With respiratory illness season in full swing, a bad night’s sleep, sore throat, and desire to cancel dinner plans could all be considered hallmark symptoms of the flu, Covid-19 or other illnesses. Although everyone has, at some point, experienced illness and these stereotypical symptoms, the mechanisms that generate them are not well understood.

Zuri Sullivan, a new assistant professor in the MIT Department of Biology and core member of the Whitehead Institute for Biomedical Research, works at the interface of neuroscience, microbiology, physiology, and immunology to study the biological workings underlying illness. In this interview, she describes her work on immunity thus far as well as research avenues — and professional collaborations — she’s excited to explore at MIT.

Q: What is immunity, and why do we get sick in the first place? 

A: We can think of immunity in two ways: the antimicrobial programs that defend against a pathogen directly, and sickness, the altered organismal state that happens when we get an infection. 

Sickness itself arises from brain-immune system interaction. The immune system is talking to the brain, and then the brain has a system-wide impact on host defense via its ability to have top-down control of physiologic systems and behavior. People might assume that sickness is an unintended consequence of infection, that it happens because your immune system is active, but we hypothesize that it’s likely an adaptive process that contributes to host defense. 

If we consider sickness as immunity at the organismal scale, I think of my work as bridging the dynamic immunological processes that occur at the cellular scale, the tissue scale, and the organismal scale. I’m interested in the molecular and cellular mechanisms by which the immune system communicates with the brain to generate changes in behavior and physiology, such as fever, loss of appetite, and changes in social interaction. 

Q: What sickness behaviors fascinate you? 

A: During my thesis work at Yale University, I studied how the gut processes different nutrients and the role of the immune system in regulating gut homeostasis in response to different kinds of food. I’m especially interested in the interaction between food, the immune system, and the brain. One of the things I’m most excited about is the reduction in appetite, or changes in food choice, because we have what I would consider pretty strong evidence that these may be adaptive. 

Sleep is another area we’re interested in exploring. From their own subjective experience, everyone knows that sleep is often altered during infection. 

I also don’t just want to examine snapshots in time. I want to characterize changes over the course of an infection. There’s probably going to be individual variability, which I think may be in part because pathogens are also changing over the course of an illness — we’re studying two different biological systems interacting with each other. 

Q: What sorts of expertise are you hoping to recruit to your lab, and what collaborations are you excited about pursuing?

A: I really want to bring together different areas of biology to think about organism-wide questions. The thing that’s most important to me is people who are creative — I’d rather trainees come in with an interesting idea than a perfectly formed question within the bounds of what we already believe to be true. I’m also interested in people who would complement my expertise; I’m fascinated by microbiology, but I don’t have any formal training.

The Whitehead Institute is really invested in interdisciplinary work, and there’s a natural synergy between my work and the other labs in this small community at the Whitehead Institute.

I’ve been collaborating with Sebastian Lourido’s lab for a few years, looking at how Toxoplasma gondii influences social behavior, and I’m excited to invest more time in that project. I’m also interested in molecular neuroscience, which is a focus of Siniša Hrvatin’s lab. That lab is interested in the hypothalamus, and trying to understand the mechanisms that generate torpor. My work also focuses on the hypothalamus because it regulates homeostatic behaviors that change during sickness, such as appetite, sleep, social behavior, and body temperature. 

By studying different sickness states generated by different kinds of pathogens — parasites, viruses, bacteria — we can ask really interesting questions about how and why we get sick. 

Numerous potential treatments for neurological conditions, including autism spectrum disorders, have worked well in mice but then disappointed in humans. What would help is a non-invasive, objective readout of treatment efficacy that is shared in both species. 

In a new open-access study in Nature Communications, a team of MIT researchers, backed by collaborators across the United States and in the United Kingdom, identifies such a biomarker in fragile X syndrome, the most common inherited form of autism.

Led by postdoc Sara Kornfeld-Sylla and Picower Professor Mark Bear, the team measured the brain waves of human boys and men, with or without fragile X syndrome, and comparably aged male mice, with or without the genetic alteration that models the disorder. The novel approach Kornfeld-Sylla used for analysis enabled her to uncover specific and robust patterns of differences in low-frequency brain waves between typical and fragile X brains shared between species at each age range. In further experiments, the researchers related the brain waves to specific inhibitory neural activity in the mice and showed that the biomarker was able to indicate the effects of even single doses of a candidate treatment for fragile X called arbaclofen, which enhances inhibition in the brain.

Both Kornfeld-Sylla and Bear praised and thanked colleagues at Boston Children’s Hospital, the Phelan-McDermid Syndrome Foundation, Cincinnati Children’s Hospital, the University of Oklahoma, and King’s College London for gathering and sharing data for the study.

“This research weaves together these different datasets and finds the connection between the brain wave activity that’s happening in fragile X humans that is different from typically developed humans, and in the fragile X mouse model that is different than the ‘wild-type’ mice,” says Kornfeld-Sylla, who earned her PhD in Bear’s lab in 2024 and continued the research as a FRAXA postdoc. “The cross-species connection and the collaboration really makes this paper exciting.”

Bear, a faculty member in The Picower Institute for Learning and Memory and the Department of Brain and Cognitive Sciences at MIT, says having a way to directly compare brain waves can advance treatment studies.

“Because that is something we can measure in mice and humans minimally invasively, you can pose the question: If drug treatment X affects this signature in the mouse, at what dose does that same drug treatment change that same signature in a human?” Bear says. “Then you have a mapping of physiological effects onto measures of behavior. And the mapping can go both ways.”

Peaks and powers

In the study, the researchers measured EEG over the occipital lobe of humans and on the surface of the visual cortex of the mice. They measured power across the frequency spectrum, replicating previous reports of altered low-frequency brain waves in adult humans with fragile X and showing for the first time how these disruptions differ in children with fragile X.

To enable comparisons with mice, Kornfeld-Sylla subtracted out background activity to specifically isolate only “periodic” fluctuations in power (i.e., the brain waves) at each frequency. She also disregarded the typical way brain waves are grouped by frequency (into distinct bands with Greek letter designations delta, theta, alpha, beta, and gamma) so that she could simply juxtapose the periodic power spectra of the humans and mice without trying to match them band by band (e.g., trying to compare the mouse “alpha” band to the human one). This turned out to be crucial because the significant, similar patterns exhibited by the mice actually occurred in a different low-frequency band than in the humans (theta vs. alpha). Both species also had alterations in higher-frequency bands in fragile X, but Kornfeld-Sylla noted that the differences in the low-frequency brainwaves are easier to measure and more reliable in humans, making them a more promising biomarker.

So what patterns constitute the biomarker? In adult men and mice alike, a peak in the power of low-frequency waves is shifted to a significantly slower frequency in fragile X cases compared to in neurotypical cases. Meanwhile, in fragile X boys and juvenile mice, while the peak is somewhat shifted to a slower frequency, what is really significant is a reduced power in that same peak.

The researchers were also able to discern that the peak in question is actually made of two distinct subpeaks, and that the lower-frequency subpeak is the one that varies specifically with fragile X syndrome.

Curious about the neural activity underlying the measurements, the researchers engaged in experiments in which they turned off activity of two different kinds of inhibitory neurons that are known to help produce and shape brain wave patterns: somatostatin-expressing and parvalbumin-expressing interneurons. Manipulating the somatostatin neurons specifically affected the lower-frequency subpeak that contained the newly discovered biomarker in fragile X model mice.

Drug testing

Somatostatin interneurons exert their effects on the neurons they connect to via the neurotransmitter chemical GABA, and evidence from prior studies suggest that GABA receptivity is reduced in fragile X syndrome. A therapeutic approach pioneered by Bear and others has been to give the drug arbaclofen, which enhances GABA activity. In the new study, the researchers treated both control and fragile X model mice with arbaclofen to see how it affected the low-frequency biomarker.

Even the lowest administered single dose made a significant difference in the neurotypical mice, which is consistent with those mice having normal GABA responsiveness. Fragile X mice needed a higher dose, but after one was administered, there was a notable increase in the power of the key subpeak, reducing the deficit exhibited by juvenile mice.

The arbaclofen experiments therefore demonstrated that the biomarker provides a significant readout of an underlying pathophysiology of fragile X: the reduced GABA responsiveness. Bear also noted that it helped to identify a dose at which arbaclofen exerted a corrective effect, even though the drug was only administered acutely, rather than chronically. An arbaclofen therapy would, of course, be given over a long time frame, not just once.

“This is a proof of concept that a drug treatment could move this phenotype acutely in a direction that makes it closer to wild-type,” Bear says. “This effort reveals that we have readouts that can be sensitive to drug treatments.”

Meanwhile, Kornfeld-Sylla notes, there is a broad spectrum of brain disorders in which human patients exhibit significant differences in low-frequency (alpha) brain waves compared to neurotypical peers.

“Disruptions akin to the biomarker we found in this fragile X study might prove to be evident in mouse models of those other disorders, too,” she says. “Identifying this biomarker could broadly impact future translational neuroscience research.”

The paper’s other authors are Cigdem Gelegen, Jordan Norris, Francesca Chaloner, Maia Lee, Michael Khela, Maxwell Heinrich, Peter Finnie, Lauren Ethridge, Craig Erickson, Lauren Schmitt, Sam Cooke, and Carol Wilkinson.

The National Institutes of Health, the National Science Foundation, the FRAXA Foundation, the Pierce Family Fragile X Foundation, the Autism Science Foundation, the Thrasher Research Fund, Harvard University, the Simons Foundation, Wellcome, the Biotechnology and Biological Sciences Research Council, and the Freedom Together Foundation provided support for the research.