Th2 immune response by the iron-regulated protein HupB of Mycobacterium tuberculosis

Choudhury, Mitali; Virivinti, Jahnavi; Kandi, Subhakar; Sritharan, Venkataraman; Sritharan, Manjula

doi:10.1016/j.ijtb.2021.04.011

Cited by 4 publications

(4 citation statements)

References 30 publications

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“…In our analysis of cytokine profile in the presence of MtbEspR, Th2 cytokines were dominant. Such observations have been made for many Mtb proteins, such as ZMP-1 (22), HupB (41), and PPE34 (42). These studies, although have indicated that many Mtb proteins skew the host responses to Th2-type, no mycobacterial factor has been shown to directly regulate the expression of Th2 cytokines by binding to host DNA elements.…”

Section: Discussionmentioning

confidence: 97%

Mycobacterium tuberculosis EspR modulates Th1-Th2 shift by transcriptionally regulating IL-4, steering increased mycobacterial persistence and HIV propagation during co-infection

Yandrapally,

Agarwal,

Chatterjee

et al. 2023

Front. Immunol.

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Mycobacterium tuberculosis (Mtb) and HIV are known to mutually support each other during co-infection by multiple mechanisms. This synergistic influence could be either by direct interactions or indirectly through secreted host or pathogen factors that work in trans. Mtb secretes several virulence factors to modulate the host cellular environment for its persistence and escaping cell-intrinsic immune responses. We hypothesized that secreted Mtb transcription factors that target the host nucleus can directly interact with host DNA element(s) or HIV LTR during co-infection, thereby modulating immune gene expression, or driving HIV transcription, helping the synergistic existence of Mtb and HIV. Here, we show that the Mtb-secreted protein, EspR, a transcription regulator, increased mycobacterial persistence and HIV propagation during co-infection. Mechanistically, EspR localizes to the nucleus of the host cells during infection, binds to its putative cognate motif on the promoter region of the host IL-4 gene, activating IL-4 gene expression, causing high IL-4 titers that induce a Th2-type microenvironment, shifting the macrophage polarization to an M2 state as evident from CD206 dominant population over CD64. This compromised the clearance of the intracellular mycobacteria and enhanced HIV propagation. It was interesting to note that EspR did not bind to HIV LTR, although its transient expression increased viral propagation. This is the first report of an Mtb transcription factor directly regulating a host cytokine gene. This augments our understanding of the evolution of Mtb immune evasion strategies and unveils how Mtb aggravates comorbidities, such as HIV co-infection, by modulating the immune microenvironment.

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Section: Discussionmentioning

confidence: 97%

Mycobacterium tuberculosis EspR modulates Th1-Th2 shift by transcriptionally regulating IL-4, steering increased mycobacterial persistence and HIV propagation during co-infection

Yandrapally,

Agarwal,

Chatterjee

et al. 2023

Front. Immunol.

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“…N. seriolae is a facultative intracellular bacterium and can survive in macrophages after being engulfed; the relative mechanism may be related to iron regulatory proteins (Yasuike et al, 2017). M. tuberculosis possesses iron regulatory proteins necessary for growing and surviving within macrophages by inhibiting the macrophage response to IFN‐α (Choudhury et al, 2022; Persson et al, 2008). The uptake of iron by microorganisms is related to the virulence of most pathogens.…”

Section: Discussionmentioning

confidence: 99%

Identification of a secretory heme‐binding protein from Nocardia seriolae involved in cell apoptosis

Wen

et al. 2022

Journal of Fish Diseases

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According to the whole‐genome bioinformatics analysis, a heme‐binding protein from Nocardia seriolae (HBP) was found. HBP was predicted to be a bacterial secretory protein, located at mitochondrial membrane in eukaryotic cells and have a similar protein structure with the heme‐binding protein of Mycobacterium tuberculosis, Rv0203. In this study, HBP was found to be a secretory protein and co‐localized with mitochondria in FHM cells. Quantitative analysis of mitochondrial membrane potential value, caspase‐3 activity, and transcription level of apoptosis‐related genes suggested that overexpression of HBP protein can induce cell apoptosis. In conclusion, HBP was a secretory protein which may target to mitochondria and involve in cell apoptosis in host cells. This research will promote the function study of HBP and deepen the comprehension of the virulence factors and pathogenic mechanisms of N. seriolae.

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“…HupB promotes the expression of MBT and cMBT, and it induces the Th2 immune response. However mutant strains lacking HupB fail to survive in macrophages, highlighting the crucial role of HupB in the host interactions ( Pandey et al., 2014b ; Choudhury et al., 2022 ). Moreover, the expression of HupB was detected in TB patients ( Yeruva et al., 2006 ), and anti-HupB antibody level was found to be elevated in these patients with low serum iron levels, indicating an up-regulation of HupB expression ( Sivakolundu et al., 2013 ).…”

Section: Metal Ion-dependent Proteinsmentioning

confidence: 99%

The role of transcriptional regulators in metal ion homeostasis of Mycobacterium tuberculosis

Wang,

Fang,

Wang

et al. 2024

Front. Cell. Infect. Microbiol.

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Metal ions are essential trace elements for all living organisms and play critical catalytic, structural, and allosteric roles in many enzymes and transcription factors. Mycobacterium tuberculosis (MTB), as an intracellular pathogen, is usually found in host macrophages, where the bacterium can survive and replicate. One of the reasons why Tuberculosis (TB) is so difficult to eradicate is the continuous adaptation of its pathogen. It is capable of adapting to a wide range of harsh environmental stresses, including metal ion toxicity in the host macrophages. Altering the concentration of metal ions is the common host strategy to limit MTB replication and persistence. This review mainly focuses on transcriptional regulatory proteins in MTB that are involved in the regulation of metal ions such as iron, copper and zinc. The aim is to offer novel insights and strategies for screening targets for TB treatment, as well as for the development and design of new therapeutic interventions.

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Th2 immune response by the iron-regulated protein HupB of Mycobacterium tuberculosis

Cited by 4 publications

References 30 publications

Mycobacterium tuberculosis EspR modulates Th1-Th2 shift by transcriptionally regulating IL-4, steering increased mycobacterial persistence and HIV propagation during co-infection

Mycobacterium tuberculosis EspR modulates Th1-Th2 shift by transcriptionally regulating IL-4, steering increased mycobacterial persistence and HIV propagation during co-infection

Identification of a secretory heme‐binding protein from Nocardia seriolae involved in cell apoptosis

The role of transcriptional regulators in metal ion homeostasis of Mycobacterium tuberculosis

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