The modulation of host cell apoptosis by intracellular bacterial pathogens

Recent years have witnessed significant advances in unraveling the elegant mechanisms by which intracellular bacterial pathogens induce and/or block apoptosis, which can influence disease progression. This intriguing aspect of the host-pathogen interaction adds another fascinating dimension to our understanding of the exploitation of host cell biology by intracellular bacterial pathogens.     

Co-evolution and exploitation of host cell signaling pathways by bacterial pathogens

Bacterial pathogens have evolved by combinations of gene acquisition, deletion, and modification, which increases their fitness. Additionally, bacteria are able to evolve in "quantum leaps" via the ability to promiscuously acquire new genes. Many bacterial pathogens - especially Gram-negative enteric pathogens - have evolved mechanisms by which to subvert signal transduction pathways of eukaryotic cells by expressing genes that mimic or regulate host protein factors involved in a variety of signaling cascades. This results in the ability to cause diseases ranging from tumor formation in plants to gastroenteritis and bubonic plague. Here, we present recent advances on mechanisms of bacterial pathogen evolution, including specific signaling cascades targeted by their virulence genes with an emphasis on the ubiquitin modification system, Rho GTPase regulators, cytoskeletal modulators, and host innate immunity. We also comment briefly on evolution of host defense mechanisms in place that limit disease caused by bacterial pathogens.     

Poisons, ruffles and rockets: bacterial pathogens and the host cell cytoskeleton

The cytoskeleton of eukaryotic cells is affected by a number of bacterial and viral pathogens. In this review we consider three recurring themes of cytoskeletal involvement in bacterial pathogenesis: 1) the effect of bacterial toxins on actin-regulating small GTP-binding proteins; 2) the invasion of non-phagocytic cells by the bacterial induction of ruffles at the plasma membrane; 3) the formation of actin tails and pedestals by intracellular and extracellular bacteria, respectively. Considerable progress has been made recently in the characterization of these processes. It is becoming clear that bacterial pathogens have developed a variety of sophisticated mechanisms for utilizing the complex cytoskeletal system of host cells. These bacterially-induced processes are now providing unique insights into the regulation of fundamental eukaryotic mechanisms.     

Influence of human gastrointestinal tract bacterial pathogens on host cell apoptosis

Several pathogenic bacteria are able to trigger apoptosis in the host cell, but the mechanisms by which it occurs differ, and the resulting pathology can take different courses. Induction and/or blockage of programmed cell death upon infection is a result of complex interaction of bacterial proteins with cellular proteins involved in signal transduction and apoptosis. In this review we focus on pro/anti-apoptotic activities exhibited by two enteric pathogens Salmonella enterica, Yersinia spp. and gastric pathogen Helicobacter pylori. We present current knowledge on how interaction between mammalian and bacterial cell relates to the molecular pathways of apoptosis, and what is the role of apoptosis in pathogenesis.     

Anti-immunology: evasion of the host immune system by bacterial and viral pathogens

Multicellular organisms possess very sophisticated defense mechanisms that are designed to effectively counter the continual microbial insult of the environment within the vertebrate host. However, successful microbial pathogens have in turn evolved complex and efficient methods to overcome innate and adaptive immune mechanisms, which can result in disease or chronic infections. Although the various virulence strategies used by viral and bacterial pathogens are numerous, there are several general mechanisms that are used to subvert and exploit immune systems that are shared between these diverse microbial pathogens. The success of each pathogen is directly dependant on its ability to mount an effective anti-immune response within the infected host, which can ultimately result in acute disease, chronic infection, or pathogen clearance. In this review, we highlight and compare some of the many molecular mechanisms that bacterial and viral pathogens use to evade host immune defenses.     

Human pathogens and the host cell SUMOylation system

Since posttranslational modification (PTM) by the small ubiquitin-related modifiers (SUMOs) was discovered over a decade ago, a huge number of cellular proteins have been found to be reversibly modified, resulting in alteration of differential cellular pathways. Although the molecular consequences of SUMO attachment are difficult to predict, the underlying principle of SUMOylation is altering inter- and/or intramolecular interactions of the modified substrate, changing localization, stability, and/or activity. Unsurprisingly, many different pathogens have evolved to exploit the cellular SUMO modification system due to its functional flexibility and far-reaching functional downstream consequences. Although the extensive knowledge gained so far is impressive, a definitive conclusion about the role of SUMO modification during virus infection in general remains elusive and is still restricted to a few, yet promising concepts. Based on the available data, this review aims, first, to provide a detailed overview of the current state of knowledge and, second, to evaluate the currently known common principles/molecular mechanisms of how human pathogenic microbes, especially viruses and their regulatory proteins, exploit the host cell SUMO modification system.     

Perturbation and exploitation of host cell cytoskeleton by periodontal pathogens

Some periodontal pathogens disrupt epithelial barriers and cellular adhesion to the extracellular matrix, which affects the cytoskeleton. Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans exploit the cytoskeleton during their uptake by epithelial cells. Treponema denticola perturbs actin and actin-regulating pathways in host cells. Cytoskeletal dysfunction due to pathogenic bacteria may impair physiologic remodeling and wound repair in the periodontium.     

Invasive and adherent bacterial pathogens co-Opt host clathrin for infection

Infection by the bacterium Listeria monocytogenes depends on host cell clathrin. To determine whether this requirement is widespread, we analyzed infection models using diverse bacteria. We demonstrated that bacteria that enter cells following binding to cellular receptors (termed "zippering" bacteria) invade in a clathrin-dependent manner. In contrast, bacteria that inject effector proteins into host cells in order to gain entry (termed "triggering" bacteria) invade in a clathrin-independent manner. Strikingly, enteropathogenic Escherichia coli (EPEC) required clathrin to form actin-rich pedestals in host cells beneath adhering bacteria, even though this pathogen remains extracellular. Furthermore, clathrin accumulation preceded the actin rearrangements necessary for Listeria entry. These data provide evidence for a clathrin-based entry pathway allowing internalization of large objects (bacteria and ligand-coated beads) and used by "zippering" bacteria as part of a general mechanism to invade host mammalian cells. We also revealed a nonendocytic role for clathrin required for extracellular EPEC infections.     

Manipulation of epithelial cell architecture by the bacterial pathogens Listeria and Shigella

Subversion of the host cell cytoskeleton is a virulence attribute common to many bacterial pathogens. On mucosal surfaces, bacteria have evolved distinct ways of interacting with the polarised epithelium and manipulating host cell structure to propagate infection. For example, Shigella and Listeria induce cytoskeletal changes to induce their own uptake into enterocytes in order to replicate within an intracellular environment and then spread from cell-to-cell by harnessing the host actin cytoskeleton. In this review, we highlight some recent studies that advance our understanding of the role of the host cell cytoskeleton in the mechanical and molecular processes of pathogen invasion, cell-to-cell spread and the impact of infection on epithelial intercellular tension and innate mucosal defence.     

Targeting host cell furin proprotein convertases as a therapeutic strategy against bacterial toxins and viral pathogens

Pathogens or their toxins, including influenza virus, Pseudomonas, and anthrax toxins, require processing by host proprotein convertases (PCs) to enter host cells and to cause disease. Conversely, inhibiting PCs is likely to protect host cells from multiple furin-dependent, but otherwise unrelated, pathogens. To determine if this concept is correct, we designed specific nanomolar inhibitors of PCs modeled from the extended cleavage motif TPQRERRRKKR downward arrowGL of the avian influenza H5N1 hemagglutinin. We then confirmed the efficacy of the inhibitory peptides in vitro against the fluorescent peptide, anthrax protective antigen (PA83), and influenza hemagglutinin substrates and also in mice in vivo against two unrelated toxins, anthrax and Pseudomonas exotoxin. Peptides with Phe/Tyr at P1' were more selective for furin. Peptides with P1' Thr were potent against multiple PCs. Our strategy of basing the peptide sequence on a furin cleavage motif known for an avian flu virus shows the power of starting inhibitor design with a known substrate. Our results confirm that inhibiting furin-like PCs protects the host from the distinct furin-dependent infections and lay a foundation for novel, host cell-focused therapies against acute diseases.     

Manipulation of the host by pathogens to survive the lysosome

Lysosomes form part of our innate immunity and are an important line of defence against microbes, viruses and parasites. Although it is more than 50?years since de Duve discovered lysosomes, it is only in more recent years that we are slowly unravelling the molecular mechanisms involved in the delivery of material to the lysosome. However, successful intracellular pathogens often have a better grip on the mechanisms involved in delivery to the lysosome and can manipulate membrane trafficking pathways to create an intracellular environment that is favourable for replication. By studying pathogen effector proteins that are secreted into the host's cytosol, we can learn about both pathogen-survival mechanisms and further regulatory elements involved in trafficking to the lysosome.