Epigenetic profiling reveals M1 macrophages as the primary drivers of trained immunity in HSV-1 latently infected mice
- 1>Center for Neurobiology & Vaccine Development, Cedars-Sinai Health Sciences University, Ophthalmology Research, Department of Surgery, Los Angeles, California, United States of America
Abstract
Macrophages play multifaceted and critical roles in controlling diverse pathogenic infections. Building on our recently published observations of macrophages exhibiting memory responses to HSV-1 infection, our current report investigates the macrophage subtype responsible for generating trained immunity against virus-induced immunopathogenesis. Using ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing), an epigenetic profiling technique, we identified chromatin accessibility changes in both M1 and M2 macrophages associated with the acquisition of IRGM1, a marker of the trained phenotype. To conduct this study, we first generated M0, M1, and M2 macrophage subtypes from bone marrow (BM) derived macrophages isolated from HSV-1 latently infected wild type (WT) mice. ATAC-seq revealed that M1-generated macrophages displayed higher IRGM1-associated chromatin accessibility peaks compared to M2 and M0 subtypes, and this response was enhanced after stimulation with UV-inactivated virus. To further dissect this response, we analyzed memory responses in bone marrow-derived macrophages, spleen macrophages, corneal macrophages, and trigeminal ganglia (TG) of latently infected M1 and M2 macrophages. Flow cytometry and ATAC-seq data showed a significantly higher proportion of IRGM1 ⁺ macrophages in infected M2-/- mice, which are enriched in M1 macrophages. These findings indicate that M1 macrophages, but not M2 macrophages, undergo trained immunity in response to HSV-1 infection. This is also confirmed by the Luminex assay, in which M1 macrophages, after stimulation, then known as primed M1 macrophages, enhance the secretion of pro-inflammatory cytokine/chemokine response to secondary HSV-1 exposure. These results uncover a previously underappreciated role for macrophage-mediated trained immunity in antiviral defense against HSV-1 infection and offer new insights into potential therapeutic targets for modulating host immune responses during HSV-1 infection. Author summary: HSV-1 is a widespread pathogen that establishes lifelong infection and can cause recurrent disease and severe immunopathology. It is well established that T cells develop memory responses to target pathogens, but little is known about whether macrophages can also develop trained immunity, which remains poorly understood in the context of viral infections. Our current report identifies M1 macrophages as the key subset responsible for acquiring trained immunity during HSV-1 infection, characterized by epigenetic reprogramming and increased accessibility of IRGM1-associated chromatin regions. In contrast, M2 macrophages do not exhibit this trained phenotype. These findings redefine the functional specialization of macrophage subsets in a previously unrecognized mechanism by which innate immune cells contribute to long-term host protection. By highlighting M1 macrophages as drivers of trained immunity, this work opens new avenues for therapeutic strategies to enhance antiviral responses while limiting immunopathology.
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BibTeX
@article{jaggi2026epigenetic,
title = {{Epigenetic profiling reveals M1 macrophages as the primary drivers of trained immunity in HSV-1 latently infected mice}},
author = {Ujjaldeep Jaggi and Shaohui Wang and Homayon Ghiasi},
journal = {PLOS Pathogens},
year = {2026},
month = sep,
doi = {10.1371/journal.ppat.1014598},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014598},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Epigenetic profiling reveals M1 macrophages as the primary drivers of trained immunity in HSV-1 latently infected mice
AU - Ujjaldeep Jaggi
AU - Shaohui Wang
AU - Homayon Ghiasi
PY - 2026
DA - 2026/09/09
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014598
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014598
AB - Macrophages play multifaceted and critical roles in controlling diverse pathogenic infections. Building on our recently published observations of macrophages exhibiting memory responses to HSV-1 infection, our current report investigates the macrophage subtype responsible for generating trained immunity against virus-induced immunopathogenesis. Using ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing), an epigenetic profiling technique, we identified chromatin accessibility changes in both M1 and M2 macrophages associated with the acquisition of IRGM1, a marker of the trained phenotype. To conduct this study, we first generated M0, M1, and M2 macrophage subtypes from bone marrow (BM) derived macrophages isolated from HSV-1 latently infected wild type (WT) mice. ATAC-seq revealed that M1-generated macrophages displayed higher IRGM1-associated chromatin accessibility peaks compared to M2 and M0 subtypes, and this response was enhanced after stimulation with UV-inactivated virus. To further dissect this response, we analyzed memory responses in bone marrow-derived macrophages, spleen macrophages, corneal macrophages, and trigeminal ganglia (TG) of latently infected M1 and M2 macrophages. Flow cytometry and ATAC-seq data showed a significantly higher proportion of IRGM1 ⁺ macrophages in infected M2-/- mice, which are enriched in M1 macrophages. These findings indicate that M1 macrophages, but not M2 macrophages, undergo trained immunity in response to HSV-1 infection. This is also confirmed by the Luminex assay, in which M1 macrophages, after stimulation, then known as primed M1 macrophages, enhance the secretion of pro-inflammatory cytokine/chemokine response to secondary HSV-1 exposure. These results uncover a previously underappreciated role for macrophage-mediated trained immunity in antiviral defense against HSV-1 infection and offer new insights into potential therapeutic targets for modulating host immune responses during HSV-1 infection. Author summary: HSV-1 is a widespread pathogen that establishes lifelong infection and can cause recurrent disease and severe immunopathology. It is well established that T cells develop memory responses to target pathogens, but little is known about whether macrophages can also develop trained immunity, which remains poorly understood in the context of viral infections. Our current report identifies M1 macrophages as the key subset responsible for acquiring trained immunity during HSV-1 infection, characterized by epigenetic reprogramming and increased accessibility of IRGM1-associated chromatin regions. In contrast, M2 macrophages do not exhibit this trained phenotype. These findings redefine the functional specialization of macrophage subsets in a previously unrecognized mechanism by which innate immune cells contribute to long-term host protection. By highlighting M1 macrophages as drivers of trained immunity, this work opens new avenues for therapeutic strategies to enhance antiviral responses while limiting immunopathology.
SN - 1553-7374
ER -