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Pathogenesis of Mycobacterium tuberculosis, gene expression,
regulation, host-pathogen interactions
A scourge to humankind throughout recorded history, tuberculosis (TB)
continues to have a devastating impact even today. The World Health Organization
has estimated that one-third of the world's population is infected with Mycobacterium
tuberculosis, with approximately 8 million new cases diagnosed annually.
Although not everyone who is infected develops active disease, of those who do,
nearly two million die each year. The severity of this global epidemic is
exacerbated by the concomitant epidemic of HIV infection and the synergistic
effect of the two diseases has profound economic implications, as well as untold
human suffering.
Understanding the mechanisms by which M. tuberculosis causes TB is the
overall goal of research conducted in the Clark-Curtiss laboratory. M.
tuberculosis is transmitted from infected humans to non-infected ones via
nasal droplets. After the bacteria are introduced into the lungs, they are
ingested by macrophages, whose normal function is to destroy invading pathogenic
microorganisms. M. tuberculosis has developed means to thwart normal
macrophage function, and the bacteria are able to survive and grow within the
phagosomal compartment. Development of TB disease occurs in individuals whose
immune systems fail to recognize the presence of the bacteria and destroy them.
Research in my lab has been directed toward understanding the genes and gene
products of M. tuberculosis that are important to the intracellular
survival and growth of the bacteria when they are in human macrophages. Areas of research that are
currently being pursued: (a) identification and characterization of
genes from M. tuberculosis that are differentially expressed by the
bacilli when they are actively growing within human macrophages, using the
selective capture of transcribed sequences (SCOTS) technique developed in my
lab; (b) analysis of the regulation of mycobacterial gene expression in response
to the environment of the human macrophage phagosome; and (c) mutagenesis of
specific genes identified in (a) and (b) and analysis of the effects of such
mutations on the ability of M. tuberculosis to survive in human
macrophages and in animal infection models.
A fourth area of research currently underway in the Clark-Curtiss laboratory
is the development of an effective vaccine against M. tuberculosis.
Although there is a vaccine currently available (an attenuated strain of M.
bovis, designated BCG) and this vaccine is effective in preventing some of
the serious sequelae of TB infection in children, the BCG vaccine does not
confer lifelong immunity. Thus, young adults, in what should be the prime of
life, are very susceptible to infection and development of disease. In
collaboration with Roy Curtiss III, we are employing the recombinant attenuated Salmonella
vaccine systems to express M. tuberculosis antigens and to deliver the
antigens to optimal sites within immunized individuals to generate protective
immune responses against the tubercle bacilli.
Recent Publications:
Haydel, S.E. and J.E. Clark-Curtiss. 2005. The Mycobacterium tuberculosis
TrcR
response regulator represses expression of the rv1057 gene encoding a
seven-bladed b-propeller protein.
Submitted to Molec. Microbiol.
Haydel, S.E. and J. E. Clark-Curtiss. 2004. Global analysis of two-component
system regulator genes during Mycobacterium tuberculosis growth in
human macrophages. FEMS Microbiol. Lett. 236: 336-342
Clark-Curtiss, J.E. and S.E. Haydel. 2003. Molecular genetics of Mycobacterium
tuberculosis pathogenesis. Annu. Rev. Microbiol. 57: 17-549.
Daigle, F., J.Y. Hou, and J.E. Clark-Curtiss. 2002. Microbial gene
expression elucidated by selective capture of transcribed sequences (SCOTS).
Meth. Enz. 358: 108-122.
Hou, J.Y., J.E. Graham, and J.E. Clark-Curtiss. 2002. Mycobacterium avium genes expressed during growth in human macrophages detected by selective capture of transcribed sequences (SCOTS)
.
Infect. Immun. 70:3714-3726.
Haydel, S.E., W.H. Benjamin, Jr., N.E. Dunlap, and J.E. Clark-Curtiss.
2002. Expression, autoregulation, and DNA binding properties of the Mycobacterium
tuberculosis TrcR response regulator. J. Bacteriol. 184: 2192-2203.
Graham, J.E., and J.E. Clark-Curtiss. 1999. Identification of Mycobacterium
tuberculosis RNAs synthesized in response to phagocytosis by human
macrophages by selective capture of transcribed sequences (SCOTS). Proc. Natl.
Acad. Sci. USA 96: 11554-11559.
Plum, G., M. Brenden, J.E. Clark-Curtiss, and G. Pulverer. 1997. Cloning,
sequencing and expression of the mig gene of Mycobacterium avium coding
for a secreted, macrophage-induced protein. Infect. Immun. 65:4548-4557.
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