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Most commensal and pathogenic bacteria interacting with eukaryotic hosts express adhesive molecules on their surfaces that promote interaction with host cell receptors or with soluble macromolecules. Even though bacterial attachment to epithelial cells may be beneficial for bacterial colonization, adhesion may come at a cost because bacterial attachment to immune cells can facilitate phagocytosis and clearing. Many pathogenic bacteria have solved this dilemma by producing an antiphagocytic surface layer usually consisting of polysaccharide and by expressing their adhesins on polymeric structures that extend out from the cell surface. In this review, we will focus on the interaction between bacterial adhesins and the host, with an emphasis on pilus-like structures.

Marine bacteria can cause harm to single-celled and multicellular eukaryotes. However, relatively little is known about the underlying genetic basis for marine bacterial interactions with higher organisms. We examined whole-genome sequences from a large number of marine bacteria for the prevalence of homologues to virulence genes and pathogenicity islands known from bacteria that are pathogenic to terrestrial animals and plants. As many as 60 out of 119 genomes of marine bacteria, with no known association to infectious disease, harboured genes of virulence-associated types III, IV, V and VI protein secretion systems. Type III secretion was relatively uncommon, while type IV was widespread among alphaproteobacteria (particularly among roseobacters) and type VI was primarily found among gammaproteobacteria. Other examples included homologues of the Yersinia murine toxin and a phage-related 'antifeeding' island. Analysis of the Global Ocean Sampling metagenomic data indicated that virulence genes were present in up to 8% of the planktonic bacteria, with highest values in productive waters. From a marine ecology perspective, expression of these widely distributed genes would indicate that some bacteria infect or even consume live cells, that is, generate a previously unrecognized flow of organic matter and nutrients directly from eukaryotes to bacteria.

Neutrophil extracellular traps (NETs) are considered to be part of the human innate immunity because they trap and kill pathogens. NETs are formed by activated neutrophils and consist of a DNA backbone with embedded antimicrobial peptides and enzymes. They are involved in host defense during pneumococcal pneumonia, streptococcal necrotizing fasciitis, appendicitis and insemination. Recently, bacterial virulence factors that counteract NETs have been identified. These include the degradation of the NET-backbone by DNases enabling the liberation of bacteria from NETs, as well as capsule formation, which reduces bacterial trapping. Furthermore, pathogens can resist NET-mediated killing by adding positive charge to their cell surface.

The evolution of multicellular organisms has been, and continues to be, paralleled by the evolution of the surrounding microbial flora. This intimate coexistence between higher host organisms and microbes has generated a myriad of adaptation strategies at both sides to cope with, or even benefit from the given conditions. On the host side, the development of an effective immune defence system allowed the maintenance of an astonishingly stable homeostasis on many body sites, and even the establishment of sterile surfaces at vulnerable anatomical sites. On the other hand, microbial diversity has led to the establishment of a large number of microbial life styles that allow persistence and proliferation in the presence of host defense mechanisms. The following review describes bacterial strategies to circumvent or modify host defenses that operate at the epithelial lining. It illustrates the enormous diversity of mechanisms that are part of the complex interplay between microbial organisms and the host. It also reflects the dramatic progress made in the understanding of the mammalian immune defense system which many times has been initiated by the surprising results from the study of microbial pathogenesis.

Selected bacterial pathogens, such as Helicobacter pylori and Mycobacterium tuberculosis, establish persistent infections in mammalian hosts despite activating inflammatory and antimicrobial responses. The strategies used to overcome host defense responses vary with the anatomical location of the infection but often rely on deliberate manipulations of the host cell responses. Phylogenetically unrelated bacteria can share similar strategies for the establishment of persistence and, in selected examples, one even can define homologous "persistence" genes. Such observations suggest that persistent infection is a specific phase in infection pathogenesis rather than a fortuitous imbalance in the host-pathogen interaction.

Spread of antibiotic resistance is mediated by clonal lineages of bacteria that besides being resistant also possess other properties promoting their success. Some vaccines already in use, such as the pneumococcal conjugate vaccines, have had an effect on these successful clones, but at the same time have allowed for the expansion and resistance evolution of previously minor clones not covered by the vaccine. Since resistance frequently is horizontally transferred it will be difficult to generate a vaccine that covers all possible genetic lineages prone to develop resistance unless the vaccine target(s) is absolutely necessary for spread and/or disease development. Targeting the resistance mechanism itself by a vaccine is an interesting but hitherto unexplored approach. [ABSTRACT FROM AUTHOR]

Globally spreading bacterial strains belong to clonal types that have the capacity to colonize, spread and cause disease in the community. Recent comparative genomic analyses of well-defined clinical isolates have led to the identification of bacterial properties that are required for the successful spread of bacterial clones. In this Review, we discuss the evolution of bacterial clones, the importance of recombination versus mutations for evolution of clones, common methods used to study clonal relationships among bacteria, factors that may contribute to the clonal spread of bacteria and the potential relevance of bacterial clones to clinical disease. We focus on the common pathogen Streptococcus pneumoniae, although other bacteria are also briefly discussed, such as Helicobacter pylori, Staphylococcus aureus and Mycobacterium tuberculosis. [ABSTRACT FROM AUTHOR]

β-Lactam resistance in enteric bacteria is frequently caused by mutations inampDencoding a cytosolicN-acetylmuramyl-l-alanine amidase. Such mutants are blocked in murein (peptidoglycan) recycling and accumulate cytoplasmic muropeptides that interact with the transcriptional activatorampR,which de-repressesβ-lactamase expression.Salmonella entericaserovar Typhimurium,an extensively studied enteric pathogen, was used to show that mutations inampDdecreased the ability ofS. typhimuriumto enter a macrophage derived cell line and made the bacteria more potent as inducers of inducible nitric oxide synthase (iNOS), as compared with the wild-type.ampGmutants, defective in the transport of recycled muropeptides across the cytoplasmic membrane, behaved essentially as the wild-type in invasion assays and in activation of iNOS. AsampDmutants also have reducedin vivofitness in a murine model, we suggest that the cytoplasmic accumulation of muropeptides affects the virulence of theampDmutants. [ABSTRACT FROM AUTHOR]

Adherence of pathogenic Neisseria to target host cells is mediated by pili. PilC1 and PilC2 are two high-molecular-weight proteins involved in pilus assembly and cellular adherence functions of the pili. Inactivation of pilC1 or pilC2 in N. meningitides resulted in clones that expressed the same number of pili as the parent, contained no alterations in pilE and showed no detectable differences in PilE glycosylation. However, the PilC2+ pilC1- mutant showed much reduced adherence to target cells, indicating that production of PilC1 is essential for pilus-mediated adherence. To study further the functional differences between the meningococcal pilC genes, we determined the complete nucleotide sequence of pilC1 and pilC2 of N. meningitides. Alignment of six PilC sequences demonstrated that PilC is composed of both conserved and variable regions. By immunogold labelling of bacterial sections we showed that PilC is present in the membranes of both piliated and non-piliated bacteria. Further, we demonstrated that PilC is associated with the bacterial cell surface. [ABSTRACT FROM AUTHOR]

Pyelonephritic isolates of Escherichia coli commonly express P-pili, which mediate bacterial attachment to glycolipids on epithelial cell surfaces. Three classes of P-pili have been defined, based on varying specificity for galabiose-containing glycolipids. Variation in adhesive capacity is correlated with a shift in preferred host, suggesting that host tropism depends largely on detailed specificity for the globoseries glycolipids. In this study we examined the importance of the PapG adhesin in determining receptor specificity. Translational fusions were constructed between the amino-terminus of the PapG adhesin from each of the three pilus classes and a reporter protein. The binding specificity of the purified fusion proteins in vitro was identical to that seen with whole bacteria. Adherence of intact bacteria to cultured kidney cells was markedly reduced by a monoclonal antibody specific for the Class III adhesin (previously denoted PrsG), confirming the importance of the amino-terminus of PapG in mediating attachment to a receptor when presented on the eukaryotic cell surface. These results suggest that the detailed receptor specificity resides solely within the amino-terminus of the PapG adhesin and is independent of the complex pilus architecture. [ABSTRACT FROM AUTHOR]

Pili of Neisseria gonorrhoeae are correlated with increased bacterial attachment to epithelial cells and undergo both phase and antigenic variation. Phase variation of gonococcal pili can be brought about by recombination events in the pilin structural gene, pilE, or by the on/off switch in expression of PilC, a pilus biogenesis protein for which two loci exist. We have studied the binding to epithelial cell lines and to fixed tissue sections of N. gonorrhoeae MS11 derivatives and mutants carrying structurally defined PilE and PilC proteins. In situ binding studies of N. gonorrhoeae to formalin-fixed tissue sections resulted in a binding pattern similar to that obtained using viable epithelial cell lines of different origin, Piliated gonococcal clones, containing different pilE sequences, varied dramatically from one another in their efficiencies at binding to corneal and conjunctival tissue, but bound equally well to cervical and endometrial tissues. Further, the binding data suggested that PJIC expression by itself, i.e. without pili, cannot confer bacterial binding and that expression of either PilC1 or PilC2 does not confer different binding properties to the bacterial cells. Possible receptors for piliated gonococci were expressed in human tissues, such as cervix, endometrium, cornea, intestine, stomach, mid-brain and meninges, but not in human kidney. Pretreatment of the target tissues with Proteinase K decreased the gonococcal binding dramatically, whereas pretreatment with neuraminidase and meta-periodate, which cleave carbon-carbon linkages between vicinal hydroxyl groups in carbohydrates, did not affect attachment of gonococci. These data argue that pilus-dependent attachment of N. gonorrhoeae to human tissue may be mediated by a eukaryotic receptor having protein characteristics, and that the pilus subunit sequence may play an important role in the interaction with human cornea. [ABSTRACT FROM AUTHOR]

The chaperone/usher pathway is responsible for the assembly of adhesive pili on the surface of gram-negative pathogenic bacteria. In this issue, present the crystal structure of the PapC usher translocation domain and images of the FimD usher bound to a pilus translocation intermediate. These new structures provide the first detailed view of a translocase in action. [Copyright &y& Elsevier]

Editorial. Looks at the research into the activities of microbes. The common set of strategies used by microbes to sense and respond to environmental clues; Hope that a better understanding of the genetic underpinnings of microbe behavior will bring with it more effective strategies against plant and animal pathogens; A series of reports in the May 2, 1997 issue of `Science.'

The BarA-UvrY two-component system family is strongly associated with virulence but is poorly understood at the molecular level. During our attempts to complement a barA deletion mutant, we consistently generated various mutated BarA proteins. We reasoned that characterization of the mutants would help us to better understand the signal transduction mechanism in tripartite sensors. This was aided by the demonstrated ability to activate the UvrY regulator with acetyl phosphate independently of the BarA sensor. Many of the mutated BarA proteins had poor complementation activity but could counteract the activity of the wild-type sensor in a dominant-negative fashion. These proteins carried point mutations in or near the recently identified HAMP linker, previously implicated in signal transduction between the periplasm and cytoplasm. This created sensor proteins with an impaired kinase activity and a net dephosphorylating activity. Using further site-directed mutagenesis of a HAMP linker-mutated protein, we could demonstrate that the phosphoaccepting aspartate 718 and histidine 861 are crucial for the dephosphorylating activity. Additional analysis of the HAMP linker-mutated BarA sensors demonstrated that a dephosphorylating activity can operate via phosphotransfer within a tripartite sensor dimer in vivo. This also means that a tripartite sensor can be arranged as a dimer even in the dephosphorylating mode. [ABSTRACT FROM AUTHOR]