Role of airway glucose in bacterial infections in patients with chronic obstructive pulmonary disease

Role of airway glucose in bacterial infections in patients with chronic obstructive pulmonary disease:

Chronic Obstructive Pulmonary Disease (COPD) describes a
group of lung conditions that make it hard to breath. The major cause of COPD is
smoking. Nearly 1.2 million people in the UK suffer with COPD, costing the NHS
more than £800 million a year. Bacterial lung infections are particularly common
in COPD patients. There are a number of reasons that COPD patients are more
susceptible to infection but most research has focussed on failures of the
immune system. We propose an alternative mechanism in our latest paper in the
Journal of Allergy and Clinical Immunology (JACI).

Bacteria, like all living things, need food to grow. The
bacteria that infect us are no exception to this and their food source is us!
The airways are surprisingly rich in nutrients for bacterial growth, some of
this comes from the food we eat (micro-inhalation) and some leaks out from the
blood or cells lining the airways. In healthy lungs, glucose is actively pumped
out of the lungs maintaining it at a low level, but in damaged lungs the flow
of sugar into the lungs exceeds the amount of sugar that can be pumped back out.
Using model systems we have linked this increased lung glucose to increasedlung infection. We think that this works a little like
leaving a jam jar open – bacteria can colonise and grow on the available sugar.

We have now extended these results to patients with COPD. We
measured glucose in samples from COPD patients and found that airway glucose was
higher compared to individuals without COPD. Moreover when COPD patients had an
acute viral infection of the lungs (called an exacerbation) the glucose
concentrations were even higher, probably because the virus further damages the
lung. There was also a direct relationship between the amount of glucose and
the amount of bacteria in the COPD patient samples. We think that
mechanistically, the glucose is elevated because of lung inflammation –
essentially COPD lungs are more leaky, the glucose moves from the blood into
the airways with an impact on bacterial growth.

Why is this
important?

Antibiotics are commonly used to treat infections in COPD,
contributing to the rise in antibiotic resistance. Antibiotic resistant
bacteria (bacteria that are not killed by antibiotics) are a crisis in global
health. If antibiotics stop working, as well as an increase in the severity of
infections that are treatable, much of the medical advances of the last 50
years including surgery and transplants also become ineffective. We therefore
need new ways of killing bacteria. Demonstrating that bacteria are need the
sugar in the airways to grow opens up a new line of attack, cut off the
bacteria’s source of sugar. Potentially this would prevent bacterial infections
in the first place, circumventing the need for antibiotics.

Self-Amplifying RNA Vaccines Give Equivalent Protection against Influenza to mRNA Vaccines but at Much Lower Doses

Self-Amplifying RNA Vaccines Give Equivalent Protection against Influenza to mRNA Vaccines but at Much Lower Doses

Make your own vaccine

With pandemic infections we are always behind the curve,
particularly when it comes to developing vaccines. Vaccines work by inducing a
protective immune memory to an infectious agent so you have to know what the
infectious agent is and which part of the infectious agent the body is going to
recognise to make an effective vaccine. Having identified that, you then have
to make the vaccine, test the vaccine and ship it to the sites where it is
needed in order to give it to people before they are exposed to the infection.
This all takes time.

Manufacture = time

A particularly time consuming hurdle is vaccine manufacture.
This is because most vaccines that we use are protein based, which can be
difficult (and expensive) to manufacture. There are however alternatives. One
approach is to utilise our understanding of how proteins are encoded in our
cells. The source information for proteins comes from genes (encoded in DNA
molecules), this genetic material is copied into an intermediary messenger
molecule called ribonucleic acid (RNA). Remarkably, if you inject either DNA or
RNA into a muscle, that muscle starts making the protein encoded in the DNA.
Even more amazingly, your immune system can then recognise the protein that is
made in your muscle cells and develop a protective response, in the same way
that it would to an injected vaccine.

RNA vaccines

The injection of RNA in particular, seems to be very
effective at triggering an immune response. In our recently published
paper, we looked at ways to improve how these RNA vaccines work. We compared
two different approaches, the first approach is to make synthetic RNA molecules
that look exactly like the messenger RNA (mRNA) your body makes when it is
making a protein. The second approach is to adapt a trick from a family of
viruses called the alpha viruses, which use the machinery of the cell to make
copies of themselves. We can insert vaccine genes into a safe version of the
alphavirus, which when injected makes multiple copies of the vaccine in the cells
it has been injected into. We call these vaccines self-amplifying as they are
able make more copies of themselves after they are injected.

We compared the two RNA approaches to see which one would
make the best influenza vaccine. Both the mRNA and the self-amplifying RNA
based vaccines protected against influenza virus infection, but strikingly the self-amplifying
vaccines gave the same protection when 60 times less RNA was used. This dose
sparing could potentially be really important in the face of an epidemic where
many people need to be vaccinated in a short time period. We also show that the
vaccine was able to protect after a single dose and it is possible to combine
multiple strains of influenza virus in the same vaccine and protect against all
of them.

We think RNA vaccines show great promise for the future and
this study gives us confidence to move forwards into human studies.