Trends in Microbiology
Volume 13, Issue 3, March 2005, Pages 103-110
Journal home page for Trends in Microbiology

Cyclomodulins: bacterial effectors that modulate the eukaryotic cell cycle

https://doi.org/10.1016/j.tim.2005.01.002Get rights and content

Microbial pathogens have developed a variety of strategies to manipulate host-cell functions, presumably for their own benefit. We propose the term ‘cyclomodulins’ to describe the growing family of bacterial toxins and effectors that interfere with the eukaryotic cell cycle. Inhibitory cyclomodulins, such as cytolethal distending toxins (CDTs) and the cycle inhibiting factor (Cif), block mitosis and might constitute powerful weapons for immune evasion by inhibiting clonal expansion of lymphocytes. Cell-cycle inhibitors might also impair epithelial-barrier integrity, allowing the entry of pathogenic bacteria into the body or prolonging their local existence by blocking the shedding of epithelia. Conversely, cyclomodulins that promote cellular proliferation, such as the cytotoxic necrotizing factor (CNF), exemplify another subversion mechanism by interfering with pathways of cell differentiation and development. The role of these cyclomodulins in bacterial virulence and carcinogenesis awaits further study and will delineate new perspectives in basic research and therapeutic applications.

Introduction

Many pathogens, when infecting a host, manipulate its signal-transduction pathways to survive. With progress in our understanding of the molecular mechanisms that bacteria use to attach to, enter into, move within and multiply inside host cells, it came to light that microbial pathogens have developed sophisticated mechanisms to block or subvert normal host-cellular processes, thereby contributing to colonization and pathogenesis. Many pathogenic bacteria adhere to and subsequently invade host cells by injecting their own proteins (which often mimic eukaryotic cell ligands) into host cells to target the cytoskeleton and various signal-transduction pathways. Manipulation of host-cell components, such as Rho GTPases, induces membrane ruffling and enables bacterial invasion. Pathogens that remain within a vacuole after bacterial invasion can control host-cell vesicular transport and endocytosis. Other pathogens can prevent their own uptake by phagocytic cells and/or kill them by triggering host-programmed cell death. Thus, there are several examples showing how bacterial pathogens hijack essential host functions, such as cytoskeleton assembly and apoptosis control (reviewed in Ref. [1]). However, until recently, little attention has been paid to emerging evidence that bacteria also have virulence mechanisms that target the cell cycle. Similar to the many viruses that perturb cell-cycle cellular machinery to suit their replication scheme [2], a growing number of pathogenic bacteria are also able to interfere actively with the host cell cycle. We propose the use of the term ‘cyclomodulins’ to describe this growing family of bacterial molecules that modulate the eukaryotic cell cycle. In this review, we describe the prominent members of the cyclomodulins, discuss their putative role in the natural history of disease and their potential implication in the cause of cancer.

Section snippets

Cytolethal distending toxin: a paradigm for cyclomodulins?

Cytolethal distending toxin (CDT) is the first bacterial toxin to be shown to block the host cell cycle at the transition between the G2 [preparation stage between the S (synthesis) phase and the M (mitosis) phase] and M phases [3] (Figure 1). Several pathogenic bacteria produce CDT, including Escherichia coli, Shigella dysenteriae, Campylobacter spp., Salmonella typhi, Haemophilus ducreyi, enterohepatic Helicobacter species (i.e. Helicobacter hepaticus) and Actinobacillus actinomycetemcomitans

Cyclomodulins promoting cellular proliferation

Infections caused by several bacteria (e.g. Helicobacter pylori, Bartonella spp., Lawsonia intracellularis and Citrobacter rodentium) can induce cellular proliferation, and in the case of H. pylori this has been associated with the development of cancer [33]. Several bacterial products are known to stimulate the proliferation of eukaryotic cells (Table 1). These include Pasteurella multocida toxin (PMT), the cytotoxic necrotizing factors (CNFs) from E. coli (Figure 3) and the dermonecrotic

Putative role of cyclomodulins in bacterial virulence

What could the advantage be for a bacterial pathogen to interfere with the host cell cycle? A bona fide cyclomodulin inhibiting cellular proliferation probably exerts its effect on cells that normally undergo continuous replication, such as the intestinal epithelium, which goes through perpetual regeneration, fuelled by a population of multipotent stem cells located at the base of the crypts of Lieberkuhn or those associated with the immune system. By inducing cell-cycle arrest, these

Potential role of cyclomodulins in cancer

Several cyclomodulins have been shown to play a role in the virulence of different pathogenic bacteria but the main target might not be the host cell cycle as tested in the ‘classical’ infection models used to study the virulence of bacterial pathogens. Conversely, chronic infection with bacteria that perturb cell-signalling processes is highly likely to contribute to cell transformation by facilitating an anti-apoptotic proliferative state or genotoxic activity that encourages tumour

Concluding remarks

The emerging concept reviewed here is still in its infancy and many questions will have to be answered to begin to understand how bacteria can manipulate host key processes that control eukaryotic cell growth. Is the production of cyclomodulins common among bacteria? What evolutionary advantage can bacteria gain from the production of cyclomodulins? What is their role in disease, in cancer causation and progression? Do commensal bacteria produce cyclomodulins, and could these interfere with

Acknowledgements

Work done in our laboratory was supported by grants from the European Union Fifth Framework Quality of Life Program (QLK2–2000–00600 and QLK2-CT-2002–00944). We apologize to authors whose studies were not included as a result of space limitation.

References (62)

  • C. Fiorentini

    Toxin-induced activation of Rho GTP-binding protein increases Bcl-2 expression and influences mitochondrial homeostasis

    Exp. Cell Res.

    (1998)
  • A. Doye

    CNF1 exploits the ubiquitin-proteasome machinery to restrict Rho GTPase activation for bacterial host cell invasion

    Cell

    (2002)
  • B.A. Wilson

    Pasteurella multocida toxin activates the inositol triphosphate signaling pathway in Xenopus oocytes via G(q)alpha-coupled phospholipase C-beta1

    J. Biol. Chem.

    (1997)
  • A. Zywietz

    Pleiotropic effects of Pasteurella multocida toxin are mediated by Gq-dependent and -independent mechanisms. involvement of Gq but not G11

    J. Biol. Chem.

    (2001)
  • H.M. Lacerda

    Pasteurella multocida toxin, a potent intracellularly acting mitogen, induces p125FAK and paxillin tyrosine phosphorylation, actin stress fiber formation, and focal contact assembly in Swiss 3T3 cells

    J. Biol. Chem.

    (1996)
  • A. De Luca et al.

    Helicobacter pylori and gastric diseases: a dangerous association

    Cancer Lett.

    (2004)
  • A.J. Lax

    The Pasteurella multocida toxin interacts with signalling pathways to perturb cell growth and differentiation

    Int. J. Med. Microbiol.

    (2004)
  • L.A. Knodler

    Pathogenic trickery: deception of host cell processes

    Nat. Rev. Mol. Cell Biol.

    (2001)
  • L.M. Schang

    The cell cycle, cyclin-dependent kinases, and viral infections: new horizons and unexpected connections

    Prog. Cell Cycle Res.

    (2003)
  • S.Y. Peres

    A new cytolethal distending toxin (CDT) from Escherichia coli producing CNF2 blocks HeLa cell division in G2/M phase

    Mol. Microbiol.

    (1997)
  • M. Lara-Tejero et al.

    CdtA, CdtB, and CdtC form a tripartite complex that is required for cytolethal distending toxin activity

    Infect. Immun.

    (2001)
  • R.B. Lee

    Interactions of Campylobacter jejuni Cytolethal Distending Toxin Subunits CdtA and CdtC with HeLa Cells

    Infect. Immun.

    (2003)
  • E. Haghjoo et al.

    Salmonella typhi encodes a functional cytolethal distending toxin that is delivered into host cells by a bacterial-internalization pathway

    Proc. Natl. Acad. Sci. U. S. A.

    (2004)
  • D. Nesic

    Assembly and function of a bacterial genotoxin

    Nature

    (2004)
  • M. Lara-Tejero et al.

    A bacterial toxin that controls cell cycle progression as a deoxyribonuclease I-like protein

    Science

    (2000)
  • C.A. Elwell et al.

    DNase I homologous residues in CdtB are critical for cytolethal distending toxin-mediated cell cycle arrest

    Mol. Microbiol.

    (2000)
  • X. Cortes-Bratti

    Cellular internalization of cytolethal distending toxin from Haemophilus ducreyi

    Infect. Immun.

    (2000)
  • L. Li

    The Haemophilus ducreyi cytolethal distending toxin activates sensors of DNA damage and repair complexes in proliferating and non-proliferating cells

    Cell. Microbiol.

    (2002)
  • D.C. Hassane

    Campylobacter jejuni cytolethal distending toxin promotes DNA repair responses in normal human cells

    Infect. Immun.

    (2003)
  • T. Frisan

    The Haemophilus ducreyi cytolethal distending toxin induces DNA double-strand breaks and promotes ATM-dependent activation of RhoA

    Cell. Microbiol.

    (2003)
  • C. Elwell

    Escherichia coli CdtB mediates cytolethal distending toxin cell cycle arrest

    Infect. Immun.

    (2001)
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