Active bacterial modification of the host environment through RNA polymerase II inhibition

Ambite, Inès; Filenko, Nina A.; Zaldastanishvili, Elisabed; Butler, Daniel; Tran, Thi Hong; Chaudhuri, Arunima; Esmaeili, Parisa; Ahmadi, Shahram; Paul, Sanchari; Wullt, Björn; Putze, Johannes; Chen, Swaine L.; Dobrindt, Ulrich; Svanborg, Catharina

doi:10.1172/jci140333

Cited by 8 publications

(7 citation statements)

References 62 publications

(59 reference statements)

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“…In early experiments, ABU strains were shown to inhibit host gene expression by targeting the RNA Pol II phosphorylation machinery 200 , 201 (Fig. 6 ).…”

Section: Immunomodulation By Molecules Of Bacterial Originmentioning

confidence: 99%

“…Productive RNA elongation requires phosphorylation of the RPB1 subunit, and this step was inhibited by most ABU strains 200 . The bacterial protein NlpD has been identified as an active inhibitor released by ABU and faecal E. coli isolates under normal growth conditions 201 , 203 , 204 . NlpD is internalized by host cells and inhibits gene expression broadly, including effects on several pro-inflammatory mediators.…”

Section: Immunomodulation By Molecules Of Bacterial Originmentioning

confidence: 99%

“…Treatment with NlpD inhibits the response to virulent strains by inhibiting Pol II Ser2 phosphorylation. d | Therapeutic effect defined by a marked reduction in bacterial counts and neutrophil infiltration in mice treated intraperitoneally with recombinant NlpD, compared with untreated mice 201 , 204 . *** P < 0.001.…”

Section: Immunomodulation By Molecules Of Bacterial Originmentioning

confidence: 99%

“… Asymptomatic bacteriuria (ABU) strains have been shown to actively modify the host environment in the urinary tract using different molecular methods 200 , 201 . a | RNA polymerase II (Pol II) is phosphorylated to initiate productive RNA elongation during the transcription cycle.…”

Section: Immunomodulation By Molecules Of Bacterial Originmentioning

confidence: 99%

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Immunomodulation therapy offers new molecular strategies to treat UTI

et al. 2022

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Innovative solutions are needed for the treatment of bacterial infections, and a range of antibacterial molecules have been explored as alternatives to antibiotics. A different approach is to investigate the immune system of the host for new ways of making the antibacterial defence more efficient. However, the immune system has a dual role as protector and cause of disease: in addition to being protective, increasing evidence shows that innate immune responses can become excessive and cause acute symptoms and tissue pathology during infection. This role of innate immunity in disease suggests that the immune system should be targeted therapeutically, to inhibit over-reactivity. The ultimate goal is to develop therapies that selectively attenuate destructive immune response cascades, while augmenting the protective antimicrobial defence but such treatment options have remained underexplored, owing to the molecular proximity of the protective and destructive effects of the immune response. The concept of innate immunomodulation therapy has been developed successfully in urinary tract infections, based on detailed studies of innate immune activation and disease pathogenesis. Effective, disease-specific, immunomodulatory strategies have been developed by targeting specific immune response regulators including key transcription factors. In acute pyelonephritis, targeting interferon regulatory factor 7 using small interfering RNA or treatment with antimicrobial peptide cathelicidin was protective and, in acute cystitis, targeting overactive effector molecules such as IL-1β, MMP7, COX2, cAMP and the pain-sensing receptor NK1R has been successful in vivo. Furthermore, other UTI treatment strategies, such as inhibiting bacterial adhesion and vaccination, have also shown promise.

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“…In early experiments, ABU strains were shown to inhibit host gene expression by targeting the RNA Pol II phosphorylation machinery 200 , 201 (Fig. 6 ).…”

Section: Immunomodulation By Molecules Of Bacterial Originmentioning

confidence: 99%

Section: Immunomodulation By Molecules Of Bacterial Originmentioning

confidence: 99%

Section: Immunomodulation By Molecules Of Bacterial Originmentioning

confidence: 99%

Section: Immunomodulation By Molecules Of Bacterial Originmentioning

confidence: 99%

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Immunomodulation therapy offers new molecular strategies to treat UTI

et al. 2022

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“…Elevated ROS may occur during UTIs, as the urine of patients with acute UTI contained malondialdehyde, a byproduct of oxidative stress and marker of lipid peroxidation (Kurutas et al, 2005). In addition, UPEC elaborate a number of genes involved in oxidative stress response (John-Bessaiah et al, 2019;Himpsl et al, 2020;Ambite et al, 2021). However, ROS has not been directly quantitated in UPEC-infected urothelial cells.…”

Section: Introductionmentioning

confidence: 99%

NRF2 promotes urothelial cell response to bacterial infection by regulating reactive oxygen species and RAB27B expression

Joshi¹,

Mora²,

Felder³

et al. 2021

Cell Reports

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Molecular determinants of disease severity in urinary tract infection

et al. 2021

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The most common and lethal bacterial pathogens have co-evolved with the host. Pathogens are the aggressors, and the host immune system is responsible for the defence. However, immune responses can also become destructive, and excessive innate immune activation is a major cause of infection-associated morbidity, exemplified by symptomatic urinary tract infections (UTIs), which are caused, in part, by excessive innate immune activation. Severe kidney infections (acute pyelonephritis) are a major cause of morbidity and mortality, and painful infections of the urinary bladder (acute cystitis) can become debilitating in susceptible patients. Disease severity is controlled at specific innate immune checkpoints, and a detailed understanding of their functions is crucial for strategies to counter microbial aggression with novel treatment and prevention measures. One approach is the use of bacterial molecules that reprogramme the innate immune system, accelerating or inhibiting disease processes. A very different outcome is asymptomatic bacteriuria, defined by low host immune responsiveness to bacteria with attenuated virulence. This observation provides the rationale for immunomodulation as a new therapeutic tool to deliberately modify host susceptibility, control the host response and avoid severe disease. The power of innate immunity as an arbitrator of health and disease is also highly relevant for emerging pathogens, including the current COVID-19 pandemic.

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Active bacterial modification of the host environment through RNA polymerase II inhibition

Cited by 8 publications

References 62 publications

Immunomodulation therapy offers new molecular strategies to treat UTI

Immunomodulation therapy offers new molecular strategies to treat UTI

NRF2 promotes urothelial cell response to bacterial infection by regulating reactive oxygen species and RAB27B expression

Molecular determinants of disease severity in urinary tract infection

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