The research in my laboratory involves developing new technologies and innovative approaches to generate useful therapies (drugs and vaccines) against human and animal infections of both bacterial and viral pathogens. With the growing support for nucleic acid vaccines, we have launched projects employing our novel adjuvant system with plasmid DNA vaccines (pDNA) for Infectious Bronchitis Virus (IBV), SARS-CoV-2, and M. avium subsp. paratuberculosis (M. ap). We recently began work on RNA vaccine platforms for both M. tuberculosis (M. tb) and SARS-CoV-2. We are also utilizing genetically modified whole organisms to develop more effective vaccines against tuberculosis (against M. tb, M. bovis) and Johne’s disease.
Our research is also greatly devoted to understanding bacterial pathogenesis in order to improve the therapies we create. We developed novel approaches to address specific questions relevant to bacterial pathogenesis such as the identification of types of genes expressed during infection and the host responses to such gene products. Currently, we are working on the functional genomics of M. tuberculosis (M. tb) and M. avium subsp. paratuberculosis (M. ap). In particular, we are investigating questions related to the role of copper metabolism on M. tb persistence and the role played by key global gene regulators on M. ap survival during infection.
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Viral Vaccine Technologies
Poultry viruses:
• Infectious Bronchitis Virus and Avian Influenza Virus cost the poultry industry billions of dollars per year and affect food security for those that consume poultry products. A sufficient vaccine would protect against infection and spread, be easily administered, and be cost effective to poultry farmers. With these factors in mind, our research team is focusing on strategies to generate novel vectored and pDNA vaccines.
SARS-CoV-2:
• In late 2019 – early 2020, the world became aware of the coronaviruses when the pandemic hit. Since then, there have been more than 63 million reported cases and almost 850K deaths in the US. The need for a vaccine became evident, and so we got to work immediately. Our lab has developed a pDNA vaccine and is currently working on an RNA-based vaccine to combat the emergence of variants.
Adjuvant Development:
• The delivery of naked nucleic acid vaccines to cells is less efficient than nucleic acid encapsulated in an adjuvant. Not only does the adjuvant assist with delivery of the nucleic acid into the cells, but it also stimulates the innate immune system. With this in mind, our lab developed a novel nanoparticle adjuvant system for pDNA. Since its development, we continue to modify and improve the design.
Bacterial Vaccine Developments
M. tuberculosis
• Tuberculosis is a serious bacterial infection of the lungs caused by Mycobacterium tuberculosis. According to the WHO, it is also the second leading infectious killer after COVID-19. Part of the reason M. tb is so dangerous is because it can only partially be prevented by current vaccines. To remedy this, our team has focused its efforts on developing sufficient vaccines against TB using strategies such as pDNA, RNA, and genetic modification.
M. avium
• Nontuberculous mycobacterial (NTM) infections are on the rise among immunocompromised and immunocompetent individuals. Treatment of NTM infection requires prolonged administration of antibiotics that leads to the rise of antibacterial resistance among NTMs. M.avium infections contribute to more than 50% of all NTM infections, and so our lab has taken what we know about other mycobacterial vaccines that we have worked on to begin construction on an NTM vaccine targeting M.avium.
Johne’s Disease
• Johne’s Disease in cattle is the cause of low milk production and increased mortality for infected animals. In WI, it is expected that 50% of cattle herds will suffer from Johne’s Disease: resulting in a $500 loss per animal in each herd. A sufficient, cost-effective vaccine against avium subsp. Paratuberculosis (M. ap), the causative agent of Johne’s Disease, is necessary to protect the dairy industry. Our lab has been working on the development of a live-attenuated vaccine that provides protective immunity against M. ap in cattle.
Bacterial Genomic Analysis and Diagnostics
Mycobacterial Pathogenesis:
• Utilizing various approaches, including transcriptomics, gene knockouts and scanning transmission electron microscopy (STEM), our lab is able to make mutations in tuberculosis for the purpose of studying pathogenesis and virulence. Knowledge gained from these experiments will lead to a better understanding of M. tuberculosis and aid in the development of a live attenuated vaccine.
Copper Metabolism
• Copper plays a key role in pathogenesis of tuberculosis and the life of many other intracellular pathogens. Our group discovered a novel copper sensitive operon (CSO) that helps in pumping out mycobacterial intracellular copper outside the cell. We are working to understand if the CSO and its transcriptional regulator (csoR) play a role in virulence and pathogenesis of tuberculosis.
Whole Genome Sequencing
• The average size of a Mycobacterium species genome is greater than 4 billion base pairs. In order to identify the species and characterize the antibacterial resistance for an isolate, our lab utilizes whole genome sequencing to understand evolution of mycobacterial infections and how they develop drug resistance phenotypes. Our lab has worked with Wisconsin Human and Dairy Isolates as well as isolates obtained from collaborators in Egypt.