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Editorial: Molecular eavesdropping: phagocytic cells spy on bacterial communication

The immediate recognition of invading bacteria and their classification as “dangerous” are crucial for an efficient host defense. Accordingly, phagocytic cells, a.k.a., “first line defense”, are equipped with an array of surface receptors recognizing bacteria by PAMPs or by bound opsonins, such as antibodies, complement, and others. Recognition of bacteria induces their phagocytosis and the production and release of bactericidal substances. Bacteria, on the other hand, have developed evasion strategies, virulence factors that permit their survival in the host. An especially challenging situation for the phagocytic cells is the formation of bacterial biofilms. Many bacteria species— rather than living as free swimming, “planktonic”, lone fighters—tend to socialize and form communities. They produce the EPS, which composed of complex carbohydrates, proteins, and bacterial DNA, because of its slimy appearance, is referred to as “film.” Embedded in the EPS, the bacteria acquire, among others, a relative resistance toward antibiotics and biocides and may also be against host defense mechanisms. Bacterial biofilms are a common cause of persistent infection [1], and consequently, there is increasing interest in factors inducing and controlling biofilm formation. In that context, the paper by Karlsson et al. [2] in this journal is of special interest. Although the authors are cautious about their interpretation, their data imply that phagocytic cells can prevent biofilm formation by intercepting bacterial signals. How does that work? Biofilm formation is a complex, wellregulated process that critically depends on the communication of the bacteria with each other. Communication occurs via so-called “quorum-sensing” molecules or “autoinducers”, which are produced and released by the bacteria. The molecules accumulate in the environment and bind to bacteria via specialized receptors and induce the production of virulence factors. Well-analyzed are the quorum-sensing molecules of Pseudomonas aeruginosa 3O-C12-HSL and the N-butanoyl-L-homoserine lactone (see excellent reviews by Karatan and Watnik [3] or Fuqua and Greenberg [4]). The former, termed 3O-C12-HSL, is of special interest, as there are numerous data in the literature that indicate that 3O-C12-HSL is an “interkingdom” signaling molecule that also interacts with mammalian cells (reviewed in ref. [5]). A number of publications describe that 3O-C12-HSL down-regulates leukocyte functions in vitro, for example, the antigenor mitogen-driven proliferation of T-lymphocytes. The seemingly selfevident interpretation was that the quorum-sensing molecules “modulate host inflammatory pathways to promote bacterial survival” (reviewed in ref. [6]). Other data in the literature, however, challenge this interpretation: Vikström and coworkers [7] and our group [8, 9] had shown that 3O-C12-HSL activates phagocytic cells: it enhances the phagocytosis, up-regulates the expression on PMNs of adhesion molecules and IgRs, and I think of utmost importance, is chemotactic for PMNs [8]. The latter activity is analyzed further in the current paper by Karlsson et al. [2]. They found that 3O-C12-HSL uses apparently similar signaling pathways as bona fide chemokines, although higher molar concentrations were required. The finding has an important implication: 3OC12-HSL, secreted by bacteria in the process of biofilm formation, could attract PMNs and as consequence, prevent biofilm formation, as planktonic bacteria, as opposed to fully developed biofilms, are an easier prey for phagocytic cells and as PMNs are known to release bactericidal substances upon activation, among others lactoferrin, which is known to prevent biofilm formation [10]. So the “seemingly self-evident interpretation” of these data is that PMNs use a bacterial signaling molecule to promote the local host defense. In other words: the PMNs intercept the communication among the bacteria, which gives them a head start in controlling biofilm formation (Fig. 1). Although this is an attractive notion, a number of questions remain. I think the most pertinent are: (1) whether the local 3O-C12-HSL concentrations