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Innate Immune Mechanisms with a Focus on Small-Molecule Microbe-Host Cross Talk

“Life would not exist with macromolecules alone” [1]. This thematic issue of the Journal of Innate Immunity takes up a slightly different angle and zooms in on the microbes describing their mutual interactions with the innate immune system via small molecules. Most of the articles focus or touch upon the bacterial multicellular lifestyle called biofilm. This is maybe not surprising as these microbial populations embedded in a self-produced extracellular matrix adherent to each other and/or to a surface or interfaces [2] have developed intricate tolerance mechanisms against the actions of the immune system and most conventional antimicrobial therapies, which enables biofilm-forming bacteria to associate with 80% of human infections [3, 4]. However, fully competent eukaryotic organisms respond with sophisticated defense mechanisms against microbial biofilms [5]. For example, antimicrobial peptides can specifically tackle biofilm bacteria at subinhibitory concentration [6, 7]. These features of antimicrobial peptides are exploited for novel anti-biofilm therapies as described by Dostert et al. [8] in this issue. The free radical NO is another innate immune component with a broad concentration-dependent activity against microbes ranging from a signaling molecule-like anti-biofilm to a bactericidal activity [9, 10]. Williams and Boon [11] describe the anti-biofilm molecular mechanisms of action to be surprisingly convergent in different bacteria with NO being consistently sensed by two types of conserved sensors covalently or noncovalently connected downstream to a quorum sensing and/or second messenger cyclic di-GMP signaling output [12]. Both, extracellular quorum sensing and intracellular cyclic diGMP signaling can be intimately connected to biofilm regulation [12]. Reactive nitrogen and oxygen species are effective bactericidal molecules, but pathogens like gastroenteritis-causing Salmonella typhimurium have also developed effective detoxification and repair defense systems as described by Rhen [13]. Perhaps not surprising, Lesouhaitier et al. [14] report that also nonprofessional innate immune components such as eukaryotic communication molecules interfere with bacterial biofilm formation, physiology, and virulence. However, the bacteria have evolved the ability to fight innate immune mechanisms. Although primarily recognized as a bacterial derived potent immune stimulatory molecule [15], secreted cyclic di-GMP surprisingly has an anti-innate immune activity preventing lipocalin 2 to sequester iron-scavenging siderophores as discovered by Cui et al. [16]. But microorganisms can not only overcome host siderophore scavenging strategies with their plethora of over 500 recognized siderophores, but counteract a diversity of innate immune mechanisms beyond their anti-scavenging activities as described by Golonka et al. [17].