Type III Secretion System Project


We are studying the Type III Secretion System (T3SS) in bacteria. This system is a major virulence factor in species such as:
  • Shigella species, which contaminate food and cause bacillary dysentery, a severe diarrheal disease. Over 165 million cases are estimated annually, leading to over 1 million deaths.
  • E. coli -- causes food poisoning and diarrhea. One type of E. coli infects 200 miliion people annually, resulting in 380,000 deaths, mainly in developing nations.
  • Salmonella species, which cause diseases such as typhoid and paratyphoid fever, accounting for 30 million illnesses and and 250,000 deaths annually.
  • Yersinia pestis -- cause of plague, including the Black Death that resulted in the deaths of an estimated 30% of the European population in the 1300s.
  • Pseudomonas aeruginosa -- a major hospital-acquired pathogen that can be fatal and is highly resistant to antibiotics.
  • Chlamydia species, which are responsible for a major sexually transmitted disease as well as the leading cause of infectious blindness globally.
The T3SS is composed of syringe-like molecular machine that injects specific proteins (called effectors) into the cells of the host organism to promote virulence. For example, Salmonella utilize a T3SS to inject actin-rearranging effectors into epithelial cells which modify the structure of the cell membranes and allow Salmonella to enter the cells.

Our specific interest is the T3SS secretion signal -- the structural motif that the T3SS machinery uses to recognize and recruit effector proteins for secretion. We are interested in this interaction because it is a key event in the infection process and because disrupting this interaction could hypothetically destroy the bacteria's ability to invade host cells. The nature of the secretion signal is unknown. Not much is known about the three dimensional structure of the T3SS signal and indeed, opposing theories have been put forth in the literature. Understanding the secretion signal would be represent a significant advance in the study of bacterial pathogenesis and, as noted above, could open the way for a new type of antibiotic -- possibly a small molecule designed to disrupt the effector-T3SS binding interface. By folding of the proposed target peptides and other non-involved peptides as a test, we want to gain structural insight to the mechanism promoting the secretion.

Bacteria that use the Type III Secretion System for infection cause severe illness in hundreds of millions of humans every year and result in a substantial loss of life. Most of these cases are young children in developing nations. Individuals with compromised immune systems such as AIDS patients are also directly threatened by these diseases. The alarming rise of antibiotic resistance in bacteria has created an urgent situation that requires new methods to fight these bacteria. The World Health Organization has identified diarrheal disease as a major challenge to global health and is calling for the immediate development of new intervention strategies. Results from this POEM@HOME project may reveal new horizons for antibiotics development.

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