When the pandemic began to accelerate in the spring of 2020, Michelle Monje was worried. Early reports showed that SARS-CoV-2 was a highly inflammatory virus, triggering a flood of immune molecules, known as cytokines. “That’s not what normal viruses do,” says Monje, a neurologist at Stanford University who studies neural inflammation and cognitive function. Given that level of inflammation, “I was worried that even in mild cases, we might see cognitive impairment.”
Monje’s concerns were soon borne out — post-COVID patients began streaming into neurologists’ offices complaining of fatigue, memory issues and difficulty concentrating, a constellation of symptoms we now associate with long COVID. For Monje, the pattern looked startlingly like the cognitive symptoms reported by some cancer patients after chemotherapy, known as chemo brain. Research by Monje and others had shown that neuroinflammation is a key culprit underlying cancer therapy’s cognitive effects, and she wondered if something similar was at play with long COVID. “I felt it was important to understand the molecular underpinnings, what the parallels really were,” Monje says. “If many of the same things were happening, it would be useful to know, because we have been working for years on ways to intervene.”
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Monje’s recent work, published in Cell in July, is helping to uncover the neuroimmune and other processes that may accompany long COVID. The study was guided by Monje’s previous efforts to unpick the molecular mechanisms underlying chemo brain, which showed that chemotherapy can have a host of effects on the brain’s immune system, including resident immune cells called microglia, which can in turn alter neural circuits. In the healthy brain, microglia help tend to neural circuits. But when they sense infection or other challenges, microglia enter a reactive state designed to stop the spread of pathogens. Sometimes reactive microglia can veer out of control, sparking harmful downstream effects — impairing neurogenesis, triggering astrocyte reactivity and harming oligodendrocytes, all of which are essential for healthy neural circuit function.
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Tronson and collaborators use a similar model to study the longer-term cognitive impacts of inflammation in mice. Her team has found that at midlife, two months after an immune challenge, the animals began exhibiting memory impairments. They also showed changes in the expression of genes involved in synaptic plasticity and neuroimmune function in the hippocampus.