Our Research Interests
1. Evasion of Innate Immunity During Plague
Subversion of Neutrophils
Neutrophils are the first responders to bacterial infections. They deploy potent antimicrobial mechanisms to kill invading bacteria. We and others have shown, however, that Y. pestis inhibits neutrophil phagocytosis and degranulation by injecting proteins directly into neutrophils through a needle-like apparatus called a Type 3 Secretion System. Without phagocytosis and degranulation, the ability of neutrophils to directly kill Y. pestis is significantly diminished.
Neutrophils also produce signals that alert other immune cells that an infection is occurring. We discovered that Y. pestis subverts two important inflammatory signals: synthesis of inflammatory lipids and production of extracellular vesicles. Using a combination of bacterial mutants, neutrophils in cell culture, and mouse models of plague infection, trainees in the Lawrenz Lab are working to define the impact of inflammatory lipid inhibition on Y. pestis immune evasion and the mechanisms used by Y. pestis to alter extracellular vesicle packaging.
Neutrophils (blue) vs. Y. pestis (red). Imaged by Katelyn Sheneman
Evasion of Macrophage Phagosome Killing
Macrophages phagocytose bacteria and kill engulfed bacteria within phagosomes inside the cell. However, Y. pestis is resistant to killing by macrophages via this mechanism. We discovered that Y. pestis evades macrophage killing by altering the phagosome into a structure called a Yersinia-containing vacuole, or YCV. The biogenesis of the YCV does not allow the delivery of antimicrobial components to the phagosome, thus limiting the macrophage's ability to kill Y. pestis. Eventually, infected macrophages die, releasing viable Y. pestis to continue the infection.
While we now understand why Y. pestis is not killed within macrophages, the bacterial factors responsible for the biogenesis of the YCV are still unknown. Using a combination of bacterial mutants and macrophages in cell culture, trainees in the Lawrenz Lab are pursuing the identification of Y. pestis genes that contribute to YCV generation.
2. Mechanisms of Zinc Acquisition by Bacteria During Infection
Bacteria require metals like iron, zinc, and manganese in order to grow. As such, our bodies restrict access to these metals through mechanisms referred to as nutritional immunity. While nutritional immunity effectively limits infection by a variety of bacteria, Y. pestis has successfully evolved mechanisms to overcome these metal sequestration strategies.
One mechanism is a small molecule synthesized by Y. pestis called yersiniabactin (Ybt), which is essential for iron acquisition and virulence. In collaboration with Drs. Bob Perry and Viveka Vadyvaloo, we discovered that Ybt also contributes to zinc acquisition during infection of mammals and of the insect vector that Y. pestis uses for transmission.
Using an innovative approach called droplet Tn-Seq developed by Dr. Tim van Opijnen, we also identified how Y. pestis secretes Ybt once it is synthesized. Since Ybt is essential for the virulence of Y. pestis and other pathogenic bacteria, trainees in the Lawrenz Lab are using drug discovery and preclinical animal models to develop potential therapeutics that target Ybt and Ybt transport systems as anti-virulence strategies.
3. New Drugs to Combat Antimicrobial-Resistant Infections
The discovery of antibiotics to control bacterial infections opened the door for many of the innovations we have seen in medicine during the last seven decades, including life-altering procedures such as open heart surgery, successful cancer therapies, joint replacement, and organ transplantation. However, as new antibiotics are employed in the clinic, bacterial pathogens quickly evolve mechanisms to become resistant to killing by these drugs.
Today, a growing number of bacteria have acquired resistance to many of the antibiotics used in the clinic. Among these are infections with multidrug resistant (MDR) bacteria that have developed resistance to most — and in some cases all — of the antibiotics currently available. Without the development of new antibiotics, even simple and routine clinical procedures run the risk of introducing life-threatening infections into patients.
In collaboration with Dr. Jon Warawa, the NIH, and the FDA, our lab has developed validated preclinical models to test novel antibiotics against MDR Pseudomonas aeruginosa. These models are key to identifying promising new antimicrobial drugs and provide important proof-of-concept data that can be used to both justify in-human clinical trials and support subsequent FDA approval. Together with researchers worldwide, we have aided in the development of over 10 novel antimicrobial drugs. We maintain support for these preclinical models for future collaborations with those interested in antimicrobial development.