Researchers in the Section of General Surgery are conducting
research in a number of areas, much of which is funded with NIH
grants:
- Pathophysiology of surgical infections (see
featured story below)
- Molecular biology of familial polyposis syndrome
and solid gastrointestinal and endocrine tumors
- Breast cancer treatment
- Evaluation of inflammatory bowel disease
Dr.
John Alverdy, Professor of Surgery, directs a research program that
studies the pathophysiology of surgical infections. This program
seeks to understand the mechansism by which infection and sepsis
arise among critically ill patients.
Despite newer and more
powerful antibiotics, the incidence and severity of sepsis continues
to rise, claiming the lives of more than 200,000 Americans annually.
An aging population, the development of invasive medical and
surgical procedures, and the ability to rescue and sustain the lives
of the most critically ill and injured patients has created an
unprecedented population of patients at risk for infection and
sepsis.
The working hypothesis of the Alverdy lab is that
during bouts of severe physiologic stress, disruption of the normal
balance of the intestinal microflora coupled with an erosion of the
protective barrier of the intestinal tract defense system, creates a
situation in which the normal resident flora is replaced by highly
lethal pathogens. They have shown that one of these
hospital-acquired pathogens, pseudomonas aeruginosa, can induce a
state of lethal systemic sepsis from within the intestinal
epithelial surface, in the absence of any visible pathology in the
intestine, and in a subversive manner that eludes clinical
detection. In fact, intestinal pseudomonas aeruginosa, if provoked
by the proper physiologic cues, can cause lethal sepsis without ever
leaving the intestinal tract, by a mechanism that creates a porous
lining in the intestinal tract to potent toxins of this organism. In
this manner, this pathogen can kill its host, at arms length from
the immune system, while itself being protected by a biofilm it
creates that makes it inaccessible to immune cells. Because
antibiotic resistance to Pseudomonas aeruginosa has increased 70% in
the last 5 years, this situation poses a real and present danger to
the public.
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| Dr.
Alverdy's Research Group | |
| In
an effort to combat this problem Dr. Alverdy and his colleagues have
developed a novel approach to the problem. By trying to understand
why P. aeruginosa would turn against (Licheng Wu, Ph.D., left; John
Alverdy, M.D., center; Olga Zaborina, Ph.D., right) its host, they
discovered that intestinal bacteria can "sense" that a host is under
extreme physiologic stress and it "responds" by enhancing its
virulence genes, such as those that produce toxins and other harmful
agents. This interesting molecular dialogue has evolved so that
opportunistic pathogens can kill their hosts, when they perceive
them to be a liability to their survival. From the standpoint of P.
aeruginosa, living in the intestinal tract of a critically ill
patient is no picnic, the environment is hostile, food is in short
supply, and the bacteria are constantly bombarded with
antibiotics.
Using specifically designed polymers, the
Alverdy lab has discovered a polymer, PEG 15-20 that interferes with
this host to bacterial signaling pathway, rendering intestinal
bacteria "insensate" to host stress. As such, research animals
drinking this polymer are completely protected from highly lethal
strains of Pseudomonas aeruginosa without the polymer having any
effect on the growth and survival of the organism. In fact,
Pseudomonas grows very well within this polymer, it simply cannot be
signaled by the host or other Pseudomonas bacteria to alter its
behavior in any way. In addition, this polymer acts like a surrogate
intestinal mucin, distancing the Pseudomonas away from the
intestinal epithelium so it cannot adhere and activate local and
systemic immunity. This ecologically neutral and novel approach to
contain rather than eliminate potential pathogens by interdicting at
their lines of communication, could substantially decrease
antibiotic use, superinfections, and virulent nosocomial infections
following high risk surgical and medical procedures. |
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