# The Dual Immunoregulatory Role of CREB3L1 Underlying Latent and Severe Tuberculosis Clinical Manifestation

## TL;DR

The study reveals that CREB3L1 has a dual role in tuberculosis, helping control infection in latent cases but contributing to severe inflammation in advanced disease.

## Contribution

The novel contribution is the identification of CREB3L1 as a context-dependent immunomodulator in TB, with distinct roles in latent and severe disease.

## Key findings

- CREB3L1 knockdown in monocytes impairs phagocytosis, bacterial killing, and apoptosis.
- Elevated CREB3L1 in severe TB correlates with inflammatory cytokines like IL-17, IL-12, and IFN-γ.
- CREB3L1 modulates immune responses in latent TB but amplifies systemic inflammation in severe disease.

## Abstract

During tuberculosis (TB), organ‐specific immune responses and intracellular pathways play critical roles in disease progression and prognosis. Identifying genes that regulate these immune mechanisms remains a key challenge in improving TB management strategies. To investigate genes potentially associated with enhanced resistance to TB and the modulation of immune responses, we analysed RNA‐seq data from whole cells isolated from the lungs and livers of mice infected with
Mycobacterium tuberculosis
(Mtb) at two time points that represent different outcomes. We hypothesised that these two organs mount distinct responses to infection, supported by differences in the immune response and bacterial burden kinetics observed in each tissue. Our analysis revealed differential gene expression profiles between the lungs and livers, primarily involving metabolic and immune‐related pathways. Through meta‐analysis, we identified orthologous genes shared between Mtb‐infected mice and human patients with latent pulmonary TB. In the omics analysis, the four genes, Creb3l1, Myo7b, Cyyr1, and Cbs, were differentially expressed and associated with either resistance or susceptibility. In vitro assays further demonstrated that knockdown of CREB3L1 in Mtb‐infected THP‐1 or primary human monocytes impaired key effector functions, including phagocytosis, bacterial killing, and apoptosis. Taken together, these findings indicate that CREB3L1 possibly contributes to the regulation of genes essential for bacterial control in the lungs during latent TB infection. In contrast, its increased expression in the peripheral blood of patients with severe TB is more likely linked to systemic inflammatory dysregulation rather than direct antimicrobial activity. Notably, CREB3L1 expression in these patients positively correlated with cytokines such as IL‐17, IL‐12, and IFN‐γ, which are central to macrophage activation and effector T cell recruitment. Thus, CREB3L1 appears to play a dual role in TB: under controlled infection, it acts as an immunomodulator limiting excessive pulmonary inflammation, while in severe disease, it may reflect an attempt by the host to amplify inflammatory responses to counteract progressive infection.

RNA‐seq of lungs and livers from
Mycobacterium tuberculosis
‐infected mice with distinct disease outcomes revealed organ‐specific responses driven by differences in immune activity and bacterial burden. Meta‐analysis identified orthologous genes shared with human latent TB and mouse liver, with Creb3l1, Myo7b, Cyyr1 and Cbs differentially expressed and associated with disease resistance.During in vitro infection of blood‐derived monocytes, CREB3L1 knockdown impaired phagocytosis, bacterial killing, and apoptosis, supporting its role in host defence.Conversely, elevated CREB3L1 expression in PBMCs from TB patients presenting advanced disease correlated with inflammatory cytokines (IL‐17, IL‐12, IFN‐γ). CREB3L1 appears to play a putative context‐dependent role in TB, modulating immunity at the infection site during latency, but amplifying systemic responses in peripheral blood during severe disease.

RNA‐seq of lungs and livers from
Mycobacterium tuberculosis
‐infected mice with distinct disease outcomes revealed organ‐specific responses driven by differences in immune activity and bacterial burden. Meta‐analysis identified orthologous genes shared with human latent TB and mouse liver, with Creb3l1, Myo7b, Cyyr1 and Cbs differentially expressed and associated with disease resistance.

During in vitro infection of blood‐derived monocytes, CREB3L1 knockdown impaired phagocytosis, bacterial killing, and apoptosis, supporting its role in host defence.

Conversely, elevated CREB3L1 expression in PBMCs from TB patients presenting advanced disease correlated with inflammatory cytokines (IL‐17, IL‐12, IFN‐γ). CREB3L1 appears to play a putative context‐dependent role in TB, modulating immunity at the infection site during latency, but amplifying systemic responses in peripheral blood during severe disease.