Infection Rewires a Histone Tag to Boost Macrophage Defenses Through an ID3-ZBP1 Circuit

When bacteria invade the body, macrophages are among the first defenders on the scene. These immune cells engulf pathogens, sound inflammatory alarms, and coordinate the broader antimicrobial response. Yet the way macrophages reprogram their internal machinery during infection has remained only partly mapped. A new study published in Cellular and Molecular Life Sciences reveals that Salmonella infection manipulates a specific chemical tag on histone proteins, setting off a chain reaction that ultimately weakens a key antibacterial pathway inside macrophages. The work identifies an epigenetic circuit that could be targeted with existing drug classes to strengthen innate immunity during systemic bacterial infection.

The research, led by Wanqiu Huang and Jinjing Ni together with colleagues at Shanghai Jiao Tong University School of Medicine and collaborating institutions, focuses on a histone modification known as H2BK16ac. This tag refers to the acetylation of lysine 16 on histone H2B, one of the proteins around which DNA is wound. Acetylation of histone tails generally loosens the chromatin structure, making genes more accessible to the transcription machinery. When the researchers examined macrophages infected with Salmonella, they found that this acetylation mark on H2BK16 was actively removed. The deacetylation was carried out by two enzymes, HDAC1 and HDAC3, which strip acetyl groups from histones and thereby tighten chromatin at specific genomic locations.

The consequence of this chromatin tightening was the transcriptional silencing of a gene called Id3, which encodes Inhibitor of Differentiation 3. ID3 is a member of the helix-loop-helix protein family and is known to influence the behavior of various immune cells, but its role in macrophage-mediated antibacterial defense had not been clearly defined. The new study shows that when Salmonella drives H2BK16 deacetylation through HDAC1 and HDAC3, the Id3 gene is switched off, and macrophages lose an important layer of antimicrobial capacity. This finding places ID3 at the center of an infection-induced epigenetic pathway that directly shapes how macrophages respond to bacterial challenge.

To establish that ID3 genuinely strengthens macrophage defenses, the team performed both loss-of-function and gain-of-function experiments. When ID3 was removed or reduced, macrophages showed a weakened inflammatory response and diminished antimicrobial activity. Conversely, when ID3 was increased, macrophages displayed enhanced antibacterial function. These results demonstrate that ID3 is not a passive bystander in the infection response but an active contributor to the macrophage arsenal against invading bacteria.

The mechanistic heart of the study lies in how ID3 controls the expression of another protein, Z-DNA binding protein 1, commonly abbreviated as ZBP1. ZBP1 is a sensor that recognizes certain nucleic acid structures and participates in immune signaling. The researchers discovered that a transcription factor called E2A binds to the ZBP1 gene and represses its transcription. ID3 counteracts this repression by sequestering E2A, effectively pulling it away from the ZBP1 promoter. With E2A occupied by ID3, the ZBP1 gene is free to be transcribed, and macrophages maintain robust ZBP1 expression. This sequestration mechanism reveals a precise molecular handoff in which ID3 acts as a decoy to relieve transcriptional braking on an antimicrobial effector gene.

The in vivo relevance of this circuit was tested in mice engineered to lack Id3 specifically in myeloid cells, the lineage that includes macrophages. When these myeloid-specific Id3-deficient mice were infected with Salmonella, they carried higher bacterial burdens and suffered greater pathological damage than control animals. This outcome confirms that the ID3-ZBP1 axis is not merely a cell-culture curiosity but a functional component of antibacterial immunity in living organisms. The data suggest that the integrity of this epigenetic pathway determines how effectively the host can contain systemic bacterial spread.

Perhaps the most translational aspect of the study involves a pharmacological intervention. The researchers treated infected mice with MS-275, an inhibitor of histone deacetylases that targets HDAC1 among other class I enzymes. Administration of MS-275 restored the H2BK16ac mark, reactivated the Id3 gene, and thereby rebuilt the ID3-ZBP1 signaling axis. In practical terms, the drug reversed the epigenetic silencing that Salmonella had imposed on macrophages. Mice receiving this treatment showed amelioration of systemic Salmonella infection, demonstrating that pharmacologically reopening the chromatin at Id3 can translate into meaningful protection against bacterial disease.

These findings carry several implications for the broader field of infection biology. First, they establish that pathogens do not merely evade immune detection; they actively reshape the epigenetic landscape of host immune cells to disable specific defense genes. The Salmonella-driven deacetylation of H2BK16 represents a concrete example of how bacterial infection can hijack the host’s own chromatin-modifying enzymes to silence protective transcriptional programs. Second, the study identifies ID3 as a previously underappreciated regulator of macrophage immunity, bridging histone acetylation status to the expression of a nucleic acid sensor involved in antimicrobial signaling. Third, the demonstration that an HDAC inhibitor can restore this axis in vivo suggests a therapeutic window in which epigenetic drugs, originally developed for oncology, might be repurposed as adjunct treatments for severe bacterial infections.

The work also raises questions that will likely drive future research. It remains to be seen whether other pathogens employ similar strategies to silence Id3 or related immune regulators through histone deacetylation. The precise kinetics of HDAC1 and HDAC3 recruitment to the Id3 locus during infection, and whether additional chromatin marks cooperate with H2BK16ac in this process, are areas that warrant deeper investigation. Furthermore, because ZBP1 has been implicated in antiviral as well as antibacterial pathways, the ID3-E2A-ZBP1 circuit could have relevance beyond Salmonella, potentially influencing how macrophages respond to a wider spectrum of infectious threats. The study by Huang, Ni, and colleagues thus opens a new line of inquiry into how epigenetic therapies might bolster innate immunity at a time when antibiotic resistance continues to limit conventional treatment options.

Subject of Research: Infection-driven epigenetic regulation of macrophage innate immunity through the H2BK16ac-ID3-ZBP1 axis

Article Title: Infection-driven epigenetics modulate macrophage innate immunity through the H2BK16ac-ID3-ZBP1 axis

Article References: Huang, W., Ni, J., Tang, H., Chen, Y., Zhou, T., Yu, J., Wang, Z., Wen, B., Yan, H., Wang, C., Tao, J., Lu, J., Zhao, G.-P., Wang, D., & Yao, Y.-F. (2026). Infection-driven epigenetics modulate macrophage innate immunity through the H2BK16ac-ID3-ZBP1 axis. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06432-6

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06432-6

Keywords: macrophage, innate immunity, epigenetics, histone acetylation, H2BK16ac, ID3, ZBP1, Salmonella, HDAC1, HDAC3, E2A, MS-275