INSIGHTS | PERSPECTIVES
egress by gametocytes, the sexual parasite
forms transmitted to mosquitos, and prevents processing of the cell traversal protein for ookinetes and sporozoites (CelTOS)
within the ookinete, the parasite form that
infects mosquitos (3). The inhibitor also interferes with egress from hepatocytes during the liver stage, leading to reduced blood
stage infections in vivo (3). SUB1 is required
for this step as well (12, 13). Therefore, notwithstanding the important roles of other
plasmepsins in these life-cycle stages, PMX is
the most probable target, and its inhibition
could provide a way to treat malaria but also
eliminate liver- and mosquito-stage parasites,
reducing the incidence of disease.
The discovery of PMIX and PMX as essential enzymes for invasion and egress could
lead to further exciting discoveries in the malaria field. For example, what are all of the
substrates at each life-cycle stage, and how do
they function? Do sporozoites require these
proteins to invade mosquito salivary glands or
human hepatocytes? Could other substrates
be new drug targets? The identification of
PMIX and PMX as druggable enzymes has
the potential to mean even more for malaria
patients of the future. Aspartyl protease inhibitors have been optimized to treat several
human conditions, including hypertension
and HIV infections, so that the expertise and
large compound libraries available should accelerate antimalarial lead identification. But,
careful consideration must be given to understanding potential mechanisms of resistance.
For example, mutations in HIV-1 aspartyl
protease gave rise to resistant virus strains.
Furthermore, amplification of the PMII and
PMIII genes was recently identified as a new
surrogate marker of piperaquine-resistant
super malaria (14, 15). It will be imperative to
understand whether malaria parasites adapt
to aspartyl protease inhibitors by amplifying
or mutating their PMIX or PMX genes and
whether targeting multiple plasmepsins can
help overcome this. The discovery of PMIX
and PMX as master regulators of egress
and invasion opens the door to new biology and drug discovery in the ongoing
fight against malaria. j
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2. N.V. Thanh et al., Malaria J. 16,27(2017).
3. P. Pino et al. , Science 358, 522 (2017).
4. A. S. Nasamu et al., Science 358, 518 (2017).
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6. C. R. Collins et al ., PLOS Pathog. 13, e1006453 (2017).
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8. N.C.SilmondeMonerri etal.,Infect Immun.79,1086(2011).
9. C. Withers-Martinez et al., Nat. Comm. 5, 3726 (2014).
10. M. Lamarque et al. , PLOS Pathog. 7, e1001276 (2011).
11. J. S. Tyler, J. C. Boothroyd,PLOSPathog. 7, e1001282 (2011).
12. C. Suarez et al ., PLOS Pathog. 9, e1003811 (2013).
13. L. Tawk et al., J. Biol. Chem. 288,33336(2013).
14. R. Amato et al., Lancet Infect. Dis. 17, 164 (2017).
15. B. Witkowski et al., Lancet Infect. Dis. 17, 174 (2017).
By Kelly T. Hughes1 and Howard C. Berg2
Many microbes undergo transforma- tions from planktonic swimmer cells to sessile surface-attached cells. This is the first step in bac- terial biofilm formation. Biofilm- associated microorganisms are
responsible for ~80% of human bacterial
infections according to the U.S. National
Institutes of Heath and are associated with
antibiotic resistance (1). Thus, methods to
disrupt biofilms are actively pursued. Bio-
film formation is initiated by the ability
of bacteria to sense surfaces, resulting in
metabolic responses that allow bacteria to
adhere and colonize the surface. Yet, how
bacteria sense surfaces at the onset of bio-
film formation has remained elusive (2).
Differentiation from swimmer to swarmer
cells in Vibrio parahaemolyticus was shown
to occur simply by increasing the viscosity
of the liquid growth medium (3). This sug-
gested that some kind of mechanosensing
mechanism was involved in surface recog-
nition, but how? On pages 535 and 531 of
this issue, Ellison et al. (4) and Hug et al.
(5), respectively, discover separate mecha-
nisms that allow bacteria to recognize a
surface by mechanosensation and initiate a
cellular response that allows them to attach
Two candidate organelles present in bacteria that could facilitate mechanosensation
are the rotary flagellum and the retractable
Type IV pilus (6–8). Bacteria swim by rotating propellar-like organelles, called flagella,
which extend from the cell surface (9).
Pioneering work on the bacterium V. parahaemolyticus revealed that surface-sensing
results in the differentiation from free-swimming bacteria that use the rotation of
single polar flagellum to elongated bacteria
that produce dozens of lateral flagella that
facilitate surface colonization and spreading (10). Pili, also called fimbriae, are hairlike structures that extend from the cell
surface and are usually associated with surface attachment. However, Type IV pili are
retractable and are used to crawl across surfaces by a process called twitching motility
(11). Inhibition of flagellar rotation or pilus
retraction upon surface contact could contribute to the mechanosensing of surfaces.
Ellison et al. and Hug et al. report separate
mechanosensing mechanisms associated
with surface recognition and induction of
an adherence organelle in Caulobacter crescentus. This bacterium has a long history
as a model system to study fundamental
mechanisms of developmental biology (12).
This is because this organism undergoes a
programmed cell cycle in which a motile,
flagellated swimmer cell differentiates into
a sessile stalked cell, which is glued to surfaces via an exopolysaccharide adhesin, the
holdfast (see the figure). Although holdfast
production is part of a slower developmental program, its production is triggered rapidly when motile cells experience surface
contact. Newborn motile cells are equipped
with a single flagellum and adjacent pili
at one pole of the cell. Although the
Caulobacter pili were known to facilitate surface attachment, whether or not they were
retractable and therefore candidates for
mechanosensing of surfaces, was unclear.
By fluorescently labeling the extracellular
pili, Ellison et al. visualized pilus dynamics
of extension and retraction, which is inhibited on surface contact. The authors demonstrate that this retraction generates a
measurable force. In the absence of surface
contact, blocking pilus retraction is enough
to initiate holdfast synthesis. These authors
The bacterium has landed
Mechanosensing mechanisms for surface recognition
by bacteria allow biofilm formation
Motile bacteria can become sessile cells that adhere
to and colonize a surface.