Dataset Information

Mycobacterium tuberculosis impedes CD40-dependent notch signaling to restrict Th₁₇ polarization during infection.

ABSTRACT: Early Th₁₇ responses are necessary to provide protection against Mycobacterium tuberculosis (Mtb). Mtb impedes Th₁₇ polarization by restricting CD40 co-stimulatory pathway on dendritic cells (DCs). We previously demonstrated that engaging CD40 on DCs increased Th₁₇ responses. However, the molecular mechanisms that contributed to Th₁₇ polarization were unknown. Here, we identify the Notch ligand DLL4 as necessary for Th₁₇ polarization and demonstrate that Mtb limits DLL4 on DCs to prevent optimal Th₁₇ responses. Although Mtb infection induced only low levels of DLL4, engaging CD40 on DCs increased DLL4 expression. Antibody blockade of DLL4 on DCs reduced Th₁₇ polarization in vitro and in vivo. In addition, we show that the Mtb Hip1 protease attenuates DLL4 expression on lung DCs by impeding CD40 signaling. Overall, our results demonstrate that Mtb impedes CD40-dependent DLL4 expression to restrict Th₁₇ responses and identify the CD40-DLL4 pathways as targets for developing new Th₁₇-inducing vaccines and adjuvants for tuberculosis.

SUBMITTER: Enriquez AB

PROVIDER: S-EPMC9108765 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mycobacterium tuberculosis impedes CD40-dependent notch signaling to restrict Th17 polarization during infection.

Enriquez Ana Beatriz AB Sia Jonathan Kevin JK Dkhar Hedwin Kitdorlang HK Goh Shu Ling SL Quezada Melanie M Stallings Kristina Larrieux KL Rengarajan Jyothi J

iScience 20220426 5

Early Th17 responses are necessary to provide protection against Mycobacterium tuberculosis (Mtb). Mtb impedes Th17 polarization by restricting CD40 co-stimulatory pathway on dendritic cells (DCs). We previously demonstrated that engaging CD40 on DCs increased Th17 responses. However, the molecular mechanisms that contributed to Th17 polarization were unknown. Here, we identify the Notch ligand DLL4 as necessary for Th17 polarization ...[more]

PMID: 35586066

Similar Datasets

Project description:Mycobacterium tuberculosis remains a significant threat to global health. Macrophages are the host cell for M. tuberculosis infection, and although bacteria are able to replicate intracellularly under certain conditions, it is also clear that macrophages are capable of killing M. tuberculosis if appropriately activated. The outcome of infection is determined at least in part by the host-pathogen interaction within the macrophage; however, we lack a complete understanding of which host pathways are critical for bacterial survival and replication. To add to our understanding of the molecular processes involved in intracellular infection, we performed a chemical screen using a high-content microscopic assay to identify small molecules that restrict mycobacterial growth in macrophages by targeting host functions and pathways. The identified host-targeted inhibitors restrict bacterial growth exclusively in the context of macrophage infection and predominantly fall into five categories: G-protein coupled receptor modulators, ion channel inhibitors, membrane transport proteins, anti-inflammatories, and kinase modulators. We found that fluoxetine, a selective serotonin reuptake inhibitor, enhances secretion of pro-inflammatory cytokine TNF-α and induces autophagy in infected macrophages, and gefitinib, an inhibitor of the Epidermal Growth Factor Receptor (EGFR), also activates autophagy and restricts growth. We demonstrate that during infection signaling through EGFR activates a p38 MAPK signaling pathway that prevents macrophages from effectively responding to infection. Inhibition of this pathway using gefitinib during in vivo infection reduces growth of M. tuberculosis in the lungs of infected mice. Our results support the concept that screening for inhibitors using intracellular models results in the identification of tool compounds for probing pathways during in vivo infection and may also result in the identification of new anti-tuberculosis agents that work by modulating host pathways. Given the existing experience with some of our identified compounds for other therapeutic indications, further clinically-directed study of these compounds is merited.

Dataset Information

Mycobacterium tuberculosis impedes CD40-dependent notch signaling to restrict Th₁₇ polarization during infection.

Publications

<i>Mycobacterium tuberculosis</i> impedes CD40-dependent notch signaling to restrict Th<sub>17</sub> polarization during infection.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets