Perspectives

25 August 2009 Dr. Kristen Kerksiek

Shape Matters: Why bacteria care how they look

Antony van Leeuwenhoek

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In 1683 a particularly curious Dutchman cleaned between his teeth with a toothpick and decided to take a look at the “white matter” underneath his homemade microscope. What Antony van Leeuwenhoek saw and documented was a sensation. In one of the first observations of living bacteria ever recorded, he described at least five different types of tiny “animalcules”: a motile bacillus, a micrococcus and a spirochete as well as curved and thread-like bacteria (most likely Selenomonas sputigena and Leptothrix buccalis, respectively) - a lively mix representing just a few of the 300+ species that call the human mouth home. (Time to floss and brush again?) With his simple microscope, van Leeuwenhoek not only discovered bacteria, he also documented that they can differ greatly in shape.

In the mean time we all know that bacteria come in different shapes. And the bacterial repertoire extends far beyond simple rods (bacilli), spheres (cocci) and spirals (spirochetes). In the 325 years since van Leeuwenhoek opened the field of bacteriology, bacteria with a vast array of bi-zarre and unexpected forms have been discovered: they can be curved, triangular or pointed; they can be shaped like teardrops, lemons, coins or even postage stamps; they can form chains, filaments or clusters; they can grow strange and irregular extensions (to mention just a few pos-sibilities). Yet few scientists have occupied themselves with the question that would seem to logically follow: Why?

Who came first, the rods or the cocci?

If it came down to pure simplicity, we might assume that the first bacterium was a coccus: without any internal structure, a membranous bag suspended in liquid will assume the shape of a sphere. However, phylogenetic studies performed over the last decade indicate that the first bacteria were rod-shaped; cocci appear to be a “dead-end” shape that has simply arisen many times independently.

The Why Question(s)

Why do bacteria have different shapes? Is it an accident or adaptation? A fluke of nature or a se-lective advantage? Are the cell walls just there to hold important stuff together, or does shape have a specific function? It’s a difficult question to address experimentally, but a number of arguments support the view that bacteria take their shape very seriously. For one, although many different bacterial shapes exist, species within the same genus tend to stick to one form – pre-sumably the one that provides the most advantages. On the other hand, prokaryotes occupying entirely different branches of the Tree of Life – Bacteria and Archaea – have evolved very similar morphologies. There must be something special about rods, spheres & Co. that makes these specific shapes so popular in the single-celled world.

van Leeuwenhoek described (and illustrated) his observations of bacteria in a letter sent to the Royal Society of London in September, 1683.

Why does a particular bacterium have a specific shape? What selective advantages do different bacterial forms offer? Only recently have bacteriologists started probing their favorite bugs for answers to this question. One of the researchers leading the inquisition is Kevin Young from the University of Arkansas for Medical Sciences. “Most of us have spent many years working on bacteria without ever thinking of why they have shapes,” says Young. “The idea of shape as something useful and important (at least in bacteria) is just beginning to take flight as a scientific specialty.”

The answer will be complex. Bacterial morphology is affected by a combination of selective pressures - access to nutrients, cell division, attachment/dispersal, predation and motility (among others). Among these different factors, our understanding of the relationship between motility and cell shape is most complete; for example, highly motile bacteria are usually rods with a spe-cific (optimal) shape and size, and movement through viscous fluids seems to a favor spiral shape. But since multiple selective forces are always in play, there is – at the moment – no way to predict cell shape based on the environment or vice versa.

The How Question

Localization of the homologues of tubulin (FtsZ), actin (MreB) and intermediate filaments (Cres) as detected in Caulobac-ter crescentus. © Tim Vickers

A meshwork of peptidoglycan (also known as murein) forms the cell wall of nearly all bacteria. It keeps the bacte-rial innards in place, resisting osmotic pressure to prevent rupture and influencing cell shape. But since the structure of peptidoglycan is similar in bacteria with vastly different forms, it can’t be the determining force in bacterial mor-phology. How do bacteria keep a specific shape?

There must be a scaffold of sorts to support the peptidogly-can shell, and researchers are finding that recently de-scribed components of a prokaryotic cytoskeleton serve exactly this function. For example, the actin homologue MreB, which is found in almost all non-spherical bacteria, controls cell diameter and rod morphology by a mecha-nism that seems to involve control of the enzymes that syn-thesize and organize peptidoglycan. FtsZ, a tubulin homo-logue responsible for cell division, may also be involved in shaping cells by managing peptidoglycan-synthesizing en-zymes. Another cytoskeletal homologue – crescentin (CreS), the prokaryotic version of intermediate filaments – is the difference between run-of-the-mill rods and crescent-shaped cells. (For more information about the How of bac-terial shape, check out the reviews by Matthew Cabeen and Christine Jacobs-Wagner, Kevin Young (Bacterial Shape) and Zemer Gital listed below).

Masters of change

Legionella pneumophila, a causative agent of Legionnaires’ disease, can take on different shapes (here singular, paired and filamentous in red) © CDC

We tend to think of bacteria as having fixed morphologies. We even name them after their shape (e.g. Streptococcus). But environments aren’t static, and neither is bacterial shape. Some bacteria – including a number of human pathogens – change their form dramatically as the go through different development pathways. For example at least eight different morphological forms are adopted by Legionella pneumophila during its developmental cycle. Helicobacter pylori is usually identified as short spiral rods but can appear as corkscrews (filaments) in biopsy specimens. And an impressive study of uropathogenic Escherichia coli identified four distinct morphological forms as the bacteria infected bladder epithelial cells: nonmotile rods, cocci, motile rods and filaments.

Does shape change have anything to do with pathogenesis? For fungi we know it does. Most pathogenic fungi are dimorphic, with yeast and hyphal (filamentous) stages, and only one form is pathogenic. The study of bacterial morphology and virulence is still in its infancy, but at least for E. coli shape change seems to play a central role during infection.

E.coli are usually rods ~2 micrometer in length. Uropathogenic strains (causing urinary tract infections) can form filaments that reach a length of 70 m. © HZI

The role of filamentation in bacterial survival is drawing particular attention. Filaments form when bacteria continue to grow but don’t divide, and they can reach lengths 10–50 times that of the corresponding rods. E. coli filaments – like the filamentous (hyphal) form of the fungus Candida albicans - are resistant to phagocytosis, enabling the bacteria to persist. Filamentous forms of other pathogenic bacteria - Haemophilus influenzae, Legionella pneumophila, Mycobacterium tuberculosis and Salmonella enterica among others - have also been observed and may be associated with increased survival. And filamentation of Burkholderia pseudomallei (the causative agent of melioidosis) results in resistance to antibiotics at a concentration that kills the bacillary form.

Shape – and shape change – seem to be a key part of the survival strategy of many pathogenic bacteria. It’s a factor that hasn’t been considered in studies of bacterial pathogenesis but may be of crucial importance for the understanding of – and treatment of – bacterial diseases. For treatment of C. albicans, an opportunistic pathogen that is increasingly resistant to standard antifungal therapies, anti-filamentation agents are already being developed. Drugs targeting fila-mentation might also be an alternative therapeutic strategy for bacterial infections. As the effectiveness of standard antibiotics continues to wane and the search for new antimicrobials becomes more critical, it may pay to remember bacterial shape: they take it very seriously, and we just may be able to use that against them.

References and additional reading:

A website with extensive information – and documentation – about Antony van Leeuwenhoek:
www.euronet.nl/users/warnar/leeuwenhoek.html

A concise review for an overview of the field:

Young, K.D. Bacterial morphology: why have different shapes? Curr. Opin. Microbiol. (2007) 10: 596–600. doi:10.1016/j.mib.2007.09.009.  dx.doi.org/10.1016/j.mib.2007.09.009 Free article at PubMed Central http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17981076

A comprehensive (but very readable) review covering various selective pressures:

Young, K.D. The selective value of bacterial shape. Microbiol. Mol. Biol. Rev. (2006) 660–703. doi:10.1128/MMBR.00001-06 http://dx.doi.org/10.1128/MMBR.00001-06 (free full text)

Reviews focusing on the how question of bacterial shape:

Cabeen, M.T. and Jacobs-Wagner, C. Skin and bones: the bacterial cytoskeleton, cell wall, and cell morphogenesis. J. Cell. Biol. (2007) 179: 381–387. doi: 10.1083/jcb.200708001  http://dx.doi.org/10.1083/jcb.200708001 (free full text)

Gitai, Z. The new bacterial cell biology: Moving parts and subcellular architecture. Cell (2005) 120: 577–586. doi: 10.1016/j.cell.2005.02.026 http://dx.doi.org/10.1016/j.cell.2005.02.026

Young, K.D. Bacterial shape. Mol. Microbiol. (2003) 49: 571–580. free full text  http://www3.interscience.wiley.com/journal/118845516/abstract (Erratum in: Mol Microbiol. 2003 50: 723. free full text http://www3.interscience.wiley.com/cgi-bin/fulltext/118845645/HTMLSTART)

A discussion of the role of stress-induced filamentation in bacterial survival:

Justice, S.S., Hunstad, D.A., Cegelski, L. and Hultgren, S.J. Morphological plasticity as a bacterial survival strategy. Nat. Rev. Microbiol. (2008) 6: 162–168. doi:10.1038/nrmicro1820   http://dx.doi.org/10.1038/nrmicro1820

Research articles:

Justice, S.S. et al. Differentiation and developmental pathways of uropathogenic Escherichia coli in urinary tract pathogenesis. Proc. Nat. Acad. Sci. USA (2004) 5: 1333–1338. doi:10.1073/pnas.0308125100  http://dx.doi.org/10.1073/pnas.0308125100   (free full text)

Chen, K. et al. Modified virulence of antibiotic-induced Burkholderia pseudomallei filaments. Antimicrob. Agents Chemother. (2005) 49: 1002–1009.  doi:10.1128/AAC.49.3.1002-1009.2005  http://dx.doi.org/10.1128/AAC.49.3.1002-1009.2005   (free full text)

Saville, S.P. et al. Inhibition of filamentation can be used to treat disseminated candidiasis. Antimicrob. Agents Chemother. (2006) 50: 3312–3316.  doi:10.1128/AAC.49.3.1002-1009.2005  http://dx.doi.org/10.1128/AAC.49.3.1002-1009.2005 (free full text)

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