Sasakawa 2010
Sasakawa 2010
Sasakawa 2010
B 86 (2010) 229
Review
A new paradigm of bacteria-gut interplay
brought through the study of Shigella
By Chihiro SASAKAWA1,†
Abstract: Bacteria-gut epithelial interplay and the mucosal immune response are the most
critical issues in determining the fate of bacterial infection and the severity of diseases. Shigella
species (abbreviated here as Shigella), the causative agent of bacillary dysentery (shigellosis), are
highly adapted human pathogens that are capable of invading and colonizing the intestinal epithe-
lium, which results in severe inammatory colitis. Shigella secrete a large and diverse number
(more then 50) of eectors via the type III secretion system (TTSS) during infection, some of which
are delivered into the surrounding bacterial space and some others into the host cell cytoplasm and
nucleus. The delivered eectors mimic and usurp the host cellular functions, and modulate host cell
signaling and immune response, thus playing pivotal roles in promoting bacterial infection and cir-
cumventing host defense systems. This article overviews the pathogenic characteristics of Shigella,
and highlights current topics related to the bacterial infectious stratagem executed by the TTSS-
secreted eectors. Though bacterial stratagems and the molecular mechanisms of infection vary
greatly among pathogens, the current studies of Shigella provide a paradigm shift in bacterial
pathogenesis.
doi: 10.2183/pjab.86.229
62010 The Japan Academy
230 C. SASAKAWA [Vol. 86,
Fig. 2. A model for Shigella infection of intestinal epithelium. See the text for details.
the M cell pocket receive the exocytosed bacteria and pattern-recognition receptors (PRRs) that recognize
antigens from the M cells, digest them, and present pathogen-associated molecular patterns (PAMPs)
the immunogenic information to activate the down- derived from intracellular invading bacteria. Within
stream immune system. However, Shigella invade the macrophage-cell cytoplasm, invading bacteria
the resident macrophages by themselves, where they release the lipopolysaccharide (LPS), peptidoglycan
are at once surrounded by phagocytic membranes, (PGN), agellin, nucleic acids, toxins, and some viru-
but can disrupt the membranes, disseminate into lence-associated proteins (called eectors hereafter)
the cytoplasm, and multiply therein (Fig. 2). As will secreted via the TTSS, which are recognized by the
be described later, the bacterial multiplication within cytoplasmic PRRs, such as NOD (nucleotide binding
the macrophages results in the induction of a strong oligomerization domain)-like receptors (NLRs).1),2),8)
inammatory response, and then macrophage cell Upon detection of various PAMPs (and also bacte-
death. Following their release from killed macro- rial eectors and toxins) and dangerous host signals,
phages, Shigella invade the surrounding enterocytes NLRs form high molecular complexes, called ina-
from the basolateral surface of the polarized epithe- mmasomes, and recruit and activate caspase-1,
lial cells by inducing macropinocytosis. Shigella are which in turn proteolytically processes pro-IL-1b
entrapped by the membrane vacuoles within epithe- and IL-18.2) For example, upon invasion of macro-
lial cells, but they can rupture the vacuole mem- phages by Shigella, NLRC4 (IPAF)-inammasome
branes and disseminate into the epithelial-cell cyto- executes the activation of caspase-1, thus inducing
plasm, where Shigella multiply and spread within, as the production and secretion of IL-1b and IL-18,
well as, into the adjacent epithelial cells (Fig. 2). By and resulting in macrophage cell death specialized
continuing cell-to-cell spreading, they are able to pyroptosis.9),10) Pyroptosis is a class of cell death dis-
expand the replicative niches among enterocytes tinctive from the silent apoptotic cell death, which
(Fig. 2).1),2),7),8) is occasionally associated with a high inammatory
condition and dependent on caspase-1 activation.11)
4. Host innate immune response to
The pyroptosis cell death has been best studied in
bacterial infection
the context of Shigella infection of macrophages
Bacterial invasion of the host cell cytoplasm is through our study.10) The activation of IPAF-
recognized by various innate immune systems, thus inammasome by Shigella is thus the major cause of
leading to a strong inammatory response, and oc- inammation and macrophage cell death at the ini-
casionally cell death. Macrophages express various tial stage of infection.8)–10)
232 C. SASAKAWA [Vol. 86,
Fig. 3. A model for Shigella-induced inammatory response in epithelial cells and the bacterial down-regulation of the host
inammatory signals. During the multiplication of Shigella in epithelial cells, the peptidoglycan (PGN), including lipopolysac-
charide (LPS), released from bacteria, can be recognized by the NOD1, which activates the downstream RICK and MAPK-
mediated signal pathways, thus leading to the production of inammatory chemokines, cytokines, and anti-microbial peptides.
Intracellular Shigella delivers a subset of eectors, including IpaHs, OspF, and OspG via the TTSS, into the host cell cyto-
plasm and nucleus, enabling the eectors to target the host signaling pathways or factors involved in the inammatory
responses and dampen the inammatory responses.
Infection of the intestinal epithelium by Shigella bacterial entry site by moving from the cytoplasm
also plays a major role in inducing inammation, to the plasma membrane, thus facilitating NOD1 to
since the intestinal epithelium also expresses a wide sensitize PGN.12) In addition, NLRX1, which is a
range of PRRs over and inside the cells, thus acting newly identied cytoplasmic NLR family protein
as sensing cells toward cytoplasmic intruding mi- that is localized in the mitochondria via its N-termi-
crobes as well as becoming a major cause for in- nal mitochondrial targeting sequence, can also sense
duction of inammation during bacterial infection. intruding Shigella and stimulate the production of
Upon multiplication of Shigella within epithelial reactive oxygen species.13) Another study indicated
cells, the PGN released from bacteria is recognized that Shigella induce mitochondrial dysfunction, re-
by NOD1, a prominent NLR expressed from epithe- sulting in caspase-independent necrotic cell death
lial cells, which in turn stimulates the NOD1-RICK through a new pathway depending on Bnip3 and cy-
pathway. The NOD1-RICK pathway in turn medi- clophilin D, two key regulators of mitochondrial per-
ates the activation of downstream NF-kB and mito- meability transition and cell death during oxidative
gen-activated protein kinases pathways, thus leading cell stress in epithelial cells.14) Therefore, bacterial
to the production and secretion of a tremendous multiplication within intestinal epithelial cells that
amount of proinammatory chemokine and cyto- is recognized by various innate immune systems
kines, and anti-microbial peptides (Fig 3).1),2) A re- can lead to an inammatory response and necrotic
cent study indicated that NOD1 is recruited to the epithelial-cell death.
No. 3] Shigella infection of intestinal epithelium and circumvention 233
Fig. 4. A model of Shigella invasive mechanism for epithelial cells. Upon contact of Shigella to epithelial cells, the bacterium
delivers several eectors (red circles) via the TTSS around the bacterial surface and into the host-cell cytoplasm. The bacterial
eectors interact with the host target molecules to stimulate several signal transduction pathways capable of activating the
Rac1-WAVE-Arp2/3 pathway, and induce local actin polymerization and protrude the membrane rufes. See the text for
details.
are also capable of inducing actin polymerization and forward within the cytoplasm (Fig. 5). Finally,
moving within as well as into adjacent cells.22),23) motile bacterium impinges on the host plasma mem-
The bacterial intracellular movement is thus called brane, causing the membrane to protrude (Fig. 2).
‘actin-based motility’. Intriguingly, to gain a propul- The tips of these bacteria-containing protrusions are
sive force within the host cells, the pathogens share a endocytosed by neighboring epithelial cells, leaving
universal activity to induce local actin polymeriza- the bacterium transiently contained within double
tion by exploiting the host Arp2/3 complex, which host plasma membrane-bound vacuoles (Fig. 2). The
directly executes actin polymerization within mam- bacterium then disrupts the protrusion vacuoles,
malian cells.22),23) In the case of Shigella, bacterium thereby disseminating into the new cytoplasm and
accumulates the VirG protein at one pole of the bac- multiply again (Figs. 2 and 5).
terium during multiplication, and the VirG protein In addition to the bacterial activity to induce
recruits N-WASP (neural Wiskott-Aldrich syndrome actin polymerization, Shigella require the activity to
protein), a member of the WASP family.24),25) The destroy the microtubules (MTs) during movement,
N-WASP is subsequently activated by interacting since the MT networks become obstacles for motile
with Cdc42 and Toca-1, where N-WASP acts as the bacterium. Indeed, the bacterial movement within
adapter as well as the stimulator to interact with and the cytoplasm is severely hindered by areas rich
activate the Arp2/3 complex (Fig. 5).25),26) By virtue with MT network structures.27) Nevertheless, motile
of some additional host proteins such as monomeric Shigella can destroy the surrounding MTs; a process
actin and prolin, the activated Arp2/3 complex executed by the VirA eector secreted via the TTSS
can direct actin polymerization at one pole of the to the surrounding bacterial surface.28) Conversely,
bacterium, thus allowing the bacterium to be pushed smooth bacterial movement within host cells and dis-
No. 3] Shigella infection of intestinal epithelium and circumvention 235
Fig. 6. Autophagy aects the fate of bacterial colonization within host cells. Shigella, L. monocytogenes, and Burkholderia
pseudomallei are capable of escaping from autophagy by exploiting the activities of IcsB, ActA, and BopA, respectively.
Group A Streptoccus (GAS) internalized into the host cytoplasm is apprehended by autophagosomes and undergoes lysosomal
degradation. M. tuberculosis, L. pneumophila, Brucella abortus, and Coxiella brunetti are sequestered by autophagosome-like
membranes and undergo lysosomal degradation, if they cannot modulate the autophagy activity in macrophages.
Fig. 7. A model of Shigella evasion of autophagy (upper panel), and the strategy used by intracellular Shigella to escape from
autophagy (lower panel). Shigella are capable of multiplying within the cytoplasm of epithelial cells and moving into adjacent
epithelial cells. However, Shigella lacking the icsB gene, which encodes the IcsB eector, and acts as an anti-Atg5 binding fac-
tor for VirG, succumbs to autophagy and undergo lysosomal degradation. The upper right panel shows the VirG protein at
one pole of bacterium, which is required for the actin-based bacterial motility.
evading autophagy to that of Shigella. We recently progenitors. The intestinal epithelium is formed by
uncovered that the L. monocytogenes ActA protein a tight-sealed monolayer but exists in a highly dy-
plays a central role in evading autophagic recogni- namic state by renewing every 4{5 days; the epithe-
tion (Fig. 8). The ActA proteins are expressed on lial cells created by the stem cells at the bottom of
the bacterial surface, which also accumulates at one crypts migrate up to the villus tips, undergoing pro-
pole of the bacterium and mediates actin polymeriza- liferation, dierentiation, maturation, and apoptosis,
tion by directly linking to the host proteins such as and then shed into the lumen.38) This renewal is also
the Arp2/3 complex and VASP/Ena. Several assays called epithelial turnover, which is crucial for limit-
demonstrate that the ability of ActA to recruit the ing bacterial colonization. Nevertheless, many bacte-
Arp2/3 complex or VASP/Ena, which is required rial pathogens are able to colonize intestinal mucosa,
for inducing actin polymerization and bacterial mo- implying that they have some maneuver to circum-
tility, is also essential for disguising the bacteria vent the innate defense system.
with the host protein, since the bacterial surface is 7.1. Shigella slow down rapid turnover of
decorated with the host proteins, the Arp2/3 com- epithelium. We have recently discovered that
plex or VASP/Ena, the surface becomes camouaged some bacterial pathogens such as Shigella and Heli-
from autophagic recognition (Fig. 8).37) Our ndings cobactor pylori possess the activity to dampen rapid
corroborate that Shigella and L. monocytogenes ex- turnover of epithelial cells, which contribute to the
ploit distinctive systems for evading autophagy. promotion of bacterial colonization.39),40) Shigella
have the ability to slow down the cell cycle progres-
7. Prolonging of epithelial-cell life
sion of epithelial progenitors, by which they can pro-
span by bacteria
long colonization within the intestinal epithelial
Self-renewal of tissues like skin, stomach, and cells.39) This bacterial activity can be executed by
intestine, are the essential innate activity for pre- IpaB, one of the eectors, secreted via the TTSS
serving tissue homeostasis, which is supported by from intracellular Shigella into intestinal progenitor
providing the regenerative potential via supplying cells at the crypts. A rabbit ileal loop assay infected
238 C. SASAKAWA [Vol. 86,
Fig. 8. A model of L. monocytogenes escaping from autophagy recognition. L. monocytogenes disrupts the membrane enclosing
bacterium by secreting LLO (Listeriolysin O), the pore-forming toxin, and disseminates into the host cell cytoplasm. During
multiplication within the cytoplasm, L. monocytogenes expresses ActA over the bacterial surface, which recruits the Arp2/3
complex, Ena/VASP, and actin, thus disguising the bacterium against autophagic recognition, and allowing the bacterium to
mediate actin polymerization and move within the host cells as well as into the neighboring cells. However, L. monocytogenes
lacking ActA or expressing ActA mutants decient in recruiting any of the host proteins become target for autophagic clear-
ance, because the bacterium is ubiquitinated, which is followed by binding with p62 and LC3, thus allowing the bacterium to
be apprehended by autophagosomes.37)
with Shigella demonstrated that bacteria allow direct tion with Mad2L2. Synchronized HeLa cells infected
access to the intestinal crypts at the middle stage of with Shigella fail to accumulate APC substrates,
infection, where bacteria invade the non-polarized such as Cyclin B1, Cdc20, and Plk1, causing cell
progenitor cells.39) At this stage, while few PCNA cycle arrest at the G2/M phase in an IpaB/Mad2L2-
(proliferation cell nuclear antigen, representing grow- dependent manner. The IpaB/Mad2L2-dependent
ing progenitor cells)-positive cells are detected in the cell cycle arrest by Shigella infection can be visual-
crypts after wild-type Shigella infection, abundant ized in the intestinal crypt progenitors of rabbit ileal
progenitor cells are detected after infection with the loops, and the IpaB-Mad2L2-mediated arrest con-
ipaB mutant (Fig. 9). An in vitro study also indi- tributes to the efcient colonization of the host cells
cated that IpaB secreted from intracellular Shigella (Fig. 9).39) Recent studies have indicated that a
into epithelial cells causes cell cycle arrest by target- growing family of bacterial small compounds, toxins,
ing Mad2L2, an anaphase-promoting complex (APC) and eectors are capable of modulating the mamma-
inhibitor. The APC is a multi-subunit complex pos- lian cell cycle, called ‘cyclomodulins’, though the tar-
sessing E3 ligase activity for the degradation of mi- get host cells for each cyclomodulin remains largely
totic Cyclin A and Cyclin B1 during mitosis and G1 speculative.41) Accordingly, our study indicates that
phases, allowing mitotic progression.39) Cyclin B1 Shigella IpaB, which targets the Mad2L2 associated
ubiquitination assays showed that APC undergoes with APC, can act as a cyclomodulin in promoting
unscheduled activation in response to IpaB interac- colonization of the intestinal epithelium.
No. 3] Shigella infection of intestinal epithelium and circumvention 239
Fig. 11. A model of Shigella strategy to antagonize the detachment of infected epithelial cells by delivering the OspE eectors.
See the text for details.
terchangeable with Shigella OspE. Therefore, the into understanding highly evolved bacterial infec-
hitherto unknown bacterial activity, driven from the tious systems. As exemplied in this article, the re-
interplay between OspE and ILK to counteract infec- cent development of a variety of areas related to
tion-induced cell detachment, represents the pivotal innate immunity, cell biology, protein structure biol-
bacterial activity required for promoting colonization ogy, bioinformatics, and animal model development
of the intestine (Fig. 11). enable us to manipulate both the determinants of
Although bacterial strategies vary greatly, simi- host defense and bacterial virulence, thus providing
lar mechanisms that prevent cell detachment were us the opportunity to uncover new infectious aspects.
also identied in UPEC, Neisseria gonorrhoeae, Furthermore, by taking a multidisciplinary approach
Neisseria meningitides, Haemophilus inuenzae, and and taking advantage of the new technologies we are
Moraxella catarrhalis.46),47) Therefore, the bacterial now able to dissect almost any class of virulence-
strategy to reinforce host cell adherence to extracel- associated factors and evaluate the impact of each
lular matrices may be a universal countermeasure bacterial and host cellular factor on the pathogenesis
against host cell detachment that occurs in response and the outcome of infectious diseases. Clearly, the
to bacterial infection of epithelial cells. The ndings molecular and cellular details about bacterial patho-
in our recent studies thus add new information that genesis will also provide us lots of clues and ideas
expands the complexity of our knowledge on how for the development of a safer, well-attenuated
bacteria employ strategies to preserve their replica- vaccine48)–50) and new animal models.51)
tive niches during infection.
9. Acknowledgements
8. Conclusion The author sincerely thanks Prof. Tamio Yama-
Bacteria-host interplay and the host immune re- kawa, the Editor-in-Chief for the Proceedings of the
sponse are the most critical aspects in determining Japan Academy Series B, for the invitation to the
the fate of infection, severity of diseases, and conva- journal. The author thanks Drs. Hitomi Mimuro,
lescent outcome. As illustrated in the present and Michinaga Ogawa, Minsoo Kim, Masato Suzuki and
current excellent reviews, in-depth studies of bacte- Yuko Yoshikawa for preparing gures. The author also
rial pathogenesis have provided a new paradigm shift thanks the members of my laboratory for their con-
of bacteria-host interplay and also many insights tributions, as well as, the contributions of my colla-
No. 3] Shigella infection of intestinal epithelium and circumvention 241
borators to the studies highlighted in this review. 12) Kufer, T.A., Kremmer, E., Adam, A.C., Philpott,
This work was supported by a Grant-in-Aid for D.J. and Sansonetti, P.J. (2007) The pattern-
recognition molecule Nod1 is localized at the
Scientic Research (S) (20229006); a Grant-in-Aid plasma membrane at sites of bacterial interaction.
for Exploratory Research (20659067); a Grant-in-Aid Cell. Microbiol. 10, 477{486.
for Scientic Research on Priority Areas (18073003); 13) Tattoli, I., Carneiro, L.A., Jehanno, M., Magalhaes,
the Strategic Cooperation to Control Emerging and J.G., Shu, Y., Philpott, D.J. et al. (2008) NLRX1
is a mitochondrial NOD-like receptor that amplies
Reemerging Infections funded by the Special Co- NF-kB and JNK pathways by inducing reactive
ordination Funds for Promoting Science and Tech- oxygen species production. EMBO Rep. 9, 293{
nology; a contract research fund for the Program of 300.
Founding Research Centers for Emerging and Re- 14) Carneiro, L.A., Travassos, L.H., Soares, F., Tattoli,
I., Magalhaes, J.G., Bozza, M.T. et al. (2009) Shi-
emerging Infectious Diseases from the Ministry of gella induces mitochondrial dysfunction and cell
Education, Culture, Sports, Science, and Technology death in nonmyleoid cells. Cell. Host. Microbe. 5,
(MEXT); and the Core Research for Evolutional 123{136.
Science and Technology (CREST) from the Japan 15) Ohya, K., Handa, Y., Ogawa, M., Suzuki, M. and
Sasakawa, C. (2005) IpgB1 is a novel Shigella
Science and Technology Agency (JST). eector protein involved in bacterial invasion of
host cells: its activity to promote membrane rung
References via Rac1 and Cdc42 activation. J. Biol. Chem.
1) Ogawa, M., Handa, Y., Ashida, H., Suzuki, M. and 280, 24022{24034.
Sasakawa, C. (2008) The versatility of Shigella 16) Handa, Y., Suzuki, M., Ohya, K., Iwai, H., Ishijima,
eectors. Nat. Rev. Microbiol. 6, 11{16. N., Koleske, A.J. et al. (2007) Shigella IpgB1 pro-
2) Ashida, H., Ogawa, M., Mimuro, H. and Sasakawa, motes bacterial entry through the ELMO-Dock180
C. (2009) Shigella infection of intestinal epithelium machinery. Nat. Cell. Biol. 9, 121{128.
and circumvention of the host innate defense sys- 17) Huang, Z., Sutton, S.E., Wallenfang, A.J., Orchard,
tem. Curr. Top. Microbiol. Immunol. 337, 231{ R.C., Wu, X., Feng, Y. et al. (2009) Structure
255. insights into host GTPase isoform selection by a
3) Shiga, K. (1898) Ueber den errenger der dysenterie family of bacterial GEF mimics. Nat. Strct. Mol.
in Japan. Zent. Bakteriol. Microbiol. Hyg. 23, Biol. 16, 853{860.
599{600. 18) Ogawa, H., Nakamura, A. and Nakaya, R. (1968)
4) Trofa, A.F., Ueno-Olsen, H., Oiwa, R. and Yoshi- Cinemicroscopic study of tissue cell cultures in-
kawa, M. (1999) Dr. Kiyoshi Shiga: discovery fected with Shigella exneri. Jpn. J. Med. Sci.
of the dysentery bacillus. Clin. Infect. Dis. 29, Biol. 21, 259{273.
1303{1306. 19) Makino, S., Sasakawa, C., Kamata, K., Kurata, T.
5) DuPont, H.L., Levine, M.M., Hornick, R.B. and For- and Yoshikawa, M. (1986) A genetic determinant
mal, S.B. (1989) Inoculum size in shigellosis and required for continuous reinfection of adjacent
implications for expected mode of transmission. J. cells on large plasmid in S. exneri 2a. Cell 46,
Infect. Dis. 159, 1126{1128. 551{555.
6) Keusch, G.T. (2001) Shigella. Mol. Med. Microbiol. 20) Lett, M.C., Sasakawa, C., Okada, N., Sakai, T.,
(ed. Sussman, M.) 2, Academic Press, London, Makino, S., Yamada, M. et al. (1989) virG, a
pp. 1279{1290. plasmid-coded virulence gene of Shigella exneri:
7) Sasakawa, C. (2004) Shigella invasion. Adv. Mol. identication of the virG protein and determina-
Cell. Microbiol. (ed. Lamont, R.J.). Cambridge tion of the complete coding sequence. J. Bacteriol.
University Press, Cambridge, U.K., pp. 25{58. 171, 353{359.
8) Sansonetti, P.J. and Di, Santo. J.P. (2007) Debug- 21) Bernardini, M.L., Mounier, J., d’Hauteville, H.,
ging how bacteria manipulate the immune re- Coquis-Rondon, M. and Sansonetti, P.J. (1989)
sponse. Immunity 26, 149{161. Identication of icsA, a plasmid locus of Shigella
9) Suzuki, T., Nakanishi, K., Tsutsui, H., Iwai, H., exneri that governs bacterial intra- and inter-
Akira, S., Inohara, N. et al. (2005) A novel cellular spread through interaction with F-actin.
Caspase-1/Toll-like receptor 4-independent path- Proc. Natl. Acad. Sci. USA 86, 3867{3871.
way of cell death induced by cytosolic Shigella 22) Cossart, P. and Sansonetti, P.J. (2004) Bacterial in-
in infected macrophages. J. Biol. Chem. 280, vasion: the paradigms of enteroinvasive pathogens.
14042{14050. Science 303, 242{248.
10) Suzuki, T., Franchi, L., Toma, C., Ashida, H., 23) Gouin, E., Welch, M.D. and Cossart, P. (2005) Actin-
Ogawa, M., Yoshikawa, Y. et al. (2007) Dierential based motility of intracellular pathogens. Curr.
regulation of caspase-1 activation, pyroptosis and Opin. Microbiol. 8, 35{45.
autophagy via Ipaf and ASC in Shigella-infected 24) Suzuki, T., Miki, H., Takenawa, T. and Sasakawa, C.
macrophages. PLos. Pathog. 3, e111. (1998) Neural Wiskott-Aldrich syndrome protein is
11) Bergsbaken, T., Fink, S.L. and Cookson, B.T. (2009) implicated in the actin-based motility of Shigella
Pyroptosis: host cell death and inammation. Nat. exneri. EMBO J. 17, 2767{2776.
Rev. Microbiol. 7, 99{109. 25) Suzuki, T., Mimuro, H., Miki, H., Takenawa, T.,
242 C. SASAKAWA [Vol. 86,
Sasaki, T., Nakanishi, H. et al. (2000) Rho family 40) Mimuro, H., Suzuki, T., Nagai, S., Rieder, G., Suzuki,
GTPase Cdc42 is essential for the actin-based mo- M., Fujita, Y. et al. (2007) Helicobacter pylori
tility of Shigella in mammalian cells. J. Exp. Med. dampens gut epithelial self-renewal by inhibiting
191, 1905{1920. apoptosis, a bacterial strategy to enhance coloni-
26) Leung, Y., Ally, S. and Goldberg, M.B. (2008) Bac- zation of the stomach. Cell Host Microbe 11,
terial actin assembly requires Toca-1 to relieve N- 250{263.
WASP autoinhibition. Cell Host Microbe 3, 39{47. 41) Nougayrede, J.P., Taieb, F., De Rycke, J. and
27) Yoshida, S., Katayama, E., Kuwae, A., Mimuro, H., Oswald, E. (2005) Cyclomodulins: bacterial eec-
Suzuki, T. and Sasakawa, C. (2002) Shigella deliver tors that modulate the eukaryotic cell cycle.
an eector protein to trigger host microtubule de- Trends Microbiol. 13, 103{110.
stabilization, which promotes Rac1 activity and 42) Tanaka, J., Suzuki, T., Mimuro, H. and Sasakawa,
efcient bacterial internalization. EMBO J. 21, C. (2003) Structural denition on the surface of
2923{2935. Helicobacter pylori type IV secretion apparatus.
28) Yoshida, S., Handa, Y., Suzuki, T., Ogawa, M., Cell Microbiol. 5, 395{404.
Suzuki, M., Tamai, A. et al. (2006) Microtuble- 43) Kim, M., Ogawa, M., Fujita, Y., Yoshikawa, Y.,
severing activity of Shigella is pivotal for intercellu- Nagai, T., Nagai, S. et al. (2009) Bacteria hijack
lar spreading. Science 314, 985{989. integrin-linked kinase to stabilize focal adhesions
29) Ashida, H., Toyotome, T., Nagai, T. and Sasakawa, and block cell detachment. Nature 459, 578{582.
C. (2007) Shigella chromosomal IpaH proteins are 44) Legate, K.R., Montanez, E., Kudlacek, O. and Fassler,
secreted via the type III secretion system and act R. (2006) ILK, PINCH and parvin: the tIPP of
as eectors. Mol. Microbiol. 63, 680{693. integrin signalling. Nat. Rev. Mol. Cell Biol. 7,
30) Ashida, H., Kim, M., Schmidt-Supprian, M., Ma, A., 20{31.
Ogawa, M. and Sasakawa, C. (2010) A bacterial E3 45) McDonald, P.C., Fielding, A.B. and Dedhar, S. (2008)
ubiquitin ligase IpaH9.8 eector targets NEMO/ Integrin-linked kinase{essential roles in physiology
IKKg to dampen the host NF-kB-mediated inam- and cancer biology. J. Cell Sci. 121, 3121{3132.
matory response. Nat. Cell Biol. 12, 66{73. 46) Mulvey, M.A., Schilling, J.D., Martinez, J.J. and
31) Rohde, J.R., Breitkreutz, A., Chenal, A., Sansonetti, Hultgren, S.J. (2000) Bad bugs and beleaguered
P.J. and Parsot, C. (2007) Type III secretion bladders: interplay between uropathogenic Escheri-
eectors of the IpaH family are E3 ubiquitin ligase. chia coli and innate host defenses. Proc. Natl.
Cell Host Microbe 1, 77{83. Acad. Sci. USA 97, 8829{8835.
32) Deretic, V. and Levine, B. (2009) Autophagy, im- 47) Muenzner, P., Rohde, M., Kneitz, S. and Hauck, C.R.
munity, and microbial adaptations. Cell Host (2005) CEACAM engagement by human patho-
Microbe 18, 527{549. gens enhances cell adhesion and counteracts bacte-
33) Ogawa, M. and Sasakawa, C. (2006) Shigella and ria-induced detachment of epithelial cells. J. Cell
autophagy. Autophagy 2, 171{174. Biol. 170, 825{836.
34) Ogawa, M., Yoshimori, T., Suzuki, T., Sagara, H., 48) Kotlo, K.L., Winicko, J.P., Ivano, B., Clemens,
Mizushima, N. and Sasakawa, C. (2005) Escape of J.D., Swerdlow, D.L., Sansonetti, P.J. et al. (1999)
intracellular Shigella from autophagy. Science 307, Global burden of Shigella infections: implications
727{731. for vaccine development and implementation of
35) Ogawa, M., Suzuki, T., Tatsuno, I., Abe, H. and control strategies. Bulletin of the World Health
Sasakawa, C. (2003) IcsB, secreted via the type III Organization 77, 651{666.
secretion system, is chaperoned by IpgA and re- 49) Yoshikawa, M., Sasakawa, C., Okada, N., Takasaka,
quired at the post-invasion stage of Shigella patho- N., Nakayama, M., Yoshikawa, Y. et al. (1995)
genicity. Mol. Microbiol. 48, 913{931. Construction and evaluation of a virG thyA double
36) Dupont, N., Lacas-Gervais, S., Bertout, J., Paz, I., mutant of Shigella exneri 2a as a candidate live-
Freche, B., Tran, V. et al. (2009) Shigella phago- attenuated oral vaccine. Vaccine 13, 1436{1440.
cytic vacuolar membrane remnants participate in 50) Suzuki, T., Yoshikawa, Y., Ashida, H., Iwai, H.,
the cellular response to pathogen invasion and are Toyotome, T., Matsui, H. and Sasakawa, C.
regulated by autophagy. Cell Host Microbe 6, (2006) High vaccine efcacy against shigellosis of
137{149. recombinanat noninvasive Shigella mutant that
37) Yoshikawa, Y., Ogawa, M., Hain, T., Yoshida, M., express Yersinia invasin. J. Immunol. 177, 4709{
Kim, M., Mimuro, H. et al. (2009) Listeria mono- 4717.
cytogenes ActA-mediated escape from autophagic 51) Shim, D.H., Suzuki, T., Chang, S.Y., Park, S.M.,
recognition. Nat. Cell Biol. 11, 1233{1240. Sansonetti, P.J., Sasakawa, C. and Kweon, M.N.
38) Radtke, F. and Clevers, H. (2005) Self-renewal and (2007) New animal model of shigellosis in the
cancer of the gut: two sides of a coin. Science 307, guinea pig: its usefulness for protective efcacy
1904{1909. studies. J. Immunol. 178, 2476{2482.
39) Iwai, H., Kim, M., Yoshikawa, Y., Ashida, H.,
Ogawa, M., Fujita, Y. et al. (2007) A bacterial
eector targets Mad2L2, an APC inhibitor, to (Received Dec. 4, 2009; accepted Jan. 8, 2010)
modulate host cell cycling. Cell 130, 611{623.
No. 3] Shigella infection of intestinal epithelium and circumvention 243
Prole
Chihiro Sasakawa was born in 1948. He graduated from the Faculty of Science
and Postgraduate School of Pharmaceutical Science at Chiba University, entered the
Postgraduate School of Medicine, University of Tokyo, and received his Ph.D. in 1978
from University of Tokyo. In 1978, he was promoted to research associate at the Insti-
tute of Medical Science, University of Tokyo. After three years of postdoctoral work-
ing in Department of Microbiology and Immunology, Washington University School of
Medicine, he started to study bacterial pathogenesis in 1983 at the Institute of Medical
Science, University of Tokyo, and was promoted to associated professor in 1986 and
professor in 1995. He was the Head of Department of Microbiology and Immunology
at the Institute of Medical Science from 1999 to 2005, and appointed also professor of
Research Institute for Microbial Diseases, Osaka University from 1999 to 2001. At
present he is a professor of Department of Microbiology and Immunology, and International Research Center for
Infectious Diseases, at the Institute of Medical Science, University of Tokyo. Over the past 30 years he has been
studying molecular and cellular interaction between bacterial pathogens and host. His current research interests
are mechanisms of bacterial countermeasure against host innate immune defense systems and the outcome of
infectious diseases. He is currently a member of editorial or advisory boards of Nature Reviews Microbiology,
Cell Host Microbe, Trends in Microbiology and several other international journals. He was awarded the Noguchi
Hideyo Memorial Prize in 1998 and the Takeda Medical Prize in 2006.