MICA: To evaluate the role of the histamine four receptor (H4R) in the clearance of lung pathogens using the H4R antagonist UCB1344778

Lead Research Organisation: Queen's University of Belfast
Department Name: Centre for Experimental Medicine

Abstract

A hallmark of cystic fibrosis (CF) is severe and persistent bacterial infections in the lungs despite massive influx of polymorphonuclear leukocytes (neutrophils). Neutrophils are the first line of defence against infecting microbes; however, CF pulmonary neutrophils have a reduced capacity to engulf pathogens. It remains unclear why the function of neutrophils is compromised in CF patients. Our project is aimed at understanding what blocks neutrophils in the lungs and how to overcome this inhibition. We believe that bacteria colonizing the lungs of CF patients produce a substance called histamine and that histamine blocks the killing capacity of neutrophils by binding to a specific receptor, the histamine-4 receptor (H4R), expressed on the membrane surface of these cells.
We hypothesize that histamine produced by Gram-negative bacteria colonizing CF lungs impairs phagocytosis by neutrophils by affecting their ability to capture pathogens and killing them after engulfment. We also believe that the inhibitory effect of histamine is due to engagement of the H4R on human neutrophils. We demonstrated that the H4R is expressed in human PMNs and it is a potent inhibitor of PMN degranulation. Further, we showed that the H4R also negatively regulates engulfment of bacteria, while treatment with a H4R antagonist overcomes this histamine-dependent inhibition of engulfment.
In this project, we will explore the role of the H4R in neutrophil engulfment by using the H4R antagonist UCB1344778. We will investigate whether UCB1344778 can prevent histamine from blocking capture of pathogens and inhibition of intracellular killing using model CF pathogens both in vitro and in vivo experiments suing a CF mouse model. The pre-clinical data generated in this project will be exploited for future clinical studies in patients with CF and other chronic lung inflammatory diseases (e.g. chronic obstructive pulmonary disease).

Technical Summary

We have evidence suggesting that bacteria-derived histamine in lung fluids impairs neutrophils (PMNs) antimicrobial functions by engaging histamine receptors, in particular the H4R. We will therefore address the role of the H4R in pathogen clearance by using the H4R antagonist UCB1344778.

The following two objectives with be achieved:

A. To test the role of H4R activation in modulating PMN phagocytosis in vitro. We will investigate whether treatment of human or murine PMNs with histamine prevents capture and killing of respiratory pathogens found in CF lungs (P. aeruginosa, and Burkholderia cenocepacia). To prove that histamine-mediated inhibition of PMN phagocytosis is caused by engagement of the H4R, we will investigate whether UCB1344778 can reverse the inhibitory effect of histamine on PMN phagocytosis. We will validate UCB1344778 as a potent booster of PMN phagocytosis and pathogen clearance.

B. To test the role of H4R activation in modulating mouse PMN phagocytosis in vivo. We will investigate whether bacteria-derived histamine is responsible for the impaired phagocytic activity of pulmonary PMNs in a mouse model of CF. To this end we will infect BALB/c mice with the stable mucoid P. aeruginosa CF sputum isolate (NH5833A) to induce a mouse model of CF which mimics human CF pathology. Two approaches will be used to prove the inhibitory role played by the H4R in the clearance of lung pathogens in this CF mouse model. First, we will create a histidine decarboxylase (hdc)-null derivative of P. aeruginosa NH5833A, which will be unable to produce histamine. We will compare lung pathology and lung bacterial clearance in mice infected with the parental isolate vs. those infected with the hdc-null mutant. Second, we will compare lung pathology and lung bacterial clearance in mice infected with both isolates, but treated orally for 7 days with UCB1344778.

Planned Impact

Enhancing research capacity is an important aspect of the proposal and will be met by the provision of high quality training and career development of the appointed PDRA. QUB offers a number of training courses and workshops aimed specifically at contract research staff. Attendance at these courses would complement the extensive laboratory-based training that the PDRA will receive and will develop the transferable skills necessary to enable engagement with, and movement between, different sectors.


The data will be published in peer-reviewed journals of high scientific standard. This will raise the level of excellence in the Uk's base science. Thus, the wide scientific community including clinical and non-clinical scientists will benefit from the proposed research project by accessing the published articles. The work will also be presented at national and overseas meetings thus demonstrating to the broad scientific community that work of excellence is carried out in the recently opened Centre for Experimental Medicine of Queen's University Belfast.

The scientific profile of the applicants will be raised, which will render their research centre and university attractive to other researchers. Recruitment of talented researchers to the UK is instrumental to maintain scientific excellence and to ensure a steady stream of world-class research. Our proposal will be instrumental in attracting funding and world class researchers to a UK University, thus securing UK's long-term economic and scientific competitiveness.


Our research is aimed at validating the H4R antagonist UCB1344778 developed by UCB pharma as a potential new therapeutic drug for the treatment of chronic lung diseases. Such validation will prove vital for the development of clininical phase studies using the H4R antagonist UCB1344778 in patients suferring from chronic lung diseases including CF and COPD.

Production and commercialisation of the H4R antagonist UCB1344778 by UCB pharma will generate substantial financial resources which can be invested in research and development and this benefits employment in the UK.

Publications

10 25 50
 
Description Research skills
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
 
Description NI Chest Heart and Stroke
Amount £58,442 (GBP)
Organisation Queen's University Belfast 
Sector Academic/University
Country United Kingdom
Start 12/2019 
End 12/2020
 
Title Treatment of Cystic fibrosis with histamine four receptor antagonists 
Description We will investigate whether administration of a histamine four receptor antagonist can improve bacterial clearance in the lungs of mice chronically infected with pseudomonas aeruginosa. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2018 
Provided To Others? No  
Impact Our work may pave the way for future clinical phase studies using a histamine four receptor antagonist in patients suffering from Cystic Fibrosis and other chronic lung diseases such as COPD. 
 
Title Data collection from experiments 
Description I will collect and handle data on capture and killing of various pathogens by human and murine neutrophils in the presence or absence of histamine or a histamine four receptor antagonist (in vitro studies). I will also collect and handle data on macroscopic description of the lungs, lung bacteriology and histopathology in infected control mice and in infected mice treated with a histamine four receptor antagonist. 
Type Of Material Data handling & control 
Year Produced 2019 
Provided To Others? No  
Impact No notable impact yet. 
 
Description Open day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The Centre for Experimental Medicine (QUB) opened its door to the general public as part of the NI Science Festival. Stands were installed in the lobby to inform the general public about the research activities carried out in the Centre. Immunology, Bacteriology, Microbiology and Stem cell technologies were presented to the public in lay terms using appropriate support.
The public engaged with staff members and discussion followed around different scientific disciplines. This event was particularly important to encourage pupils embarking on a scientific path ultimately joining QUB for a science degree in the near future.
Year(s) Of Engagement Activity 2018
URL https://www.nisciencefestival.com/2018/programme.php?c=all