(PI) Host lab Website and Contact Title Project Summary



(PI) Host lab Website and Contact Title Project Summary
Cii Summer Studentship Projects 2014
Investigator (PI)
Host lab
Website and
Project Summary
Prof. Miguel Valvano
Intracellular survival
of opportunistic
bacteria in
New ways to treat pulmonary chronic infection and inflammation in patients
with cystic fibrosis (CF) are urgently needed. Infecting bacteria are normally
destroyed by macrophages and neutrophils, which are cells from the immune
system that engulf bacteria. However, we have observed that engulfed CF
pathogens, such as several strains of the B. cepacia complex bacteria are
capable to survive intracellularly in macrophages. Engulfed bacteria damage the
membrane-bound vacuole, enter in contact with the cytosol and are re-up
taken into newly formed membrane compartments called autophagosomes. In
this project, the Summer Student will learn various microscopy techniques that
will enable her/him to follow the intracellular bacterial infection to characterise
novel host and pathogen molecules involved in host-pathogen interplay, which
we hope will help unravel new avenues for the treatment of infection in CF
Evaluating the
antimicrobial activity
of a novel class of
short cationic
The oral cavity provides a unique habitat for micro-organisms as the teeth are
the only non-shedding surfaces in the body. Bacterial levels on teeth have been
reported to reach more than 1011 microorganisms per mg of dental plaque. The
anatomic closeness of this microflora to the bloodstream can facilitate entry of
microorganisms into the circulation and thus oral bacteria can act as reservoir
for systemic infections. The oral microflora exists as a complex biofilm which
typically displays increased resistance to conventional antimicrobials. Thus the
need for development of novel therapeutics for oral infections has become
paramount. In this project we will test a new class of short cationic
antimicrobials for their activity against a range of oral pathogens in planktonic
and biofilm form. The student will develop laboratory research skills in oral
microbiology and will have the opportunity to work alongside experienced
[email protected]
Dr. Fionnuala Lundy 1. http://www.qub.ac.uk/r
[email protected]
Dr. Denise Fitzgerald
The role of
inflammasomes in
brain repair
Myelin is the protecting sheath around neurons that facilitates signal
conduction in the brain. Damage to myelin (demyelination) can have
devastating outcomes such as permanent disability and blindness. Currently,
there is no cure for demyelinating diseases such as Multiple Sclerosis (MS). Our
neuroimmunology research group is identifying novel therapeutic targets to
repair myelin in the brain in MS.
Inflammasomes are multi-protein complexes that process the pro-inflammatory
cytokines IL-18. Inflammasomes are known to drive inflammation in
animal models of MS. Brain repair is partly dependent on inflammation
however, to date it is not known if inflammasomes play a role in brain repair.
This project aims to understand the role of inflammasomes in remyelination in
animal models of demyelination.
This work will contribute to the understanding of how the innate immune
system facilitates brain repair. This research could have implications for
developing future therapeutics for the treatment of Multiple Sclerosis.
Investigation of the
mechanism of upregulation of
transient receptor
potential (TRP)
cation channels by
respiratory virus
envelope proteins.
Members of the transient receptor potential (TRP) cation channel family,
expressed in cell types in the lung are known to regulate the tussive response
to airway irritants and are important in asthma. We have recently shown that
TRP channels are up-regulated by respiratory virus infection. Measles virus
(MV) and respiratory syncytial virus (RSV) induce soluble factors which alone
are capable of TRPV1 (TRP channel) up-regulation. However, non-infectious
virus particles were also found to up-regulate TRPV1. Membrane Toll like
Receptors (TLRs) respond to specific microbial components, including proteins
found on virus envelopes, and induce cytokines. The envelope proteins
haemagglutinin (H) of MV and fusion (F) protein of RSV are known to interact
with TLR2 and TLR4, respectively. Our hypothesis is that virus envelope proteins
up-regulate TRP channels by activating particular membrane TLRs. The student
would investigate this with a view to new therapeutic strategies for respiratory
virus infection including asthma exacerbations.
[email protected]
[email protected]
Prof. Louise Cosby
1. http://www.qub.ac.uk/r
[email protected]
Dr. Bettina Schock
Induction of zinc
finger protein A20:
compounds with
The zinc finger protein A20 regulates NFinfection. In CF epithelial cells, A20 expression and function is reduced, and
accompanied by persistent activation of NFcytokines. We have identified Gibberellin (GA), a diterpenoid, to induce
A20/ZnF proteins, thereby exerting anti-inflammatory properties. Using
bioinformatics (connectivity mapping) we have now identified further
compounds and drugs, some of them already licensed for use in humans that
would induce A20. This project will test the ability of the predicted compounds
to induce A20 in airway epithelial cells. Results of this work will help to assign
new anti-inflammatory functions to already existing drugs (drug repositioning).
Techniques employed include sterile working, cell culture, qPCR (mRNA for A20
and p65) Western Blotting (A20) and ELISA (pro-inflammatory cytokines).
zinc finger protein
A20: Mechanism of
The zinc finger protein A20 regulates NF-kappaB activation in response to
bacterial infection. In CF epithelial cells, A20 expression and function is
reduced, and accompanied by persistent activation of NF-kappaB and release of
inflammatory cytokines. We have identified Gibberellin (GA), a diterpenoid, to
induce A20/ZnF proteins, thereby exerting anti-inflammatory properties.
However, the mechanism of action of A20 is not fully understood, especially as
A20 itself is induced via NF-kappaB (p65 subunit). Phosphorylation of p65 can
modifying the activity of NFA20 has been shown to increase through
phosphorylation of p65 on serine536. Our hypothesis is that GA pre-treatment
changes the phosphorylation on p65 upon LPS stimulation, thereby enhancing
the expression of anti-inflammatory A20. Techniques employed include sterile
working, cell culture and Western Blotting (A20, phospho p65 protein) and
ELISA (pro-inflammatory cytokines).
[email protected]
Dr. Bettina Schock
[email protected]
Prof. Jose Bengoechea
Is there a way to
treat infections
without antibiotics?
In the UK, respiratory infections are the leading cause of infectious disease
mortality and morbidity. This problem is getting worse by growing numbers of
multidrug-resistant microorganisms, the so-called superbugs. Antimicrobial
resistance is not only a major UK health problem but a global one as highlighted
by the World Health Organization. Therefore, there is a need to develop
effective therapeutics based on new approaches.
In this ground-breaking project, we will explore whether by targeting the
strategies employed by the superbugs to manipulate our host defences system
we can eradicate the infection without need of antibiotics. To address this
hypothesis, we will use our recently developed infection model of the wax
moth Galleria mellonella. Larvae will be infected with the superbug Klebsiella
pneumoniae and then treated with drugs that block the host molecules
targeted by Klebsiella already discovered by my laboratory.
Determining the
antiviral potential of
a novel antirespiratory syncytial
virus (RSV)
RSV is the principal viral cause of severe lower respiratory tract disease in
infants and young children. However, there are no vaccines or specific
therapeutics available against this virus. As part of a research project funded by
a biotech company, we are studying the therapeutic potential of a novel
nanobody against RSV infection of well-differentiated primary paediatric
bronchial epithelial cell cultures (WD-PBECs). Nanobodies are recombinant
single variable chains derived from functional Ilamas antibodies composed of
only heavy chains. WD-PBECs are airway epithelial cell cultures that look and
behave like they would in the lungs. Airway epithelial cells are the primary
targets for RSV infection in infants. This project will help to generate data
necessary to support the hypothesis that the novel anti-RSV nanobody has
therapeutic potential by titrating apically-release RSV by infection assays and
quantitative RT-PCR assays and quantifying cytopathogenesis following RSV
infection of nanobody treated and untreated WD-PBECs.
[email protected]
Dr. Ultan Power
1. http://www.qub.ac.uk/r
[email protected]
Dr. Tammie
Strategies to limit
Resistance in Gramnegative bacteria
[email protected]
Dr. Beckie Ingram
Treg control of Th9
and Th2 cells
[email protected]
Dr. Beckie Ingram
[email protected]
Using a Wax Moth
larvae model to
investigate the role
of the lung
microbiome in the
pathogenicity of
The emergence and spread of antimicrobial resistance in bacteria now presents
the stark reality that continued antibiotic treatment is under threat. This is
especially relevant in gram-negative bacteria, where the situation has reached
crisis point, resulting in an increasing reliance on last resort agents. Klebsiella
pneumoniae is a significant gram-negative nosocomial pathogen which is a
major cause of bacteraemia in the UK (http://www.bbc.co.uk/news/health21737844) and due to rising resistance levels presents an increasing challenge
for antimicrobial therapy. Antimicrobial resistance in K. pneumoniae can occur
either through target specific mutations or via the increased expression of
intrinsic mechanisms. These intrinsic mechanisms generally confer a pan-drug
resistance phenotype linked to perturbations of influx and efflux mechanisms.
Studies also link the elevated levels of these regulators to pleiotropic
phenotypes, which impact on microbe-drug interactions. Thus the challenge is
to elucidate how intrinsic systems facilitate microbial survival in the face of
continued antibiotic challenge.
Regulatory T cells (Tregs) are the control system for the immune response.
When they function correctly they prevent damage to surrounding tissues
during an immune response to infection and the development of
autoimmunity. There is a clear understanding of how Tregs control the wellcharacterised Th1 and Th2 helper T cell subsets. However in the last few years
there has been a huge expansion of the number of distinct Th subsets
identified. This project will explore the ability of Tregs to suppress the activity
of the more recently identified Th9 and Th22 subsets. The project will include
cell culture, proliferation assays, ELISA and flow cytometry.
It is now well established that the gut microbiome has a huge impact on the
human immune response. An interaction between the gut commensal bacteria
and immune system has the ability to greatly alter the immune response to
pathogenic bacteria either positively or negatively. The human lung was
previously thought to be a sterile site in the absence of active infection. With
the advent of modern deep sequencing techniques it is now known that this
isn’t the case and there is a diverse bacterial community within the lung. This
project will use a moth larvae model to examine if these lung commensal
organisms alter the virulence of lung pathogenic bacteria Pseudomonas.

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