Charlie Mo
· Assistant Professor of BacteriologyVerifiedUniversity of Wisconsin-Madison · Bacteriology
Active 2013–2025
About
Charlie Mo is an Assistant Professor of Bacteriology at the University of Wisconsin-Madison, with a research focus on the interface between bacterial immunity and evolution. His lab studies how bacterial defense systems, such as CRISPR-Cas, influence bacterial variation and adaptation during active immunity. His work investigates the mechanisms by which cellular processes like transcription modulate bacterial immunity and how different selective pressures shape the activity of bacterial defense systems. Mo's research aims to understand how CRISPR-Cas immunity impacts bacterial evolution, particularly in relation to horizontal gene transfer, mutagenesis, and antimicrobial resistance. His contributions include demonstrating that CRISPR-Cas immunity can promote increased mutation rates inside bacteria, enabling adaptation to stressors, and exploring how bacterial immune systems influence genetic variation and bacterial adaptability over time.
Research topics
- Biology
- Genetics
- Computational biology
- Computer Science
- Combinatorics
- Physics
Selected publications
Nature Communications · 2025-07-01 · 5 citations
articleOpen accessA remarkable feature of CRISPR-Cas systems is their ability to acquire short sequences from invading viruses to create a molecular record of infection. These sequences, called spacers, are inserted into the CRISPR locus and mediate sequence-specific immunity in prokaryotes. In type II-A CRISPR systems, Cas1, Cas2 and Csn2 form a supercomplex with Cas9 to integrate viral sequences. While the structure of the integrase complex has been described, a detailed functional analysis of the spacer acquisition machinery is lacking. We developed a genetic system that combines deep mutational scanning (DMS) of Streptococcus pyogenes cas genes with a method to select bacteria that acquire new spacers. Here, we show that this procedure reveals key interactions at the Cas1-Cas2 interface critical for spacer integration, identifies Cas variants with enhanced spacer acquisition and immunity against phage infection, and provides insights into the molecular determinants of spacer acquisition, offering a platform to improve CRISPR-Cas-based applications.
eLife · 2025-06-02 · 1 citations
preprintOpen accessSenior authorAbstract Bacteriophage (phage) therapy is a promising means to combat drug-resistant bacterial pathogens. Infection by phage can select for mutations in bacterial populations that confer resistance against phage infection. However, resistance against phage can yield evolutionary trade-offs of biomedical relevance. Here we report the discovery that infection by certain staphylococcal phages sensitizes different strains of methicillin-resistant Staphylococcus aureus (MRSA) to β-lactams, a class of antibiotics against which MRSA is typically resistant. MRSA cells that survive infection by these phages display significant reductions in minimal inhibitory concentration against different β-lactams compared to uninfected bacteria. Transcriptomic profiling reveals that these evolved MRSA strains possess highly modulated transcriptional profiles, where numerous genes involved in S. aureus virulence were downregulated. Phage-treated MRSA exhibited attenuated virulence phenotypes in the form of reduced hemolysis and clumping. Despite sharing similar phenotypes, whole-sequencing analysis revealed that the different MRSA strains evolved unique genetic profiles during infection. These results suggest complex evolutionary trajectories in MRSA during phage predation and open up new possibilities to reduce drug resistance and virulence in MRSA infections.
Systematic, high-throughput characterization of bacteriophage gene essentiality on diverse hosts
Cell Host & Microbe · 2025-07-22 · 10 citations
articleOpen access2025-06-02
peer-reviewOpen accessSenior authorBacteriophage (phage) therapy is a promising means to combat drug-resistant bacterial pathogens. Infection by phage can select for mutations in bacterial populations that confer resistance against phage infection. However, resistance against phage can yield evolutionary trade-offs of biomedical relevance. Here we report the discovery that infection by certain staphylococcal phages sensitizes different strains of methicillin-resistant Staphylococcus aureus (MRSA) to β-lactams, a class of antibiotics against which MRSA is typically resistant. MRSA cells that survive infection by these phages display significant reductions in minimal inhibitory concentration against different β-lactams compared to uninfected bacteria. Transcriptomic profiling reveals that these evolved MRSA strains possess highly modulated transcriptional profiles, where numerous genes involved in S. aureus virulence were downregulated. Phage-treated MRSA exhibited attenuated virulence phenotypes in the form of reduced hemolysis and clumping. Despite sharing similar phenotypes, whole-sequencing analysis revealed that the different MRSA strains evolved unique genetic profiles during infection. These results suggest complex evolutionary trajectories in MRSA during phage predation and open up new possibilities to reduce drug resistance and virulence in MRSA infections.
2025-07-10
peer-reviewOpen accessSenior authorMRSA (short for methicillin-resistant Staphylococcus aureus) is a commonly found group of bacteria that spread primarily through skin-to-skin contact. Unlike other S. aureus strains, MRSA is resistant to a class of commonly used antibiotics known as ß-lactams. As a result, MRSA infections are extremely difficult to treat and can lead to potentially life-threatening conditions, such as pneumonia and sepsis. It has been suggested that another way to eliminate drug-resistant bacteria like MRSA is to treat them with bacteriophages, viruses that specifically infect and kill bacteria. However, bacteria can become resistant to these phages as well. Interestingly, this can result in an evolutionary trade-off: as bacteria become more resistant to phages, they become less resistant to antibiotics. Could this trade-off also occur in MRSA? To investigate, Tran et al. exposed different strains of MRSA to bacteriophages. While most bacterial cells were killed off, a small fraction survived and regrew to form a new population. Tran et al. found that the phage-resistant MRSA population became sensitive once again to ß-lactam antibiotics. Genetic analysis also revealed that the regrown MRSA population activated a different set of genes. Specifically, they downregulated genes that trigger and promote infections, as well as genes associated with cell-to-cell communication. These findings suggest that bacteriophages could be a valuable tool for restoring antibiotic sensitivity in MRSA and offer fresh insights into how drug resistance evolves. Additionally, the study highlights how S. aureus bacteria genetically respond to bacteriophage infections. Further research is needed to better understand the molecular mechanisms behind this phage- and antibiotic-resistance trade-off.
eLife · 2025-07-10
articleOpen accessSenior authorBacteriophage (phage) therapy is a promising means to combat drug-resistant bacterial pathogens. Infection by phage can select for mutations in bacterial populations that confer resistance against phage infection. However, resistance against phage can yield evolutionary trade-offs of biomedical relevance. Here, we report the discovery that infection by certain staphylococcal phages sensitizes different strains of methicillin-resistant Staphylococcus aureus (MRSA) to β-lactams, a class of antibiotics against which MRSA is typically resistant. MRSA cells that survive infection by these phages display significant reductions in minimal inhibitory concentration against different β-lactams compared to uninfected bacteria. Transcriptomic profiling reveals that these evolved MRSA strains possess highly modulated transcriptional profiles, where numerous genes involved in S. aureus virulence are downregulated. Phage-treated MRSA exhibited attenuated virulence phenotypes in the form of reduced hemolysis and clumping. Despite sharing similar phenotypes, whole-sequencing analysis revealed that the different MRSA strains evolved unique genetic profiles during infection. These results suggest complex evolutionary trajectories in MRSA during phage predation and open up new possibilities to reduce drug resistance and virulence in MRSA infections.
eLife · 2024-10-25 · 1 citations
articleOpen accessSenior authorBacteriophage (phage) therapy is a promising means to combat drug-resistant bacterial pathogens. Infection by phage can select for mutations in bacterial populations that confer resistance against phage infection. However, resistance against phage can yield evolutionary trade-offs of biomedical relevance. Here, we report the discovery that infection by certain staphylococcal phages sensitizes different strains of methicillin-resistant Staphylococcus aureus (MRSA) to β-lactams, a class of antibiotics against which MRSA is typically resistant. MRSA cells that survive infection by these phages display significant reductions in minimal inhibitory concentration against different β-lactams compared to uninfected bacteria. Transcriptomic profiling reveals that these evolved MRSA strains possess highly modulated transcriptional profiles, where numerous genes involved in S. aureus virulence are downregulated. Phage-treated MRSA exhibited attenuated virulence phenotypes in the form of reduced hemolysis and clumping. Despite sharing similar phenotypes, whole-sequencing analysis revealed that the different MRSA strains evolved unique genetic profiles during infection. These results suggest complex evolutionary trajectories in MRSA during phage predation and open up new possibilities to reduce drug resistance and virulence in MRSA infections.
Systematic, high-throughput characterization of bacteriophage gene essentiality on diverse hosts
bioRxiv (Cold Spring Harbor Laboratory) · 2024 · 2 citations
- Computer Science
- Biology
- Computational biology
Understanding core and conditional gene essentiality is crucial for decoding genotype-phenotype relationships in organisms. We present PhageMaP, a high-throughput method to create genome-scale phage knockout libraries for systematically assessing gene essentiality in bacteriophages. Using PhageMaP, we generate gene essentiality maps across hundreds of genes in the model phage T7 and the non-model phage Bas63, on diverse hosts. These maps provide fundamental insights into genome organization, gene function, and host-specific conditional essentiality. By applying PhageMaP to a collection of anti-phage defense systems, we uncover phage genes that either inhibit or activate eight defenses and offer novel mechanistic hypotheses. Furthermore, we engineer synthetic phages with enhanced infectivity by modular transfer of a PhageMaP-discovered defense inhibitor from Bas63 to T7. PhageMaP is generalizable, as it leverages homologous recombination, a universal cellular process, for locus-specific barcoding. This versatile tool advances bacteriophage functional genomics and accelerates rational phage design for therapy.
If you can’t beat them, join them: Anti-CRISPR proteins derived from CRISPR-associated genes
Cell Host & Microbe · 2024
1st authorCorresponding- Biology
- Genetics
- Computational biology
eLife · 2024-10-25 · 1 citations
preprintOpen accessSenior authorAbstract Bacteriophage (phage) therapy has been proposed as a means to combat drug-resistant bacterial pathogens. Infection by phage can select for mutations in bacterial populations that confer resistance against phage infection. However, resistance against phage can yield evolutionary trade-offs of biomedical use. Here we report the discovery of staphylococcal phages that cause different strains of methicillin-resistant Staphylococcus aureus (MRSA) to become sensitized to β-lactams, a class of antibiotics against which MRSA is typically highly resistant. MRSA cells that survive infection by these phages display significant reductions in minimal inhibitory concentration against different β-lactams compared to uninfected bacteria. Phage-treated MRSA further exhibited attenuated virulence phenotypes in the form of reduced hemolysis and clumping. Sequencing analysis revealed that the different MRSA strains evolved unique genetic profiles during infection. These results suggest complex evolutionary trajectories in MRSA during phage predation and open up new possibilities to reduce drug resistance and virulence in MRSA infections.
Recent grants
Biochemical and cellular DNA targeting by the type III-A CRISPR-Cas system
NIH · $120k · 2018–2020
Frequent coauthors
- 9 shared
Luciano A. Marraffini
Howard Hughes Medical Institute
- 8 shared
Rahul M. Kohli
University of Pennsylvania
- 6 shared
Matthew J. Culyba
University of Pittsburgh
- 3 shared
Jacob Mathai
Rockefeller University
- 3 shared
Jeffrey Kubiak
University of Minnesota Medical Center
- 3 shared
Jakob T. Rostøl
Imperial College London
- 3 shared
Mark Goulian
University of Pennsylvania
- 2 shared
Ning Jia
Tongji University
Labs
Mo LabPI
Education
- 2016
Ph.D., Biochemistry & Molecular Biophysics
University of Pennsylvania Perelman School of Medicine
- 2010
B.A., Chemistry & Biochemistry
Swarthmore College
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