My PhD dissertation: The intersection of bacterial pathogenesis and immunology

In my previous life as a research scientist, I spent 10 years studying microbiology. As an undergraduate, I majored in microbiology (with a chemistry minor), and as a graduate student, I spent six years getting a PhD in microbiology. After that, I joined the team at RealClearScience as its Founding Editor. Inevitably, whenever I tell people this story, they ask, “What did you study in grad school?”

My doctoral dissertation (which is available in part here) examined how structural changes in a bacterial membrane molecule influence the human immune response. Specifically, I examined a bacterial molecule called “lipid A,” which is found only in the outer membrane of Gram-negative bacteria. (Gram-positive bacteria have one membrane, and Gram-negative bacteria have two — an inner and an outer membrane.)

Credit: Jeff Dahl via Wikimedia Commons / CC BY-SA 4.0

The lipid A molecule is medically relevant. The best-known version of the molecule is the one produced by Escherichia coli, and it is the most immunologically active lipid A known. The E. coli lipid A (and other lipid A molecules with a similar structure) strongly activates the human immune response.

This particular immune response, known as inflammation, is normally a good thing. It helps clear our bodies of pathogenic bacteria. But, taken too far, inflammation can be deadly. That’s why blood infections are so serious. Bacteria circulating in the bloodstream can trigger systemic inflammation, which can cause leaky blood vessels, a dramatic drop in blood pressure, multiple organ failure, and death.

Credit: Edgar181 via Wikimedia Commons / Public Domain

However, not all lipid A molecules are created equal. Some are much more immunologically active than others. Look at the E. coli lipid A structure above. See those long, dangly-looking things? Those are fatty acids. E. coli lipid A has six of them. Also, in the upper-left and upper-right corners of the molecule, you should see a “P” (which stands for phosphorus) surrounded by oxygen atoms. Those are phosphate groups. E. coli lipid A has two of them. Deviations from this structure usually result in a much less potent lipid A. That’s where my project comes in.

I was investigating the lipid A molecules produced by Bacteroides fragilis (a two-faced gut bacterium that is sometimes friendly and sometimes evil), Bacteroides thetaiotaomicron (a much friendlier gut bacterium), and the evolutionarily related Porphyromonas gingivalis (the bacterium associated with periodontitis, i.e., severe gum inflammation which can lead to tooth loss.) All three bacteria produce a lipid A molecule with only five fatty acids (instead of six) and one phosphate group (instead of two). All three lipid A molecules are much less potent than that of E. coli, but they are not equal in potency.

In my first paper, we discovered that both species of Bacteroides produce a lipid A molecule that is much more immunologically active than the one produced by Porphyromonas. In my second paper, we figured out why: Bacteroides produces lipid A with a single phosphate group in the upper-right corner of the molecule, while Porphyromonas produces a lipid A with a single phosphate group in the upper-left corner of the molecule. That small difference was responsible for the enormous disparity in immunological potency between the lipid A molecules.

What are the applications of our work? First, understanding the basic microbiology of how bacterial molecules can make us sick is important in and of itself. And second, understanding how lipid A structures activate the immune response could prove useful in designing more effective adjuvants, which are important in producing good vaccines.

This article was originally published on RealClearScience.