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Faculty
 Hung Ton-That
Assistant Professor of Molecular, Microbial & Structural Biology
ton-that@uchc.edu
Areas of Interest:
Molecular assembly on the cell surface of Gram-positive bacteria,
bacterial pathogenesis and host-pathogen interactions.
Pilus assembly
Pili have been identified in many Gram-positive pathogens, however, the
mechanism of pilus assembly and function of pili are just beginning to
be unraveled. Best understood is the mechanism of the prototype SpaA
pili found in Corynebacterium diphtheriae, the causative agent of
diphtheria that assembles three distinct pilus structures, designated as
SpaA-type, SpaD-type and SpaH-type pili (Spa for sortase-mediated pilus
assembly). Similar to other types, the SpaA-type pili are composed of
three pilin subunits, SpaA, SpaB and SpaC. SpaA, the major pilin, forms
the pilus structure, while SpaB is incorporated along the pilus shaft
and SpaC largely positioned at the tip. The assembly of SpaABC pili
requires sortase SrtA located within the pilus gene cluster. According
to the current model, pilus precursor proteins containing the N-terminal
secretion signal are synthesized in the cytoplasm and transported across
the cytoplasmic membrane by the general secretion (Sec) machinery. Upon
translocation to the exoplasm, the pilus precursor proteins are captured
by a specific sortase and assembled into high molecular weight
structures which are subsequently anchored on the bacterial cell wall.
Interestingly, our recent work revealed that the minor pilins SpaB and
SpaC are not only part of the pilus structures, but they are also
anchored in close clusters on the cell wall. These observations open up
several intriguing mechanistic and biological problems. How are pilins
assembled? Is pilus assembly compartmentalized? Are there factors that
regulate pilus polymerization and the surface display of pilins? Does
this regulation involve cues from the host? Our current work is devoted
to answering these fundamental questions using C. diphtheriae as
a model.
Universality of pilus assembly in Gram-positive bacteria
Our prediction that sortase-mediated pilus assembly
is universal in Gram-positive bacteria is supported by recent work by
several research groups. Consequently, our laboratory is now
investigating the assembly and function of pili in Actinomyces
spp., early colonizers of human teeth, and in group B streptococcus,
which is the leading cause of bacterial pneumonia, sepsis and meningitis
among neonates. Efforts are made to find the common features of pilus
assembly and the role of pili in pathogenesis.
Pili in pathogenesis
Available evidence indicates that Gram-positive pili are involved in
host-tissue adhesion, co-aggregation and immuno-modulation. Importantly,
Gram-positive pili have been explored as vaccine candidates. We are
employing ex-vivo tissue cultures, infection of worms and rodent models
to address several aspects of bacterial pathogenesis: Are pili required
for bacterial infection? How are pili involved in tissue tropism? How do
pili modulate the host immune system?
Lab Rotation Projects:
The projects will be designed centering on the three major problems
above and individual student interests. Basic approach to these studies
is a combination of immuno-fluorescence and electron microscopy, mass
spectrometry, biochemical assays, molecular biology, immunology and in
vitro and in vivo infection models (tissue cultures and rodent models).
Postdoctoral Positions Available (please inquire directly)
Ton-That Publications
Ton-That Lab Webpage
Selected Publications:
Anjali Mandlik, Arlene Swierczynski, Asis Das and Hung Ton-That.
(2008) Pilus assembly in Gram-positive bacteria and function in
colonization and biofilm development. Trends in Microbiology,
16(1):33-40.
Anu Swaminathan*, Anjali Mandlik*, Arlene Swierczynski, Andrew Gaspar,
Asis Das and Hung Ton-That. (2007) Housekeeping sortase facilitates the
cell wall anchoring of pilus polymers in Corynebacterium diphtheriae.
Molecular Microbiology, 66(4): 961–974.
Vengadesan Krishnan†, Andrew H. Gaspar†, Naiqing Ye, Anjali Mandlik,
Hung Ton-That*, and Sthanam V L Narayana*. (2007) An IgG-like domain in
the minor pilin GBS52 of Streptococcus agalactiae mediates lung
epithelial cell adhesion. Structure, 15(8):893–903.
Anjali Mandlik, Arlene Swierczynski, Asis Das and Hung Ton-That.
(2007) Corynebacterium diphtheriae employs specific minor pilins to
target human pharyngeal epithelial cells. Molecular Microbiology,
64(1):111-24.
Arunima Mishra, Asis Das, John O. Cisar and Hung Ton-That. (2007)
Sortase-catalyzed assembly of distinct heteromeric fimbriae in
Actinomyces naeslundii. Journal of Bacteriology, 189(8):3156-65.
Arlene Swierczynski and Hung Ton-That (2006) Type III pilus of
corynebacteria: Pilus length is determined by the level of its major
pilin subunit. Journal of Bacteriology, 188(17):6318-25.
Andrew H. Gaspar and Hung Ton-That. (2006) The Assembly of Distinct
Pilus Structures on the Surface of Corynebacterium diphtheriae.
Journal of Bacteriology, 188(4): 1526-33.
Andrew H. Gaspar, Luciano A. Maraffini, Hung Ton-That, and
Olaf Schneewind. (2005) Bacillus anthracis sortase A (SrtA) anchors
LPXTG motif containing surface proteins to the cell wall envelope.
Journal of Bacteriology, 187 (13):4646-55.
Hung Ton-That, Luciano A. Maraffini, and Olaf Schneewind. (2004)
Protein Sorting to the Cell Wall Envelope of Gram-positive Bacteria.
Biochimica et Biophysica Acta, 1694: 269-278.
Hung Ton-That, Luciano A. Maraffini, and Olaf Schneewind. (2004)
Sortases and Pilin Elements Involved in Pilus Assembly of
Corynebacterium diphtheriae. Molecular Microbiology, 53(1):251-261
Hung Ton-That and Olaf Schneewind (2004) Pilus Assembly in
Gram-positive Bacteria. Trends in Microbiology, 12(5):228-234
Hung Ton-That and Olaf Schneewind. (2003) Assembly of Pili on the
Surface of Corynebacterium diphtheriae. Molecular Microbiology,
50(4):1429-1438.
rev. 4-08
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