Immune ‘bouncers’ protect the brain from infection

The itching, redness and swelling of an allergic reaction are caused by mast cells — the vigilant first responders of the immune system that spring into action with histamine-filled granules in response to a perceived threat.

Now, researchers at Washington University School of Medicine in St. Louis have revealed that the same cells that cause misery for millions of allergy sufferers can help protect the brain from bacterial and viral infections. In mice, they found that so-called mast cells stand guard at tiny gates through which fluid waste leaves the brain, mounting a response when a pathogen is detected to close the gates and prevent the invaders from accessing the brain.

The findings were published July 24 in Cell and could have important implications for preventing or treating brain infections.

“These findings open up an entirely new avenue to developing interventions that would protect the brain from infection,” explained senior author Jonathan Kipnis, PhD, the Alan A. and Edith L. Wolff Distinguished Professor of Pathology & Immunology at WashU Medicine and a BJC Investigator. “We now know how mast cells shield the brain, so we can explore enhancing their function during the threat of infections.”

Such infectious diseases include bacterial meningitis, a potentially life-threatening infection that affects the tissue layers, called meninges, that envelop the brain underneath the skull. Tiny gates within these layers create passageways that carry fluid waste out of the brain into lymphatic vessels, where immune cells monitor the fluid for signs of danger or infection. But such openings also can provide opportunities for bacteria to infiltrate.

Kipnis’ lab had discovered the presence of lymph vessels in the mouse dura mater, the outer tissue layer enveloping the brain underneath the skull, into which brain fluid flows through tiny gates. To better understand how such fluid flow is regulated, the Kipnis lab collaborated with Felipe Almeida de Pinho Ribeiro, PhD, an assistant professor of medicine at WashU Medicine who studies the neuroimmune interactions that contribute to human disease. Together with Tornike Mamuladze, MD, an immunology graduate student in Kipnis’ laboratory, they found that mice infected with Streptococcus agalactiae or S. pneumoniae, types of spherical bacteria that cause meningitis, had reduced brain fluid flow through the gates compared with healthy mice.

They discovered that the presence of bacteria in the tissues enveloping the mouse brain activated mast cells to release histamine-containing granules that caused veins that pass through the tiny gates to dilate, or widen. By expanding into the space that brain fluid ordinarily passes through, the enlarged veins created a temporary closure that also blocked bacteria from entering and infecting the brain.

The study found that activated mast cells also initiate a fast immune response, recruiting bacteria-engulfing immune cells called neutrophils to destroy the pathogens in the infected tissue. When mice in the study lacked mast cells, more bacteria got into the brain by passing through the tiny gates, the researchers found, whereas enhancing mast cells’ activity before an infection reduced the bacterial load.

To see if viral pathogens were similarly blocked by mast cells, the team collaborated with Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine at WashU Medicine, who is recognized internationally for his research on understanding how Zika, West Nile, chikungunya and related emerging viruses interact with and evade the body’s defenses. The researchers also detected more West Nile virus, which spreads through the bite of an infected mosquito, in the brains of infected mice without mast cells compared with infected mice with mast cells.

“We think that enhancing mast cell function could help protect the brain from bacterial and viral infection,” said Kipnis. “But mast cell activation is a double-edged sword. Long-term activation of these cells blocks fluid movement and can potentially cause junk, such as amyloid beta, to accumulate in the brain.”

In future work, the team aims to understand if chronic activation of mast cells could have negative implications for Alzheimer’s disease, which is characterized by an accumulation of amyloid beta.

“Mast cells have an important role to play in the brain,” said Mamuladze, the first author on the study. “Understanding how to target their function at the gates to the brain to keep pathogens out while allowing waste to leave will be critical for optimizing brain health.”

Mamuladze T, Zaninelli TH, Smyth LCD, Wu Y, Abramishvili D, Silva R, Imbiakha B, Verhaege D, Du S, Papadopoulos Z, Gu X, Lee D, Storck S, Perrin RJ, Smirnov I, Dong X, Song Hu, Diamond MS, Pinho-Ribeiro FA, Kipnis J. Mast cells regulate the brain-dura interface and CSF dynamics. Cell. July 24, 2025. DOI: 10.1016/j.cell.2025.06.046.

This work was funded by grants from the National Institutes of Health, grant numbers R01AI183879, P01AG078106 and R37AG034113 and the Cure Alzheimer’s Fund BEE consortium. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Kipnis is a co-founder of Rho Bio. Diamond is a consultant or advisor for Inbios, Moderna, IntegerBio, Merck, GlaxoSmithKline, Bavarian Nordic, and Akagera Medicines. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Emergent BioSolutions, Bavarian Nordic, Moderna, and IntegerBio.

About Washington University School of Medicine

WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with 2,900 faculty. Its National Institutes of Health (NIH) research funding portfolio is the second largest among U.S. medical schools and has grown 83% since 2016. Together with institutional investment, WashU Medicine commits well over $1 billion annually to basic and clinical research innovation and training. Its faculty practice is consistently within the top five in the country, with more than 1,900 faculty physicians practicing at 130 locations. WashU Medicine physicians exclusively staff Barnes-Jewish and St. Louis Children’s hospitals — the academic hospitals of BJC HealthCare — and treat patients at BJC’s community hospitals in our region. WashU Medicine has a storied history in MD/PhD training, recently dedicated $100 million to scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physical therapy, occupational therapy, and audiology and communications sciences.