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C-di-AMP signaling in bacterial physiology and pathogenesis
C-di-AMP signaling in bacterial physiology and pathogenesis
In order to adapt, bacteria need to survey environmental conditions and reprogram themselves accordingly. There are many signaling mechanisms that enable bacteria to sense the environment, relay the signals, and regulate relevant molecular targets. Nucleotide second messengers are important components of all these events that ultimately facilitate bacterial growth and adaptation.
C-di-AMP is a ubiquitous nucleotide second messenger produced by thousands of bacterial species representing important human pathogens, gut symbionts, and environmental bacteria. C-di-AMP is essential to the growth of many bacteria, and its depletion results in loss of virulence, increased antibiotic susceptibility, among other defects. However, bacteria that produce c-di-AMP also need to maintain a balanced level of this nucleotide, since c-di-AMP accumulation also attenuates virulence and diminishes stress response.
A major focus of our lab is to understand how c-di-AMP mediates bacterial stress response, adaptation, and pathogenesis. Our models for c-di-AMP work are the human pathogen Listeria monocytogenes, the first bacterium found to make c-di-AMP; and the Gram-positive model Bacillus subtilis. Active projects address the following themes:
How do bacteria regulate c-di-AMP levels to achieve homeostasis?
How does c-di-AMP regulate its molecular targets?
How does c-di-AMP regulate bacterial adaptation in mammalian hosts?
Mechanisms of antibiotic resistance
Mechanisms of antibiotic resistance
Antibiotic resistance is a prominent public health threat, with estimated 2.8 million antibiotic-resistant infections a year in the US. A long-term goal of our lab is to develop novel antibiotics or adjuvants that potentiate the efficacy of current antibiotics. We currently focus on understanding resistance mechanisms to cell wall-targeting antibiotics, including beta-lactams and D-cycloserine. Active projects address the following themes:
The mechanisms by which c-di-AMP regulates bacterial cell wall synthesis and integrity
The resistance mechanisms to D-cycloserine in Gram-positive bacteria
The impacts of listeriosis on gut health
The impacts of listeriosis on gut health
Listeria monocytogenes is abundant in the natural environments, especially in dairy farms, and readily contaminates the food chain. Although listeriosis can cause devastating health consequences in susceptible individuals, the vast majority of healthy people and animals are asymptomatic upon L. monocytogenes infection. During the intestinal phase of infection, L. monocytogenes can antagonize and kill related species in the GI tract. Thus, asymptomatic listeriosis may impact gut health. Using cattle as a model, we currently investigate the following questions:
Does asymptomatic carriage of L. monocytogenes reduce microbial complexity in the GI tract?
Does the composition of the GI tract microbiota affect the outcome of Listeria infection?
Discovery of natural antimicrobials for food safety and infectious disease treatments
Discovery of natural antimicrobials for food safety and infectious disease treatments
Combating antibiotic resistance requires continual discovery and development of new antibiotics, or adjuvants that increase the efficacies of current antibiotics. We employ both culture-based and culture-independent approaches to identify novel antimicrobials from diverse environmental and food fermentation microbiota. Active projects address the following themes:
Develop biocontrol agents for foodborne pathogens, such as Listeria monocytogenes, from the food microbiota and food-grade microorganisms
Discover novel antimicrobials from various microbiota for treatment of infectious diseases in humans and animals
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