Microscopy image of vagus nerve sensory cells
Clusters of mouse vagus nerve sensory cells reveal the presence of TRPV1, a molecular sensor that detects irritants, heat, and inflammation. A new HMS study reveals nerve cells with this sensor play a central role in taming inflammation and tissue damage in the lung during flu infection. Image: Chiu Lab

At a glance:

  • Vagus nerve cells that sense heat, irritation, and tissue damage also help prevent harmful immune overreactions during flu infection.

  • Disabling these inflammation-curbing nerve cells worsened disease in mice, causing them to experience more lung inflammation, greater viral spread, and worse survival.

  • Understanding how these nerve cells “brake” harmful immune reactions could lead to treatments that prevent immune-driven damage in flu, other viral infections.

Work described in this story was made possible in part by federal funding supported by taxpayers. At Harvard Medical School, the future of efforts like this — done in service to humanity — now hangs in the balance due to the government’s decision to terminate large numbers of federally funded grants and contracts across Harvard University.

A group of nerve cells known for their role in detecting chemical irritation, tissue damage, heat, and pressure now emerge as critical defenders against the worst ravages of the flu caused by an overactive immune response, according to new research by scientists at Harvard Medical School and the Harvard T.H. Chan School of Public Health.

The cells, called TRPV1 vagal nociceptors, live in the vagus nerve, which sends signals from internal organs — including the heart, lungs, and gut — to the brain to help regulate heart rate, breathing, digestion, and other functions. In the lungs, these cells trigger the protective cough reflex that forces the airways to expel foreign particles, mucus, and other irritants.

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But the new research, published Aug. 1 in Science Immunology and conducted in mice, shows that in the setting of flu, these cells do much more — they rein in the immune system and avert the smoldering inflammation that often occurs in the aftermath of a viral infection and can injure healthy tissue.

Each year, the flu sickens millions and kills between 290,000 and 650,000 people worldwide, according to the World Health Organization. While the immune system helps fight off the virus, an excessive inflammatory response can inflict tissue damage and worsen illness. The findings are especially relevant in the wake of the COVID-19 pandemic, which revealed how an aberrant immune response following viral infection can sometimes lead to serious organ damage and even organ failure.

“Our research shows that the infected lung is a battleground where nerves and immune cells engage in a delicate dance to safeguard our health,” said co-senior study author Isaac Chiu, professor of immunology in the Blavatnik Institute at HMS. “Understanding this powerful neuro-immune signaling axis will be increasingly important as we design better ways to prevent and treat immune-mediated damage in viral infections, which can sometimes be worse than the direct damage caused by the virus itself.”

The findings, he added, raise the possibility that vagus nerve function may be one variable that explains why some people with the flu go on to develop long-lasting and devastating immune-driven damage in their lungs while others recover once the initial infection is resolved.

Authorship, funding, disclosures

Additional authors include Daping Yang, Jingya Xia, Swalpa Udit, Prabhu Joshi, Sandeep Adhikari, Daisy A. Hoagland, Stephen T. Yeung, Camille Khairallah, Tomas Huerta, Antonia Wallrapp, Benjamin D. Umans, Nicole Sarden, Ozge Erdogan, Nadia Baalbaki, Jiawei Hou, Anna Beekmayer-Dhillon, Juhyun Lee, Kimberly A. Meerschaert, Stephen D. Liberles, Ruth A. Franklin, Bryan G. Yipp, Kamal M. Khanna, Pankaj Baral, and Adam L. Haber.

The work was supported by the National Institutes of Health (grants 5R01DK127257 and 5R01AI168005), the Burroughs Wellcome Fund, Jackson-Wijaya Fund, and Food Allergy Science Initiative. Additional support was provided by the Parker B. Francis Fellowship; American Lung Association; National Natural Science Foundation of China (grants 82495204 and 92474109); and NIH (grants 5T32HL007118, T32 AI007061, R01AI143861, NS122767, F31HL132645, R35GM155117, and P20GM113117).

Chiu consults for Panther Life Sciences, Fzata, H Ventures, and Nilo Therapeutics. His laboratory has received sponsored research support from AbbVie and Moderna Inc.; Liberles is a cofounder and consultant for Nilo Therapeutics; Udit is currently an employee of Vertex Pharmaceuticals and may own stock in the company.