Studying signaling and gene regulation in bacteria

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Lee Kroos (view larger image)

Countless communities of bacteria called microbiomes live on and inside the human body. They can also develop on food and within drain pipes, to name just a few other places. In fact, one study estimates that there are 10 times more bacterial cells than human cells within the body. And another shows as many as 20,000 species of bacteria in 1 quart of seawater. To discover ways to break down and fend off infectious bacteria, scientists must understand how cells integrate signals from one another and the environment, and how they respond by changing gene expression, metabolism, motility and morphology.

Unraveling how these mechanisms work will likely spur advancements of medical, agricultural and environmental importance. Michigan State University (MSU) AgBioResearch scientist Lee Kroos is conducting basic research on Bacillus subtilis and Myxococcus xanthus, soil bacteria that are model organisms for understanding cell-to-cell signaling and changes in gene expression that cause cell differentiation. B. subtilis is well-studied by the scientific community, in part because of its ability to form spores. Spores are extremely difficult to kill and facilitate the spread of some infectious bacteria. M. xanthus is known for the rapid formation of multicellular structures, some consisting of up to 100,000 cells, called fruiting bodies.

Kroos, professor in the MSU departments of Biochemistry and Molecular Biology, and Microbiology and Molecular Genetics, studies the biochemical and genetic simplicity of these bacteria during development to explore the molecular mechanisms of signaling and gene regulation. Ultimately, he aims to establish new paradigms based on these well-documented bacteria that can be applied to other more difficult-to-work-with and less-well-understood microorganisms.

“Manipulation of microbial communities to improve life and solve global problems will depend on knowledge of how bacteria interact with one another and their environment,” Kroos said. “Microbial communities affect global processes such as cycling of elements between soil, water and air, and primary productivity of the oceans. They have impacts on ecosystems and all the
organisms that inhabit them.”

In 2014, Kroos published a paper that provides key insight into the formation of fruiting bodies. M. xanthus are predatorlike and feed on other bacteria. When they run out of food, the microbes go through a developmental process by which thousands of cells aggregate to form the fruiting body. The long, rod-shaped bacterial cells then convert into round spores. With funding from the National Science Foundation, Kroos and his team discovered that there are two coordinated signaling pathways responsible for prompting the cells to change shape.

“You have these two transcription factors — things that control gene expression — one that responds to starvation and the other that responds to the cells being close together,” he said. “If you have both signals, we found that the two transcription factors bind cooperatively to the DNA to regulate genes that are needed for sporulation. It’s a way to integrate the signals with these transcription factors.”

Like M. xanthus, B. subtilis also undergoes development when starved. The cell is partitioned into two compartments — the mother cell and the forespore — each of which expresses distinct sets of genes in an ordered temporal fashion under the control of different subunits of RNA polymerase. The signaling between the forespore and the mother cell is based on an enzyme that is present in nearly all living organisms. In human health, it regulates diverse signaling pathways and is implicated in some disease processes. In a study funded by the National Institutes of Health, Kroos and his research team isolated a stable form of the enzyme along with its substrate to create the first such data-based model of its kind.

“Nobody else has been able to isolate a stable complex like that,” he said. “We have done cross-linking studies where we form crosslinks between the two proteins. We can tell where those cross-links are. It’s allowed us to build a model of the enzyme-substrate complex. There is currently no other model for such a complex. It’s a model, not a structure – but structures of these things are extremely hard to obtain.”

In the midst of drafting a manuscript on the project, Kroos is excited about the possibilities. He said other scientists will be able to use this model in efforts to figure out how to inhibit the enzyme, thereby stopping sporulation of related bacteria and making them less infectious. He said that could be a step toward designing a new antibiotic. Kroos has devoted much of his 27-year career at MSU to studying these two bacteria. M. xanthus is part of the myxobacteria family, which has been used as biological control agents. They also make lots of compounds, including a new anticancer compound used in breast cancer treatment.

B. subtilis is not pathogenic to humans, but it is related to Bacillus anthracis, which causes anthrax. Kroos said the research is important because limited understanding of how microbes control complex behaviors in response to one another and their environment impedes our ability to harness the microbes for pollution and climate control, and for increased bioenergy and food production. He said more work needs to be done in educating the general public about such things as beneficial bacteria. Therefore, in addition to training postdocs and graduate and undergraduate students in the lab, Kroos conducts outreach with various community organizations.

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