Matthew B. Lawrenz, Ph.D.

Matthew B. Lawrenz, Ph.D.

Current Lab Members:
Sarah Price - PhD Student
Amanda Pulsifer - PhD Student
Stephanie Lunn - MS Student
Shane Reeves - Undergraduate

Past Lab Members:
Michael Connor, PhD (Institut Pasteur)
Yanwen Sun, MS
Tiva VanCleave, PhD

General Research Interests

  • Host-pathogen interactions
  • Overcoming nutritional immunity by bacterial pathogens
  • Vaccine and antimicrobial development

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 Tier 1 Select Agent.

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

  • molecular biology to generate bacterial mutants,
  • cell culture and microscopy techniques to study bacterial interactions with immune cells,
  • infection models to determine the impact of putative virulence factors on disease and to understand the immune response directed towards Yersinia,
  • preclinical models to study efficacy of novel vaccines and antimicrobials.

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: Zinc acquisition by Y. pestis during infection

Transition metals such as iron (Fe), zinc (Zn) and manganese (Mn) are essential co-factors required for bacterial growth. As such, eukaryotic organisms have developed mechanisms to limit the availability of these metals to restrict the growth of invading bacteria, commonly referred to as nutritional immunity. However, successful bacterial pathogens have in turn evolved high-affinity metal acquisition systems that allow them to acquire these metals and overcome nutritional immunity. The siderophore yersiniabactin, which allows Y. pestis to acquire Fe during infection, is a prime example of a virulence mechanism that allows Y. pestis to overcome nutritional immunity.

Recently, the yersiniabactin biosynthesis machinery has also been shown to be important for Zn acquisition by Y. pestis, likely through the production of a novel zincophore. In collaboration with Drs. Bob Perry and Sylvie Garneau-Tsodikova at the University of Kentucky, we are using a combination of biochemical and genetic approaches to identify and purify this novel zincophore. Furthermore, with Dr. Viveka Vadyvaloo at Washington State University, we are using mammalian and insect models to define the contribution of yersiniabactin-dependent Zn acquisition on the virulence of Y. pestis.

Specific Research Topic 3: 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. Connor M.G., A.R. Pulsifer, D. Chung, E. Rouchka, B.K. Ceresa, and M.B. Lawrenz. 2018. Yersinia pestis subverts the host endosome recycling pathway during macrophage infection. MBio. 9(1). pii: e01800-17. doi: 10.1128/mBio.01800-17. PMID: 29463656.
  2. Bobrov, A.G., O. Kirillina, M.Y. Fosso, J.D. Fetherston, M.C. Miller, T.T. VanCleave, J.A. Burlison, W.K. Arnold, M.B. Lawrenz, S. Garneau-Tsodikova, and R.D. Perry. 2017. Zinc transporters YbtX and ZnuABC are required for the virulence of Yersinia pestis in bubonic and pneumonic plague in mice. Metallomics. 2017 Jun 21;9(6):757-772. doi: 10.1039/c7mt00126f. PMID: 28540946.
  3. Connor, MG., AR. Pulsifer, CT. Price, Y. Abu Kwaik, and MB. Lawrenz. Yersinia pestis requires host Rab1b for survival in macrophages. PLoS Pathogens. October 23, 2015. DOI: 10.1371/journal.ppat.1005241. PMID: 26495854.
  4. Lawrenz, MB., A. Biller, D. Cramer, J. Kranzle, J. Sotsky, C. Vanover, D. Yoder-Himes, A. Pollard, and JM. Warawa. 2015. Development and evaluation of murine lung-specific disease models for Pseudomonas aeruginosa applicable to therapeutic testing. Pathog Dis. 2015 Jul;73(5). pii: ftv025. PMID: 25857733 (Editor's Choice Article for the July 2015 Issue).
  5. 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. 32(39):5035-40. PMID: 25045812.