Matthew B. Lawrenz, Ph.D.

Matthew B. Lawrenz, Ph.D.

Current Lab Members

Amanda Pulsifer – Graduate Student
Michael Connor - Graduate Student
Tiva Vancleave - Graduate Student

General Research Interests

  • Host-pathogen interactions

  • Identification of bacterial virulence factors

  • Regulation of virulence factors in bacteria

The genus Yersinia contains three pathogenic species that cause human infection. Two of these species, Y. enterocolitica and Y. pseudotuberculosis, are transmitted by contaminated food or water to cause yersiniosis. Y. pestis is responsible for a significantly more deadly disease known as the plague. Y. pestis has recently evolved from Y. pseudotuberculosis to be transmitted to mammalian hosts by an insect vector (the flea).Y. pestis can also be transmitted from person to person by aerosols. Because of the ability for Y. pestis to infect people through aerosols, the lack of an effective vaccine, and the history of development of Y. pestis as a potential bioweapon, Y. pestis is classified by the federal government as a Select Agent.

In my laboratory, students will be exposed to techniques used to understand host-pathogen interactions. Opportunities are available to study pathogenesis from both the perspective of the bacterium and/or the host. Examples of techniques that will be learned and applied by students in the lab include:

  • using molecular biology to generate bacterial mutants,

  • analyzing gene regulation mechanisms in Yersinia using classical genetics and RNA-based technologies (RT-PCR, microarray analysis),

  • using infection models to determine the impact of putative virulence factors on disease and to understand the immune response directed towards Yersinia,

  • using cell culture and microscopy to study specific interactions between bacteria and host cells.

Specific Research Topic 1: Understanding the ability of Y. pestis to survive in macrophages

Upon phagocytosis, phagosomes undergo a defined maturation process, ultimately resulting in the formation of an acidified phagolysosome where cargo is degraded. To survive this process, intracellular pathogens can either escape from the phagosome or inhibit this maturation process. In the case of Y. pestis, the bacterium remains within the phagosome but actively inhibits phagosome acidification. Eventually this phagosomal compartment is remodeled to form a spacious vacuole called the Yersinia containing vacuole (YCV), where the bacteria replicate. A subset of YCVs also acquires attributes of autophagosomes, suggesting a role for autophagy in Y. pestis intracellular survival/replication.

Despite decades of evidence indicating that Yersinia pestis can survive within macrophages, we have a very poor understanding of how this pathogen overcomes killing by macrophages to form an intracellular replicative niche. With growing data demonstrating the importance of Y. pestis intracellular survival in the development of bubonic plague, it has become critical to understand Y. pestis intracellular growth in order to fully appreciate the early stages of mammalian infection. Our long term goals are to define the mechanisms used by Y. pestis to evade macrophage killing and to elucidate the contribution of intracellular survival to Y. pestis pathogenesis and colonization of the mammalian host.

Specific Research Topic 2: Developing adjuvants to improve plague vaccines

Currently there is not a plague vaccine available. While Y. pestis infection can be treated with antibiotics, the effective treatment window for primary pneumonic infection is very short (less than 24 h after exposure). Furthermore, naturally acquired resistance to antibiotics has been reported, and weaponized Y. pestis could likely be modified to be resistant to antibiotic treatment. Therefore, the development of novel vaccines with protective efficacy against bubonic and pneumonic plague is important to protect against a potential plague epidemic or bioterrorism event.

The rF1-V subunit vaccine for plague adjuvanted with alum generates a protective humoral response in mice, but preclinical studies in nonhuman primates (NHPs) have been less efficacious. Several lines of evidence suggest that the rF1-V vaccine elicits a poor cellular response and this may be responsible for the limited efficacy in NHPs. Because Th1 cell mediated immune responses have been shown to be important for the control/clearance of Y. pestis, an adjuvant system that generates a balanced humoral and cellular immune response could likely improve the efficacy of subunit plague vaccines. Working with Dr. Haval Shirwan’s group, we are testing novel adjuvants to improve cellular responses of this lead candidate subunit vaccine.

Selected publications

  1. Lawrenz, M.B., R. Fodah, M. Gutierrez, and J.M. Warawa. 2014. Intubation-mediated intratracheal (IMIT) instillation: A non-invasive, lung-specific delivery system. JOVE. In Press.

  2. Dinc, G., J.M. Pennington, E.S. Yolcu, M.B.Lawrenz, and H. Shirwan. 2014. Improving the Th1 cellular efficacy of the lead Yersinia pestis rF1-V subunit vaccine using SA-4-1BBL as a novel adjuvant. Vaccine. pii: S0264-410X(14)00941-4.

  3. J.M. Warawa and M.B. Lawrenz. 2014. Bioluminescent imaging of bacteria during mouse infection. Bioluminescent Imaging. Methods Mol. Biol., 1098:169-81.

  4. M.B. Lawrenz, J.M. Pennington, and V.L. Miller. 2013. Acquisition of omptin reveals cryptic virulence function of autotransporter YapE in Yersinia pestis. Mol. Microbiol. 89(2):276-87.

  5. Sun, Y., M.G. Connor, J.M. Pennington, and M.B. Lawrenz. 2012. Development of bioluminescent bioreporters for in vitro and in vivo tracking of Yersinia pestis. PLoS One. 7(10):e47123. PMID: 23071730.

  6. Lenz, J.D., M.B., Lawrenz, D. G.Cotter, M.C. Lane, R.J. Gonzalez, M. Palacios, and V.L. Miller. 2011. Expression during host infection and localization of Yersinia pestis autotransporter proteins (Yaps). J Bacteriol. 193(21):5936-49.

  7. Weening, E.H.,  J.S. Cathelyn, G. Kaufman, M.B. Lawrenz, P. Price, W.E. Goldman, and V.L. Miller. 2011. Dependence of Yersinia pestis capsule for pathogenesis is influenced by mouse background. Infect Immun. 79(2):644-52.

  8. M.B. Lawrenz. 2010. Model systems to study plague pathogenesis and develop new therapeutics. Front. Microbio. doi: 10.3389/fmicb.2010.00119.

  9. Lawrenz, M.B., J.D.  Lenz, and V.L. Miller.  2009. A novel autotransporter adhesin is required for bubonic plague.  Infect. Immun. 77(1):317-326.

  10. Felek, S., M.B. Lawrenz, and E.S. Krukonis. 2008. The Yersinia pestis autotransporter YapC mediates host cell binding, autoaggregation, and biofilm formation. Microbiology. 154 (Pt 6): 1802-1812.