- Professor & Chair, Dept. of Microbiology, University of Chicago
- Director, Great Lakes Center for Excellence for Biodefense & Emerging Infectious Diseases Research
The Department of Microbiology
The University of Chicago
920 East 58th Street, CLSC 1117B
Chicago, IL 60637
Phone: 773 834 9060
Fax: 773 834 9060
Our laboratory examines the mechanisms and strategies whereby pathogenic bacteria cause human disease. Several different microbes are being investigated.
The cell wall of Staphylococcus aureus and other Gram-positive pathogens can be viewed as a surface organelle with anchored proteins that interact with the host environment during infection. Our research has revealed four different mechanisms of protein anchoring to the cell wall envelope. Surface proteins bearing a C-terminal sorting signal with a LPXTG motif are cleaved by the sortase A enzyme and linked to the cell wall crossbridges of peptidoglycan. This group of surface proteins is essential for pathogenesis and mediates bacterial attachment to host tissues and escape from the immune system. Surface proteins bearing a C-terminal sorting signal with a NPQTN motif are cleaved by sortase B. This mechanism is involved in iron transport during infection and is required for bacterial persistence in the host. Autolysins are enzymes that cleave the cell wall envelope at defined sites. One group of autolysins, e.g. lysostaphin and f11 hydrolase, is targeted to a receptor that is distributed uniformly over the bacterial surface. Another autolysins is targeted to the equatorial surface rings of staphylococci and mediates peptidoglycan cleavage at cell divisions sites. Our laboratory entertains genetic, molecular biological, biochemical, microscopic as well as animal infectious strategies to reveal mechanisms of protein targeting and the role in the establishment of disease. Our results are useful for the design of new therapies that can be used for the treatment of human infections caused by S. aureus and other Gram-positive bacteria.
Pathogenic Yersinia spp. invade their human hosts and colonize lymphoid tissues. This unique infectious strategy requires bacterial mechanisms of immune evasion. Yersinia type III secretion prevents the phagocytic killing of bacteria during infection. Further, the type III machinery intoxicates and kills immune cells, thereby impairing the host’s ability to clear invasive Yersinia. In fact, the pathogenesis of the most notorious of all pathogens, Yersinia pestis - the causative agent of plague, relies on the type III secretion machinery. We are interested in the mechanisms of protein recognition and transport by the type III machinery. Our results suggest that mRNAs of Yops, the substrates of the type III machinery, harbor signals that lead to the secretion of the encoded polypeptide chains. Current work is mapping the secretion signals and analyzing the mode of mRNA recognition by the type III machinery. A second area of research is the regulation of the type III secretion machinery. Upon bacterial entry into the host, Yersinia sense three environmental signals: a temperature shift to 37 ºC, glutamate ions as well as serum proteins. These signals trigger yersiniae to express and assemble the type III machinery and to transport YopB, YopD, YopR and LcrV into the extra-cellular milieu. Docking of yersiniae on the surface of immune cells leads to the insertion of type III secretion machinery needles into the plasma membrane of host cells and in sensing of the low calcium concentration of the cell’s interior. Yersinia respond to the low calcium signal by transporting YopE, YopH, YopM, YopN, YopO, YopP, YopT and YscM (LcrQ) into the cytosol of host cells. The sum of the function of these toxic proteins leads to a block in phagocytosis and in the killing of macrophages. Research on type III secretion represents a hotly contested frontier of microbiological science. Our results will be useful for the treatment of human infections caused by Yersinia, including the biological warfare agent Yersinia pestis, as well as several other Gram-negative pathogens.