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Immunometabolic hijacking of immune cells by a Pseudomonas aeruginosa quorum-sensing signal

Arunava Bandyopadhaya, Vijay K Singh, Arijit Chakraborty, A. Aria Tzika, Laurence G Rahme

Preprint posted on October 03, 2021 https://www.biorxiv.org/content/10.1101/2021.10.03.462785v1

Pseudomonas virulence factor 2-AA promotes glycolytic shift in macrophages that prevents inflammatory immune response.

Selected by Joao Mello-Vieira

Categories: cell biology, microbiology

Background

Bacterial virulence factors are important for the persistence of infection by changing the bacterium and the host cells. For example, Pseudomonas aeruginosa produce 2-aminoacetophenone (2-AA), a metabolite produced by the carbon metabolism of this bacterium, promotes chronic infection by preventing the activation of the immune cascade in the host.

In a paper published in 2016 in Nature Microbiolgy, Arunava Bandyopadhaya and colleagues reported that long exposures to 2-AA (over 24 hours) lead to immunosuppression of macrophages. They detailed the mechanism of this factor as increasing the expression of Histone Deacetylase 1 (HDAC1), while decreasing the activity of histone acetyltransferases. These changes effectively maintain the chromatin of macrophages in a “silent state”.

However, it is still unclear how 2-AA led to this epigenetic silencing. For this preprint, Bandyopadhaya and colleagues wanted to see if changes in the epigenetic landscape (caused by long term exposure to 2-AA) are a consequence of metabolic changes in the exposed cells.

 

Key Findings and Results

  • Mouse macrophages were exposed to 2-AA for 48 hours and later activated with 2-AA for another 24 hours (i.e., they were tolerized and then activated). These two treatments lead to the accumulation of pyruvate and lactate in the cytosol of the cell, with only a modest increase in acetyl-coA and ATP concentrations. Using a variety of enzyme and metabolite transporter inhibitors, the authors observed that this accumulation was due to a metabolic shift, away from oxidative phosphorylation to glycolysis.
  • Importantly, when naïve macrophages were exposed to 2-AA, they produced TNF alpha (an inflammatory cytokine). If cells had been tolerized to 2-AA and again exposed to 2-AA, their TNF alpha production was comparable to untreated and unstimulated macrophages. Yet, if tolerized macrophages were exposed to 2-AA in the presence of ATP, they were able to express TNF alpha as if they had not been tolerized. Conversely, if naïve cells were exposed to 2-AA in the presence of lactate, their TNF alpha production was hindered.
  • Finally, mice exposed to 2AA for 4 days and then infected with aeruginosa showed higher bacterial loads than infected, non-treated mice. Mice tolerized to 2AA also showed increased levels of lactate and decreased levels of acetyl-coA, validating the results obtained in vitro.

 

Significance

This manuscript shows very elegantly that 2-AA exposure leads to a metabolic shift, which results in the accumulation of lactate and limitation on ATP production that decreases the inflammatory potential of the exposed macrophage. These changes are caused by an increase in histone deacetylase activity, which in turn helps to metabolically reprogram macrophages into glycolysis. The practical consequence of this shift for P. aeruginosa is that the immune cells will respond poorly to 2-AA, delaying or blocking an effective immune response against the bacteria.

P. aeruginosa joins other bacteria (like Chlamydia pneumoniae, Legionella pneumophila, and Mycobacterium tuberculosis) that induce Warburg-like metabolic shifts in immune cells, enabling persistent infections. Other bacteria toxins (LPS and beta-glucan) can also affect Sirtuins, mammalian proteins that sense the nutritional status of the host cell, upregulating glycolysis. Yet, this is the first report of a bacterial protein directly leading to decreased levels of ERR-alpha and MPC-1 proteins, which are gatekeepers for the oxidative phosphorylation metabolism.

These findings highlight the sophisticated strategies pathogens have evolved to overcome the innate immune response. Because innate cells are short-lived (unlike T and B cells), information on how to fight bacteria is encoded by epigenetic changes, called trained immunity. By hijacking histone deacetylases, P. aeruginosa drives innate cells away from trained immunity, dampening the immune response.

The authors were able to reverse the effects of 2-AA in vitro by providing ATP to tolerized macrophages. Since 2-AA acts through epigenetic changes, they can be reversed using external stimuli. This provides an opportunity for the treatment of persistent P. aeruginosa infections and possibly other infectious diseases by using immunomodulation to overcome tolerance, favouring trained immunity.

Tags: glycolysis, immunity, innate immunity, metabolism, pseudomonas

Posted on: 14th October 2021

doi: https://doi.org/10.1242/prelights.30826

Read preprint (No Ratings Yet)




Author's response

Laurence G Rahme shared

JMV: Can these findings be extended to other virulence factors of P. aeruginosa, apart from 2-AA? For example, if 2-AA-tolerized cells are exposed to another virulence factor, do they also respond poorly? Or is this mechanism restricted to 2-AA?

LGR: 2-AA-tolerized cells indeed restrict P. aeruginosa virulence – Please see work work published in PLOS Pathogens (Bandyopadhaya et al. 2012).  We have not tried its effect against other pathogens but we plan to test it.

 

JMV: In your studies, you focused on mouse macrophages and on macrophage cell lines. Do you think your findings can be extended to other cells of the immune system, especially T and B cells? Is it possible that the metabolic shift caused by 2-AA leads to exhaustion of these cells?

LGR:  We are planning to address this question.

 

JMV: How do you think these findings will affect treatment options for P. aeruginosa? Do you think “metabolic-modulating” drugs (such as resveratrol, rapamycin or bezafibrate) should be given in combination with antibiotics for the treatment of persistent infections?

LGR: I’m not sure about resveratrol as 2-AA dampens the pro-inflammatory responses and  resveratrol has anti-inflammatory effect besides an anti-oxidant. Rapamycin will have the opposite than desire effects as it is an immunosuppressant. As for the bezafibrate – it might be worth testing.

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