Sensory neuron production of substance P and TAFA4 promotes disease tolerance during viral infection
Host resistance to infection relies on coordinated interactions between the immune and nervous systems. However, the molecular mechanisms underlying this cross-regulation remain unclear, particularly during viral infections. We have shown that herpes simplex virus type 1 directly activates sensory neurons, inducing production of the neuropeptide substance P (SP) and the neurokine TAFA4. These mediators played independent, tissue-specific immunoregulatory functions in the skin and dorsal root ganglia (DRGs), the main sites of viral replication. In the skin, the SP produced by transient receptor potential vanilloid type 1 (TRPV1)<sup>+</sup> sensory neurons limited neutrophil infiltration through the Mas-related G protein-coupled receptor member A1 (MRGPRA1) receptor and promoted skin healing, revealing an unexpected anti-inflammatory role for this neuropeptide. In infected DRGs, a TAFA4-interleukin (IL)-10 pathway promoted the resolution of inflammation after viral clearance. Together, these neuroimmune regulatory pathways reduced the detrimental impact of the infection on host fitness without directly altering pathogen elimination, revealing how the sensory nervous system has developed several mechanisms to promote disease tolerance.
Authors
- Eva Kaufmann (ORCID: https://orcid.org/0000-0001-7965-9200)
- Magali Irla (ORCID: https://orcid.org/0000-0001-8803-9708)
- Julie Mielle (ORCID: https://orcid.org/0000-0003-2064-8958)
- Pierre Milpied (ORCID: https://orcid.org/0000-0003-1873-5358)
- Sara Teimouri Nezhad
- Sébastien Talbot (ORCID: https://orcid.org/0000-0001-9932-7174)
- Jordi Gouilly (ORCID: https://orcid.org/0000-0001-8684-7429)
- Guillaume Hoeffel (ORCID: https://orcid.org/0000-0002-2534-4972)
- Surbhi Gupta (ORCID: https://orcid.org/0000-0002-6178-5759)
- Théo Crosson
- Pierre-Vincent Barbon (ORCID: https://orcid.org/0000-0002-5416-1251)
- Hakim Medjouel Khlifi
- Sophie Ugolini (ORCID: https://orcid.org/0000-0003-4041-0103)
- Naina Gour (ORCID: https://orcid.org/0000-0003-3853-4377)
- Ana Reynders
- Vidthiya Jeyanathan
- Ugo Mardelle
- Ninon Bretaud
- Bertrand Escalière
- Alissa Dory
- Aziz Moqrich
- Anaïs. Compositeur présumé Roger
- Tiphaine Fohrer
- Andisheh Liaghat
- Achille Broggi
- Sam Basta
- Vincent Feuillet
- Elena Brunet
- Jeremy C. Santamaria
- Noushin Mossadegh-Keller
- Isaac Thomas
- Xinzhong Dong
Institutions
- Centre National de la Recherche Scientifique (FR)
- Johns Hopkins University (US)
- Inserm (FR)
- Queen's University (CA)
- Aix-Marseille Université (FR)
- Institut de Biologie du Développement Marseille (FR)
- Centre d’Immunologie de Marseille-Luminy (FR)
Publication Details
- Journal
- Immunity
- Published
- 2026-02-25
- DOI
- https://doi.org/10.1016/j.immuni.2026.01.022
- Primary Topic
- Neuropeptides and Animal Physiology
- Type
- article
- Field-Weighted Citation Impact
- 0.00