Article In Brief
New research suggests microglia in the olfactory bulb may take up viral debris from neurons and present it to T cells. These findings may present a possible new therapeutic strategy for lessening the harmful effects of an overactive immune response and preventing central nervous system infections.
Microglia in the olfactory bulb take up viral debris from neurons and present it to T cells, defending the brain against invasion by upper respiratory viruses, according to a study published June 5 in the journal Science Immunology.
The finding expands the number of roles microglia play in the brain and provides a potential new therapeutic strategy for both preventing central nervous system infections and minimizing the harmful effects of an overactive immune response.
“Olfactory sensory neurons in the nose are challenged regularly by respiratory pathogens,” said Dorian McGavern, PhD, principal investigator on the new study and senior investigator in Viral Immunology and Intravital Imaging at the National Institute for Neurological Disorders and Stroke (NINDS).
“We don't usually think about them trying to enter the brain, but there are direct pathways from the nasal tissue into the central nervous system, so we're interested in understanding the immune response to prevent those pathogens from entering the brain.”
Viruses that infect the nasal epithelium, including vesicular stomatitis virus (VSV), may infect olfactory sensory neurons as well and be transported from the nose into the central nervous system, beginning with the olfactory bulb.
“We wanted to conduct this study in order to understand how such a virus is contained once it reaches the olfactory bulb,” Dr. McGavern said.
Study Methods, Findings
To that end, Dr. McGavern, first author Ashley Moseman, PhD, and their team infected the nasal epithelium in mice with VSV and tracked the ensuing viral and immune system activity using a variety of imaging techniques. They showed that the virus made its way into the olfactory bulb within a day of infection, which led to a massive infiltration of T cells into the olfactory bulb over the ensuing week.
There, the T cells became less motile, “suggesting they were encountering antigen,” Dr. McGavern said.
T cells recognize antigen on the surface of other cells when the antigen is presented in the pocket of the major histocompatibility complex type I (MHC I). Neurons express very little MHC I, Dr. McGavern explained, so despite being the target of viral infection, they may not be ideal antigen presenters.
When the team blocked neuronal presentation of antigen, survival in the mice was not impaired, suggesting antigen presentation was the primary responsibility of some other cell type.
In contrast, Dr. McGavern found that after infection, microglia in the olfactory bulb dramatically upregulated its MHC I, and that when a T cell encountered an activated microglial cell, the T cell exhibited a flux in intracellular calcium indicating viral peptide recognition. When the team reduced the population of microglia before infection, the virus was able to escape into the brain and cause a fatal encephalitis.
“Instead of engaging the infected neurons, the T cells were engaging microglia,” Dr. McGavern said. The microglia themselves were not infected, they found, but they were nonetheless displaying viral peptides.
To determine their origin, the team injected fluorescent cholera toxin into the nasal epithelium, so they could follow it as it was transported back to the olfactory bulb within the sensory neurons. Within several days, microglia in the olfactory bulb were found with toxin inside them, indicating neuron-to-microglia transfer. They repeated the experiment with a fluorescent labeled virus and found that it too was taken up by microglia.
Engagement of the viral antigens in the microglial MHC I led the T cells to release antiviral cytokines, which caused neurons in the vicinity to upregulate multiple proteinases and other antiviral molecules, destroying the virus within without killing the neuron.
“The important result was that the neurons survived after viral clearance,” Dr. McGavern said. While it is not yet clear whether the microglia survive the process, they would be able to repopulate, he noted, replacing any cells lost along the way.
The acquisition and presentation of viral peptides is part of the larger repertoire of microglia, “which are the surveillance system of the brain parenchyma,” he said. “Microglia are constantly surveying neurons, picking up debris.” And this ability to present antigens is unlikely to be restricted to microglia of the olfactory bulb, he added.
“I don't think this mechanism is unique to the olfactory bulb—I think it is going to be universal. Microglia have the same properties in any region of the brain and spinal cord. They are constantly surveying that entire space.”
“This is a beautiful study,” commented Robyn Klein, MD, PhD, professor of internal medicine, infectious diseases, pathology and immunology, and neuroscience at Washington University in Saint Louis. “It is an important paper, because it is among the first to demonstrate that microglia can take up antigens and present them to T cells.”
The reigning view had been that only after restimulation in the periphery, by dendritic cells, do T cells enter the central nervous system. “But it became apparent some time ago that cells that enter the parenchyma often get restimulated once they are there,” Dr. Klein said, but how that occurred was unknown.
The addition of antigen presentation to the microglial portfolio makes sense, since the immune system itself has its evolutionary origins in the nervous system. “It is really the neuro-immune system,” she said.
The discovery also bolsters the idea that there are multiple subtypes of microglia in the brain, that serve different functions depending on the region and the context.
“Microglia are critically important for sculpting neural networks,” Dr. Klein said, as shown by her own work and that of others, and their ability to eliminate synapses plays a part in “normal forgetting.” But they can also mediate pathological forgetting, she noted, which can occur with dementing illnesses or may be triggered by infection, as seen in patients that survive viral encephalitis, who often go on to develop long-term memory dysfunction.
Clinically, she said, the discovery here may lead to strategies to stimulate microglia early in the course of infection, thus limiting the amount of virus in the brain. “The caveat is that until we understand the different types of microglia, and specifically target those that are beneficial, we could cause activation of microglia that could lead to post-infectious cognitive sequelae.”
The discovery may be equally important for limiting immune responses in the brain, commented Avindra Nath, MD, FAAN, senior investigator in the Section of Infections of the Nervous System at NINDS. “A hyperactive response to viral antigen can be a significant problem,” he said. “Being able to block that activity by targeting microglia could be valuable.”
“Patients with COVID-19 are showing symptoms that match the disruption of these olfactory sensory neurons, such as loss of sense of smell and taste,” Dr. McGavern noted. “It is likely that the coronavirus is disrupting these sensory neurons, either directly, or disrupting their surroundings. We need to determine if the virus is accessing these neurons and trying to enter the olfactory bulb.”
Drs. McGavern, Klein, and Nath had nothing to disclose.