Abstract 摘要
Bacteriophages and bacterial biofilms are widely present in natural environments, a fact that has accelerated the evolution of phages and their bacterial hosts in these particular niches. Phage-host interactions in biofilm communities are rather complex, where phages are not always merely predators but also can establish symbiotic relationships that induce and strengthen biofilms. In this review we provide an overview of the main features affecting phage-biofilm interactions as well as the currently available methods of studying these interactions. In addition, we address the applications of phages for biofilm control in different contexts.
噬菌体和细菌生物膜广泛存在于自然环境中，这一事实加速了噬菌体及其细菌宿主在这些特殊环境中的进化。生物膜群落中噬菌体与宿主的相互作用相当复杂，噬菌体并不总是单纯的捕食者，也可以建立共生关系，诱导并强化生物膜。在这篇综述中，我们将概述影响噬菌体与生物膜相互作用的主要特征，以及研究这些相互作用的现有方法。此外，我们还讨论了噬菌体在不同情况下控制生物膜的应用。
Keywords 关键词
biofilms, phage therapy, phage biocontrol
生物膜、噬菌体疗法、噬菌体生物控制
1. INTRODUCTION 1.引言
Most of the bacteria found in nature live in microbial communities called biofilms (1), where the microbial cells are attached to a surface and encased in a self-producing matrix of extracellular polymeric substances (EPSs) that confers on them an environment protected from hostile conditions (2, 3). In turn, bacteriophages (phages), the natural predators of bacteria, are considered the predominant biological entities on earth and can be found in almost all ecological niches where their host bacteria are present (4, 5). Although phages and biofilms have coexisted in natural environments for millions of years, the complex interactions between them are far from fully understood. So far, most phage-bacteria studies are conducted in suspended cultures; in addition, the biofilm studies that have been reported are usually performed under specific conditions that are unable to mimic the high complexity of real biofilms found in nature or in health contexts (6). This makes it difficult to draw conclusions about the impact biofilms may have had on phage evolution over the years, as well as the role of phages in shaping the bacterial diversity in these particular niches. Combining in vitro, ex vivo, or in vivo biofilm infection assays with computational simulations can, however, help us to uncover and better understand the phage-biofilm interactions. In this review, we address the mechanisms underlying phage-bacteria interactions in biofilm communities, the possible methods of studying these interactions, and the potential applications of phages for biofilm control in different contexts.
自然界中发现的大多数细菌都生活在被称为生物膜的微生物群落中（1），微生物细胞附着在表面上，并被包裹在由细胞外高分子物质（EPSs）组成的自产基质中，这种基质为它们提供了一个免受恶劣环境影响的环境（2，3）。噬菌体则是细菌的天敌，被认为是地球上最主要的生物实体，几乎在所有存在宿主细菌的生态位中都能找到噬菌体（4、5）。尽管噬菌体和生物膜在自然环境中共存了数百万年，但人们对它们之间复杂的相互作用还远未完全了解。迄今为止，大多数噬菌体-细菌研究都是在悬浮培养物中进行的；此外，已报道的生物膜研究通常是在特定条件下进行的，无法模拟自然界或健康环境中真实生物膜的高度复杂性（6）。因此，很难就生物膜多年来可能对噬菌体进化产生的影响，以及噬菌体在这些特定壁龛中塑造细菌多样性的作用得出结论。然而，将体外、体内或体内生物膜感染试验与计算模拟相结合，可以帮助我们发现并更好地理解噬菌体与生物膜之间的相互作用。在本综述中，我们将探讨生物膜群落中噬菌体与细菌相互作用的基本机制、研究这些相互作用的可能方法以及噬菌体在不同情况下控制生物膜的潜在应用。
2. PHAGE-BIOFILM INTERACTION FROM MOLECULAR, EVOLUTIONARY, AND ECOLOGICAL PERSPECTIVES
2.从分子、进化和生态学角度看噬菌体与生物膜的相互作用
As biofilms are ubiquitous in nature, so are phages (1, 7). The coevolution between phages and bacteria has been an important driver for the huge phenotypic and genotypic diversity found in these microbial populations (8). Although biofilms can protect bacteria from harsh environmental conditions and phage predation, phages can encode in their genomes EPS-degrading enzymes, such as depolymerases, to obtain an advantage against these complex structures (9). On the other hand, bacteria within biofilms have coevolved to find new counter-defense mechanisms, leading to an endless arms race between phages and bacteria (8, 10–12). There is also growing evidence that phages can promote biofilm formation and bring benefits to their bacterial hosts (13). All of these aspects regarding phage-biofilm interactions are discussed below and are represented in Figure 1.
生物膜在自然界无处不在，噬菌体也是如此（1，7）。噬菌体和细菌之间的共同进化是导致这些微生物种群具有巨大表型和基因型多样性的重要原因（8）。虽然生物膜可以保护细菌免受恶劣环境条件和噬菌体捕食的影响，但噬菌体可以在其基因组中编码 EPS 降解酶（如解聚酶），以获得对抗这些复杂结构的优势（9）。另一方面，生物膜内的细菌也在共同进化，寻找新的反防御机制，从而导致噬菌体与细菌之间无休止的军备竞赛（8、10- 12）。还有越来越多的证据表明，噬菌体能促进生物膜的形成，并给细菌宿主带来益处（13）。下文将讨论噬菌体与生物膜相互作用的所有这些方面，并在图 1 中加以说明。
