Dr. Caroline M. Grunenwald

Caroline Grunenwald
Assistant Professor of Biological Sciences
305 Tucker Hall

Ph.D. Microbiology, University of Tennessee-Knoxville

Research Summary

Staphylococcus aureus stress responses at the host-pathogen interface

Research Description

During infection of a host, bacterial pathogens encounter tremendous stress imposed by the host immune system and the antibiotics used treat the infection. My lab is broadly interested in understanding the types of stress pathogens encounter during infection and the molecular mechanisms that enable bacteria to circumvent these assaults and cause disease.

Staphylococcus aureus, a Gram-positive bacterium, asymptomatically colonizes a third of the human population and is capable of infecting nearly every site within the human body. S. aureus is a leading cause of skin and soft tissue infections, infective endocarditis, osteomyelitis, and hospital-acquired pneumonia.  The public health threat of S. aureus is compounded by the rise of antibiotic resistance, most notably methicillin-resistant S. aureus (MRSA). We hypothesize the ability of S. aureus to sense environmental changes and accordingly shift cellular physiology enables S. aureus to occupy diverse tissue niches and confers intrinsic resistance to antibiotic treatments. These stress responses promote S. aureus virulence, persistence, and success as a pathogen. 

One important way bacteria respond to environmental stress is through kinase signal cascades where a kinase phosphorylates partner proteins in response to a specific trigger (e.g.  cell wall damage, low pH, nutrient deprivation, etc.). Phosphorylation of a partner protein may affect enzymatic activity, regulation of transcription, protein abundance, etc., ultimately leading to shifts in cellular physiology. Two component systems consisting of a histidine kinase and a corresponding response transcriptional regulator are the most well recognized and studied phospho-signaling systems in bacteria. Bacteria also encode for serine/threonine and tyrosine kinases, however a clear understanding of this class of post-translational modifications and their role in bacterial physiology is lacking. 

Our laboratory and others have identified Stk1, a eukaryotic-like serine/threonine kinase with penicillin-binding-protein and serine/threonine kinase-associated (PASTA) domains, as a master regulator of S. aureus metabolism that plays a central role in regulating intrinsic β-lactam antibiotic resistance in Methicillin-resistant Staphylococcus aureus (MRSA). Deletion or pharmacologic inhibition of stk1 drastically sensitizes MRSA to β-lactams, suggesting targeting Stk1 or Stk1 substrates could be an effective strategy towards developing novel antimicrobial therapies. However, we still lack a comprehensive understanding of the Stk1-dependent signaling cascades and their contribution to antibiotic resistance and persistence on or within a host. Recently our laboratory and others have identified several putative Stk1 interaction partners with diverse functions in cell physiology that include DNA repair, purine metabolism, carbohydrate utilization, cell signaling, transcriptional regulation, cell wall remodeling, oxidative stress responses, and metal metabolism. Utilizing a combination of bacterial genetics, biochemistry, microscopy, -omics studies, and animal models, we ask fundamental questions about how signaling systems like Stk1 and post-translational protein modifications of kinase substrates are used to fine tune S. aureus physiology and subsequently promote survival in a host. By elucidating these molecular mechanisms of resistance, we seek to identify novel antimicrobial targets for the development of innovative antibiotic targets and antimicrobial strategies. 

Awards and Honors

American Heart Association Postdoctoral Research Fellowship Award, 2021
University of Dubuque Alumni Award of Merit, 2018
UTCVM Dr. John C. New, JR. Award for Excellence in Public Health or Epidemiological Research, 2014
Gamma Sigma Delta Honor Society Graduate Student Award of Merit for Excellence in Agricultural Research, 2014
University of Tennessee Graduate Teaching Assistant Award for Outstanding Teaching, 2014
University of Dubuque Robert M. Miller Excellence in Biology Award, 2008

Selected Publications

See Google Scholar for a list of Dr. Grunenwald's publications.