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Perspectives Series: Host/Pathogen Interactions

Regulation of Bacterial Virulence Gene Expression by the Host Environment

Donald G. Guiney
Department of Medicine, UCSD School of Medicine, La Jolla, California 92093

Bacterial pathogens must adapt to a wide variety of changing osmolarity, O2, CO2, pH, reactive oxygen and nitrogen com-
environmental conditions during the infection cycle. Upon en- pounds, nutrient availability, and inorganic ion concentrations.
countering the host, pathogens must express specific gene Many of these factors change in the transitions from the exter-
products to persist and proliferate in the appropriate location nal environment to the host, between different locations in the
and to circumvent host defenses. During the course of the in- host, and between different hosts. Bacteria are able to respond
fection, the host environment may change markedly. All to a complex environment by integrating the signals from a va-
pathogens must also ensure successful transmission, which riety of these cues to sense their location and express the ap-
may entail prolonged periods in external environments or ad- propriate genes.
aptation to an intermediate host of a different species. All bac- Temperature is a particularly useful signal for mammalian
teria regulate gene expression in response to different environ- pathogens since the host temperature is relatively constant and
mental signals, a property that is crucial to their ability to elevated with respect to the ambient environment. Tempera-
compete with other organisms. In general, gene products that ture-sensitive gene expression allows the organism to discrimi-
confer a growth or survival advantage in a particular situation nate between the host and the outside world, and certain genes
are expressed, while unnecessary functions are downregulated. required to produce disease, such as the invasion genes of Shi-
The same principle applies to genes encoding virulence traits gella and the plasmid genes encoding secreted proteins of
in pathogens. These virulence genes are subject to complex Yersinia, are not expressed at 258C but are induced at 378C (1,
regulatory mechanisms that ensure expression in the appropri- 2). Elevations in temperature also induce the heat shock stress
ate host environment. response, a prominent regulatory circuit important for many
Since regulation of virulence genes is a common property pathogens.
of pathogens, strong selective pressures must operate against While simple chemical cues are not unique to the host, they
simple constitutive expression of virulence traits. The general can be used by the bacteria to discriminate between different
metabolic economy of the bacterial cell selects against unnec- locations. Osmolarity varies in the gastrointestinal tract and
essary expenditure of energy. However, there are likely to be tissue osmolarity is higher than fresh water environments.
specific reasons that a pathogen does not display all of its viru- High osmolarity stimulates Salmonella invasion and the osmo-
lence features simultaneously and continuously. Surface mole- sensor, OmpR, is essential for virulence in several bacterial
cules that localize the bacteria to a specific site in the host have species (3, 4). O2 concentrations vary greatly between the lumen
to be altered if the organism is to change its location or be of the bowel and perfused tissue, and low oxygen stimulates
transmitted to a new host. Invasive pathogens need one set of Salmonella invasion from the gastrointestinal tract. CO2 con-
genes to gain access to the host and a different set to prolifer- centration of tissues and the respiratory mucosa is elevated
ate and circumvent host defenses in the tissues. Certain key with respect to the normal atmospheric level, and CO2 has
virulence structures may become a liability for the organism as been shown to regulate M-protein synthesis in streptococci (5).
antigens when the host mounts an immune response. Some pH changes abruptly in the intestinal tract and regulates syn-
pathogens can downregulate or switch antigens during the thesis of acid stress proteins in bacteria exposed to gastric con-
course of infection. To survive in the environment during tents or signals localization in the small bowel by the increase
transmission, different genes may be important, and for those in pH. Invasive pathogens are exposed to the toxic effects of
organisms that infect an intermediate host, an entire new set of reactive oxygen and nitrogen intermediates produced by phago-
virulence genes is required. cytic cells, inducing crucial resistance and repair mechanisms
Despite the complex regulatory requirements of bacterial (6). Lack of nutrients induces a global stress response in bacte-
pathogens, the environmental cues that act as signals for the ria that regulates virulence gene expression in Salmonella and
control of virulence gene expression in animal pathogens are also is likely to be important for survival in hostile external en-
generally simple physical and chemical factors: temperature, vironments during transmission of pathogens (7). Inorganic
ion concentrations are used by pathogenic bacteria to sense
Address correspondence to Donald G. Guiney, M.D., Department of their location. Iron plays a key regulatory role, since virtually
Medicine 0640, UCSD School of Medicine, 9500 Gilman Drive, La all available iron on mucosal surfaces and in the tissues is
Jolla, CA 92093-0640. Phone: 619-534-6030; FAX: 619-534-6020; E-mail: bound to host proteins (8). Low iron induces a variety of viru-
dguiney@ucsd.edu lence traits including toxin production in Corynebacterium
Received for publication 7 January 1997. diphtheriae and synthesis of a specialized siderophore, aero-
bactin, in uropathogenic Escherichia coli. Low Mg21 in the
J. Clin. Invest. macrophage phagosome is sensed by the two-component regu-
© The American Society for Clinical Investigation, Inc. latory system PhoPQ of Salmonella, leading to induction of
0021-9738/97/02/0565/05 $2.00 genes required for intracellular survival (9).
Volume 99, Number 4, February 1997, 565–569 In contrast to mammalian pathogens, virulence gene regu-

Regulation of Bacterial Virulence Gene Expression by the Host Environment 565

latory mechanisms involving host-pathogen and pathogen- centisome 63 on the chromosome (3). The expression of these
pathogen communication mediated by more specific diffusible invasion genes is regulated in response to environmental cues
molecules are commonly found in bacteria that infect plants. present in the small bowel. To cause systemic disease, nonty-
The virulence genes of Agrobacterium tumefaciens, the cause phoid Salmonella serovars must survive and replicate inside
of crown gall tumors, are controlled by a two-component regu- host cells, probably primarily within macrophages (12). In this
latory system that responds to the presence of phenolic com- second stage of pathogenesis, regulatory mechanisms signal
pounds produced by plants. The system ensures that the viru- the induction of specific chromosomal and plasmid-encoded
lence genes are expressed when the bacteria are in close virulence genes required for survival and growth inside the
proximity to the plant. This precedent should stimulate a phagocytic vacuole. At both stages of the infection, Salmonella
search in animal pathogens for similar systems that respond to gene expression involves both virulence-specific gene products
specific products made by the host. Certain plant pathogens of as well as global bacterial regulatory mechanisms.
the genera Agrobacterium, Erwinia, and Pseudomonas use a The regulation of Salmonella invasion of epithelial cells is
form of communication between bacterial cells termed “quo- depicted in Fig. 1. Efficient entry of Salmonella into epithelial
rum sensing” (10). Bacteria synthesize acylated derivatives of cells requires production of secreted invasion proteins (Sips)
homoserine lactone which accumulate in the extracellular en- which act both on the epithelial cell surface and internally to
vironment at levels related to the cell density of the bacteria. remodel the cell membrane into ruffles, leading eventually to
When a certain density is reached, the acylated homoserine macropinocytosis of the bacteria (3, 13, 14). The Sips are ex-
lactone induces synthesis of the target genes in the entire bac- ported from the bacteria by a type III contact-dependent pro-
terial population. This system is also used by the symbiotic tein secretory system. The secretion of the Sips is stimulated by
light-emitting bacteria that infect certain deep sea fish. Al- contact between the bacteria and the epithelial cell membrane
though this quorum sensing mechanism mediated by acylated (3). Both the Sips and the type III system are encoded by the
homoserine lactone has not yet been shown to regulate viru- Salmonella pathogenicity island 1, and expression of these
lence in primary, nonopportunistic pathogens of higher ver- genes is coordinately regulated by the hilA gene product (15).
tebrates, cell density–dependent regulation based on an
octapeptide pheromone has been reported recently in Staphy-
lococcus aureus (11). The pheromone accumulates in the post-
exponential phase of growth, signaling the cells to express se-
creted virulence proteins and repressing the production of
surface proteins. Additional quorum sensing regulatory sys-
tems are likely to be found in animal pathogens for which colo-
nization with a certain inoculum precedes disease.
These conditions that control virulence gene expression in
pathogens also stimulate global regulatory changes in many
genes common to both pathogens and commensal bacteria.
Therefore, virulence gene expression must be integrated with
regulatory circuits for a variety of “housekeeping” genes. Dur-
ing evolution, pathogens have faced a genetic problem with
this regulatory integration since virulence genes have been ac-
quired frequently on accessory genetic elements, such as plas-
mids and phage, or as blocks of genetic information inserted
into the chromosome as pathogenicity islands. Integration with
the global bacterial regulatory circuits often involves an adapter
mechanism in which the virulence gene cluster encodes its own
regulatory element, but this element also responds to selected
global control signals of the organism. In this manner, viru-
lence genes that are specific for a pathogen are found to be
regulated by control elements that are widespread among both
pathogens and nonpathogens. Thus, virulence genes have
adopted the specific bacterial signal transduction systems that
respond to the appropriate environmental cues and ensure op- Figure 1. Model for the regulation of Salmonella invasion genes dur-
timal virulence gene expression at the proper time during in- ing intestinal infection. A Salmonella cell is depicted in association
fection. with an intestinal epithelial cell in the small bowel. Exposure to envi-
Salmonella species are facultative intracellular pathogens ronmental cues present in the bowel lumen, including low O2 concen-
that illustrate many of these principles of virulence gene regu- trations, relatively high osmolarity, and alkaline pH, acts to induce
lation during pathogenesis. Salmonella infection is acquired by expression of the hilA gene located on SPI1. HilA in turn induces op-
erons in SPI1 encoding the components of a type III protein secretion
ingestion and the organisms must colonize and invade the
system as well as the secreted proteins (Sips). Contact between the
small bowel mucosa to initiate disease. This first stage in
bacterium and the epithelial cell stimulates Sip secretion by the type
pathogenesis is dependent on a 40-kb block of genes compris- III system located at the bacterial cell surface. The Sips interact with
ing the Salmonella pathogenicity island 1 (SPI1),1 located at the epithelial cell membrane and certain secreted proteins enter the
cytoplasm. The Sips promote uptake of the bacterium into a mem-
1. Abbreviations used in this paper: pags, PhoP-activated genes; Sips, brane-bound intracellular vacuole. The virulence plasmid spv genes
secreted invasion proteins; SPI1, Salmonella pathogenicity island 1. are not required in this stage of pathogenesis.

566 D.G. Guiney

The HilA protein activates transcription of several operons phage, Salmonella proliferate in the membrane-bound phago-
within the pathogenicity island. hilA itself is also located in the cytic vacuole, and numerous genes are required for survival
SPI1 and appears to be a unique and specific regulator for the and growth in this environment. Two regulatory circuits that
Salmonella invasion genes. hilA expression increases in re- control virulence gene induction in the intracellular environ-
sponse to the environmental cues that lead to invasion gene ment of macrophages have been characterized in detail: one
expression: low O2 levels, relatively high osmolarity, and alka- mediated by the alternate sigma factor ss (RpoS) and the other
line pH, conditions present in the lumen of the small bowel. involving the two-component regulatory system PhoPQ (Fig. 2).
The mechanisms by which these external conditions regulate After uptake of Salmonella by macrophages in vitro, there is a
hilA expression are unknown, but recent work indicates that lag period of up to several hours in which little or no net growth
hilA is controlled in part through a common sensory transduc- of the bacteria occurs. This limitation of growth appears to be an
tion circuit not specific for Salmonella. The sirA gene, located early signal sensed by the bacteria soon after phagocytosis and
outside the pathogenicity island and allelic with the E. coli leads to rapid induction of the rpoS gene on the chromosome,
uvrY gene, is required for efficient hilA expression (16). The encoding an alternative sigma factor for the bacterial RNA
sequence of SirA indicates that it is a transcriptional response polymerase (17). ss controls a global stress response that has
regulator of a two-component regulatory system, suggesting a been found widely distributed among gram-negative bacteria.
role in the transduction of environmental signals for the regu- Growth limitation, mediated by a variety of adverse conditions
lation of hilA expression. For invasion gene expression, HilA including nutrient starvation, high osmolarity, and low pH, sig-
appears to be the adapter that integrates regulatory signals nals the ss stress response. rpoS expression is regulated by
from the bacterial cell to produce a coordinate response in ex- complex mechanisms operating at the levels of transcription,
pression of the invasion locus. translation, and protein stability. Recent evidence suggests
In the second stage of Salmonella pathogenesis, the organ- that a two-component signal transduction system including the
isms are taken up by macrophages in the bowel, located prima- response regulator rssB controls ss levels by regulating the ac-
rily in Peyer’s patches, and later disseminate to macrophages tivity of the ClpXp protease involved in ss degradation (18).
in systemic organs. Survival of Salmonella within macrophages Increased levels of ss in the bacterial cell cause global changes
is an essential virulence phenotype (12). Inside the macro- in gene expression due to replacement of the vegetative s70
with ss in the RNA polymerase holoenzyme. Expression of
ss-dependent genes increases while the transcription of a variety
of other genes decreases. The ss-dependent stress response
renders Salmonella more resistant to oxidative agents, DNA
damage, high osmolarity, acid pH, and prolonged starvation (7).
In Salmonella, ss is also required for the expression of the
plasmid-encoded spv genes (7). Virulence plasmids carrying
the spv genes are found in certain nontyphoid Salmonella sero-
vars that are highly associated with severe systemic disease,
such as S. choleraesuis, S. dublin, and S. typhimurium (19). The
spv genes greatly enhance the ability of these Salmonella
strains to proliferate at extraintestinal sites, most likely within
tissue macrophages. The spv locus consists of five genes, desig-
nated spvRABCD, and is highly conserved among Salmonella
serovars. SpvR encodes a transcriptional activator which posi-
tively regulates its own synthesis and is required for expression
of the spvABCD operon. SpvR binds to both the spvR and
spvA promoters (20). However, efficient transcription from
both spv promoters requires ss, and its level within the bacte-
rial cell regulates expression of both spvR and the spvABCD
operon (21). For the spv genes, SpvR is the adapter that links
specific expression of the spv locus to the general bacterial
stress response mediated by ss.
Figure 2. Model for the regulation of Salmonella virulence genes in- ss levels, as measured by an RpoS::LacZ protein fusion, in-
volved in the extraintestinal infection of tissue macrophages. After crease rapidly in the first hour after ingestion of S. typhimu-
phagocytosis, Salmonella cells remain within the phagocytic vacuole. rium by macrophages (17). This increase in ss induces spvR,
This environment limits the growth of the organism, leading to in- and positive autoregulation of spvR ensures a rapid increase in
creased levels of the alternative sigma factor ss, the product of the SpvR levels in response to the ss signal. SpvR and ss act in
chromosomal rpoS gene. ss increases synthesis of the transcriptional concert at the spvA promoter to induce expression of the
activator SpvR which acts together with ss to induce the spv operon spvABCD genes, leading to sustained synthesis of the Spv pro-
on the virulence plasmid. The Spv proteins appear to enhance prolif-
teins for up to 6 h after uptake of the bacteria by macrophages.
eration of the Salmonella in the intracellular environment. During
The Spv proteins appear to act by an unknown mechanism to
maturation of the phagocytic vacuole, low Mg21 levels activate the
two-component PhoPQ regulatory system, leading to synthesis of increase proliferation of the bacteria in the intracellular envi-
several proteins designated Pags, the products of PhoP-activated ronment (Libby, S., L. Adams, T. Ficht, C. Allen, H. Whitford,
genes. The Pags appear to be involved in survival of the bacteria in- N. Buchmeier, S. Bossie, and D. Guiney, manuscript submit-
side macrophages. PhoP also negatively regulates hilA and inhibits ted for publication).
production of invasion gene products. A second regulatory circuit consisting of the two-compo-

Regulation of Bacterial Virulence Gene Expression by the Host Environment 567

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Work cited from my laboratory was supported by grants from the lence. Proc. Natl. Acad. Sci. USA. 86:5054–5058.
National Institutes of Health (AI-32178 and DK-35108) and from the 25. Galán, J.E., and R. Curtiss III. 1989. Cloning and molecular character-
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568 D.G. Guiney

“Host/Pathogen Interactions: Understanding the Strategies of Microbial Virulence and Host Defense”
Series Editors, Donald G. Guiney and Martin F. Kagnoff
February 1, 1997 Arthropod- and host-specific gene expression by Borrelia burgdorferi ................................................. Aravinda M. de Silva
February 15, 1997 Regulation of bacterial virulence gene expression by the host environment ......................................... Donald G. Guiney
April 1, 1997 The cytotoxic T lymphocyte response to hepatitis B and C virus infection............................................. Francis V. Chisari
June 15, 1997 Mechanisms of nitric oxide–related antimicrobial activity....................................................................... Ferric C. Fang
August 15, 1997 Mechanisms of the long-term interaction between Helicobacter pylori

Regulation of Bacterial Virulence Gene Expression by the Host Environment 569

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