Host-Pathogen Interactions in Microbial 
Pathogenesis 
B. Brett Finlay, Ph.D. — International Research Scholar 
Dr. Finlay is Assistant Professor in the Biotechnology Laboratory and the Departments of Biochemistry 
and Microbiology at the University of British Columbia, Vancouver. He is a member of the Canadian 
Bacterial Diseases Center of Excellence. After receiving his B.Sc. and Ph.D. degrees in biochemistry from 
the University of Alberta, Edmonton, he conducted postdoctoral work on microbial pathogenesis in the 
laboratory of Stanley Falkow at Stanford University as a fellow of the Alberta Heritage Foundation for 
Medical Research. 
IN all cases of bacterial disease, the bacterium 
or a bacterial product interacts with host cells 
or surfaces in either of two ways. It may adhere to 
the cell surface or may actually enter the cell and 
grow within (intracellular pathogen) . Pathogens 
residing in an intracellular environment are pro- 
tected from the host's immune systems, antibi- 
otics, and other therapeutic agents. They often 
use this safe niche to multiply before disseminat- 
ing to other sites and deeper tissue. 
Our laboratory uses a multidisciplinary ap- 
proach to define the interactions that occur be- 
tween pathogenic bacteria and host cells. Essen- 
tial to continuation of these interactions is the 
exchange of signals between pathogen and cell. 
We are studying the molecular nature of these 
signal transduction events in an effort to deter- 
mine the mechanisms involved. Knowledge of 
these mechanisms should point the way to novel 
therapeutic strategies. 
Several bacterial pathogens are used in these 
studies, since each organism has its individual 
features. Additionally, comparison of the signals 
generated by different pathogens can tell which 
mechanisms are common and which are unique. 
Salmonella typhimuriumi 
A Model for Intracellular Parasitism 
For several reasons, 5. typhimurium provides 
an excellent model for the study of intracellular 
parasitism. Salmonella species continue to cause 
significant health problems in both developed 
and less developed countries. These organisms 
have the capacity to enter into, survive, and repli- 
cate within host cells — features that contribute 
to virulence. Since 5. typhimurium is z close velz- 
tive of the nonpathogenic Escherichia colt, we 
have been able to use established molecular ge- 
netic techniques to study several aspects of Sal- 
monella pathogenesis. Finally, 5. typhimurium 
infection of the mouse closely mimics human ty- 
phoid fever. 
Since Salmonella species (and many other 
pathogens) interact with intestinal epithelial 
cells following oral ingestion, we have been able 
to utilize monolayers of polarized epithelial cells 
grown on permeable substrates to study the inter- 
actions. These systems have several properties in 
common with columnar epithelial cells of the in- 
testine. Salmonella species have the capacity to 
enter and penetrate through these polarized epi- 
thelial monolayers. Moreover, transposon mu- 
tants that are defective for such penetration have 
been isolated from 5. typhimurium. Molecular 
characterization of the genetic loci that are 
disrupted by these transposons will provide clues 
about the bacterial products required for cell 
entry and penetration. 
Once inside a vacuole within an epithelial cell, 
5. typhimurium finds itself within a presumably 
quite different environment. Very little is known 
about the microenvironment of any intracellular 
pathogen. To probe and define aspects of the va- 
cuolar habitat, we have been using a bacterial re- 
porter gene (tocZ) fused to several S. typhimur- 
ium genes that are variously regulated. For 
example, one can measure expression of reporter 
genes that are affected by oxygen levels, carbon 
source, pH, or iron or magnesium concentra- 
tions. These studies are providing clues about the 
nature of this intracellular niche. Additionally, 
we have begun to search for other S. typhimur- 
ium loci that are only induced when the bacte- 
rium is inside host cells, in the hope of finding 
other regulated genes. 
After initial survival inside a host cell, 5. typhi- 
murium begins to multiply within its intracellu- 
lar vacuole. Virtually nothing is known about its 
requirements there. We have identified three bac- 
terial genes that are needed for S. typhimurium 
to multiply within host cells but not without. 
Characterization of these genes and other experi- 
ments may provide information about bacterial 
products necessary for intracellular growth. 
Signal Transduction Between Host 
and Pathogen: Involvement of the Host 
Cytoskeleton and Tyrosine Kinases 
Most intracellular pathogens require participa- 
tion of the host cell for successful pathogen inter- 
nalization. Functional actin filaments are often 
involved in bacterial uptake, and 5. typhimur- 
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