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NIH grant 1R01AI192345-01A1: Post-Translational Encoding of Innate Immune Memory
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Quen J Cheng. Award: $667505.
Start: 2026-07-22T00:00:00.
PROJECT SUMMARY/ABSTRACT
Cells of the innate immune system such as monocytes, macrophages, and their progenitors, can be
reprogrammed by exposure to cytokines and pathogen-associated molecules. This phenomenon, termed “innate
immune memory” (IIM), can either potentiate or diminish transcription of cytokine genes when cells encounter a
subsequent pathogen-associated stimulus. When IIM leads to an improved host response to infection, it has
been termed “trained immunity.” b-glucan from fungi been a model ligand to induce IIM and trained immunity.
IIM is thought to arise from epigenomic reprogramming. When monocytes are exposed to b-glucan, widespread
chromatin opening and histone modifications are induced, forming new enhancers. The assumption is that these
epigenomic changes enhance transcription of cytokine genes such as TNF, IL6, and IL1a, resulting in a trained
state of immunity. In this proposal, however, we advance an innovative hypothesis that stretches current
paradigms in the field. We propose that epigenetic and transcriptional changes are insufficient to explain
observed differences in cytokine secretion, and that post-translational mechanisms also play an important role.
Our data show that for many cytokines, b-glucan potentiates secreted protein levels but has no effect on mRNA
levels or intracellular protein levels. This implies the presence of post-translational regulation which has been
described in other immune processes but not for IIM or trained immunity. We have found that b-glucan induces
the expression of a protease, FURIN, that is responsible for regulating many cellular processes. We hypothesize
that FURIN increases the rate of cytokine secretion by increasing the efficiency of cytokine processing.
In Aim 1, we will examine how b-glucan induces FURIN expression in human monocytes. We will define the
signaling pathways downstream of b-glucan and the regulatory logic of the FURIN gene. This Aim will build on
prior work in non-immune cells that suggest b-glucan signaling activates the transcription factor HIF-1a, which
induces FURIN expression by binding to a distinct promoter that controls a specific isoform of the gene.
In Aim 2, we will investigate what FURIN does in b-glucan trained macrophages after it is expressed. We
hypothesize that FURIN induction is both necessary and sufficient for potentiating the secretion of cytokines like
TNF. We will also identify the proteolytic targets of FURIN and examine whether FURIN also plays a role in IIM
induced by other ligands such as BCG.
In Aim 3, we will explore whether post-translational regulation also plays a role in b-glucan trained immunity in
vivo. We will generate a genetically modified mouse in which FURIN cannot be induced by b-glucan signaling.
We will then test our hypothesis using established mouse models of b-glucan training followed by infection.
This proposal will expand our understanding of how IIM is encoded at a molecular level, with the long-term goal
of developing therapies to harness the potential of trained immunity. If our hypothesis is correct, FURIN may
represent a novel and druggable target for trained immunity.document fetched 2026-08-02 08:24