与抗菌剂之间协同作用的机会。在本研究中，我们证明[物种名称]的幼虫是研究细菌感染的群体和进化生物学及其治疗的有效体内模型。为此，我们测试了关于固有免疫系统在感染过程中作用的三个假设。我们发现：i）足够高的细菌密度能够使固有免疫系统饱和，ii）抑菌药物和噬菌体在预防死亡和控制细菌密度方面与杀菌抗生素一样有效，iii）对治疗抗生素耐药的少数细菌群体不会增加。使用一种高毒力的[菌株名称]菌株和一个数学计算机模拟模型，我们进一步探讨了短期内感染的动态如何决定最终的感染结果。我们发现，对高密度细菌的过度免疫激活会导致强烈但短暂的免疫反应，最终导致高死亡率。总体而言，我们的研究结果说明了[物种名称]模型系统与已建立的体内模型相结合在研究传染病进展和治疗中的实用性。
