IAmA respiratory infection researcher specialising in finding ways to develop better treatments and vaccines. AMA!

Would you expect more complex sugars (sucrose, sucralose) in the airways to have the same increase in bacterial load? Or do the bacteria have a tough time breaking those down?

Sucralose is a common sweetener in e-cigarette liquids, so I’m wondering if vaping in general would significantly increase the severity of a pulmonary infection.

That is a really interesting question.

First part - would more complex sugars have the same effect on bacterial load - depends a bit on the bacteria that is colonising. Some bacteria (e.g. Pseudomonas) are very promiscuous in their usage of sugars and can use a range of sources, others and speculatively those that colonise the airways are much more fastidious and may only benefit from some sugars. With something like sucrose or other non-body sugars, you would normally not find those in the lungs.

As you say, vaping does change matters since it leads to direct uptake of some foreign sugars into the lungs. However, for there to be an effect, the bacteria in the lung would have to be able to break down the sugar in question. I don’t know very much about this sugar, but a quick look at what has been published (https://www.hindawi.com/journals/jt/2013/372986/) suggests it may not be easily broken down and therefore not beneficial to the bacteria.

But taking a step back, the hypothetical risk from vaping on a bacterial lung infection, is considerably smaller than the proven damage of inhalation smoke into the lungs.

Good day to you and thanks for this AMA.

By increased airway glucose, do you mean locally or something systemic like Diabetes mellitus? And with this, since a country like the Philippines has a large population of diabetics- is this related to why Tuberculosis is more rampant in such a population? Thank you for your time!

In this case we mean glucose local to the airway, but there is an interplay with the systemic levels of glucose. We think there are (at least) two different mechanisms that lead to changes in airway glucose.

In the case of Diabetes, the systemic level is higher and the pumps in the lungs that would normally remove the glucose from the airways cannot keep up with the level in the blood. In the case of inflammatory conditions such as Chronic Obstructive Pulmonary Disease (COPD) or cystic fibrosis (CF), we speculate that the lungs are more leaky and so glucose from the blood leaks into the airways.

In terms of the knock on effect on infection, glucose availability in the airways is one factor, particularly for a complex infection like tuberculosis (TB) where the bacteria lives inside your cells. High systemic glucose can also alter the ability of the host immune system to fight off infections. But we think airway glucose is a contributory factor, and may be one we could alter and therefore have a beneficial effect on lung infection.

How does the lung microbiome affect infections? I know there is talk of fecal transplants for gut microbiome issues, so do you think it would be possible to transplant 'healthy' lung microbiomes?

Until relatively recently, the dogma was that the lung (and particularly the lower airways) was sterile of bacteria. Changing the way we detect bacteria, moving from growing the bacteria to measuring them using sequencing techniques has changed our thinking about this.

It is now clear that there are bacteria that can live in the lower airways (the microbiome). Research at Imperial has demonstrated that alterations in the lung microbiome are associated with certain chronic respiratory diseases.

Whether it is then possible to alter this microbiome is less clear. The fecal transplant approach aims to outcompete pathogenic bacteria (for example Clostridium difficile, a hospital acquired infection) with non-pathogenic bacteria. We don’t know enough about what defines a ‘healthy’ airway microbiome yet to try and introduce new things into it.

One fascinating thing is that we can carry many of the bacteria that we consider to be pathogens - for example S. aureus and S. pneumoniae without any noticeable disease, it is only when they become invasive that they can cause disease. We hope that by understanding more about what the bacteria eat in the airways, we can then understand what tips them to being infectious.

Hi John! Which respiratory infection currently poses the greatest risk to human populations, and do you think a solution will come in the form of new drugs or vaccines...or something else?

Depends which funding body I was applying to…

If I had to make a massive sweeping guess, I would probably say influenza, based on its history - the 1918 influenza pandemic killed more people than the First World War (https://en.wikipedia.org/wiki/Spanish_flu). But there were potentially unique circumstances that led to this death toll, particularly the displacement of the First World War itself and the lack of antibiotics (this was a problem because influenza infection can be followed by bacterial infections - which the antibiotics would treat; antibiotics have no effect on influenza infection itself). Influenza certainly has the potential to spread very quickly and cause severe disease.

The other risk area is antibiotic resistant bacteria (ones that are no longer killed by the drugs we have). This is a problem for infections such as tuberculosis, with the emergence of strains that are extremely drug resistant.

In terms of solutions, I think vaccines are the answer to both influenza and antibiotic resistant bacteria. There have been a lot of really interesting breakthroughs in vaccines. And vaccines clearly work. Globally, research agencies are now working together to develop vaccines before the pandemics come, The Coalition for Epidemic Preparedness Innovations (CEPI) http://cepi.net are approaching this problem in a number of innovative ways.

Not sure if this is relevant to what you do, but a few years ago my uncle was in the hospital with ARDS and sepsis and responded very well to the vitamin C and steroid treatment, are you familiar with this and if so can you comment?

Hi there. I’m afraid this is outside of my area of expertise. However there is some commentary on this here: https://www.sciencedirect.com/science/article/pii/S0883944117310596

What do you think about Anti-Vaccine people?

I disagree with the stand they take. Vaccines work. They save lives.

The problem comes because unlike other medicines, vaccines work best at a population. So for example, say an individual said to me, they do not believe headache pills work and therefore didn’t take them, only they would get a headache. However, with vaccines, if a person doesn’t get vaccinated, or doesn’t get their children vaccinated, they are not only putting themselves at risk, they are also endangering others.

What about COPD (Chronic Obstructive Pulmonary Disease)?

How is the outlook on that?

COPD is rising in prevalence and we still do not fully understand what mechanisms are driving this or the best approach to reduce the burden of disease. We are focusing on one aspect of it – how glucose levels in the airway change, but there is so much more to be studied.

Hi, thanks for doing this AMA.

I was wondering if the increase in bacterial levels, related to airway glucose, after viral infections could be reversed in Ifnar-/- mice?

Potentially yes, depends a bit on what is driving the inflammation in the lungs and specifically what is leading to the opening up of the respiratory epithelia that enables the glucose to get through. Collaborators of ours in London, showed that inflammation driven by bacterial endotoxin (LPS) disrupted glucose homeostasis in the airways (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3605804/)

Speculatively, since IFNa (interferon alpha - a messenger molecule the body uses) is at the top of the inflammatory chain after viral infection, it may then lead to the inflammation that leads to leakiness and more bacterial infection. In the context of glucose and bacterial infection, we have not done viral-bacterial co-infection studies in mice, yet, but this is a really interesting experiment and something we will consider thank you.

Hello, thank you for doing this AMA.

I'm interested in microbiology myself and I would like to ask you if you think research should focus on developing drugs that work through new mechanisms, or drugs like clavulanic acid that combat the resistance to existing drugs?

Combating antimicrobial resistance needs to be taken across a broad spectrum of approaches, which includes developing new drugs, optimising old ones, changing behavioural and prescription practices, improving hygiene practices etc. So I don’t think there should be a specific focus, rather multiple strands of mutually supporting work.

Non-publication of negative or inconclusive animal research is a big problem for science, both in terms of publication bias and research waste. Does Imperial College have a mandate to publish/disseminate non-positive results where possible? Does AWERB consider the likelihood of publication as relevant during animal protocol review? Thanks!

This is a really interesting question. In UK every research project that involves the use of animals needs to have specific licences (that have to be approved by internal and external ethical committees) and needs to clearly justify every single experiment they plan to do.

Our main focus as the AWERB (Animal Welfare and Ethical Review Body) is, in line with the legislation, to look at the benefit to harm ratio of any animal research performed at Imperial. Within this, the dissemination of knowledge (mainly by the publication of data) is a key consideration.

We have ongoing discussions about how to improve the AWERB process and next time we meet, I will raise the topic of publishing negative data and how we can better consider this in the process.

There is a move to make publishing negative data, especially involving studies with animals, easier and the NC3Rs (which is a UK organisation dedicated to the implementation of reduction, replacement and refinement in animal research) has recently launched a partnership with an open access journal (https://f1000research.com/NC3Rs) to provide all NC3Rs grant holders a place to publish their work, regardless of the result (positive vs negative data).

Hello! Thank you for doing this Ama. I have a question as a CF patient. I'm mid 20's now and have long since colonized Psedumonas Aeruginosa in my lungs. When it 'flares up', multiple times a year, I require a course of IV antibiotics. My question is, do you know what causes it to flare up? I can be fine for a few months and then all of a sudden Pseudomonas kicks off again and I need IVs. Do we know why that is? Is it something I've done or haven't done that aggravates the Pseudomonas? I should mention that I'm on daily nebulized antibiotics all year round to try to keep it at bay. I hope you understand my question! Thanks and thank you for the incredible work you're doing.

Unfortunately, I do not know the answer to this and it is a really important question. One possibility (and this is highly speculative) is that you might get a viral infection that alters the balance of something in the lungs, for example access to glucose or lung mucus, enabling the Pseudomonas to grow more rapidly at that time.

This is something that we and others are researching as a priority area. But one thing to emphasize is that Pseudomonas is highly adapted to the CF lung and flare ups are independent of anything you have or haven’t done.

Thank you for your reply. Any other promising research on CF that is being done either by you or that you know of elsewhere? Orkambi wasn't quite the miracle drug for me that it seemed to be for others.

I think the most exciting is the work on gene therapy (https://www.nhs.uk/news/genetics-and-stem-cells/gene-therapy-breakthrough-for-cystic-fibrosis/) but this is still a long way from being a clinical reality. Beyond that I am afraid I don’t know the field well enough to say. The Cystic Fibrosis Trust in the UK (https://www.cysticfibrosis.org.uk/news/five-things-our-cf-researchers-are-working-on) has more on their website about current research.

Dear Dr Tregoning, a previous AMA touched on the hygiene hypothesis and its role in disease. Specifically, there was reference to Amish barn dust, which is presumably introduced to the body via the lungs. Would you envisage that a practical therapy could be derived from this, or should I have my kids go sit in a barn for their summer holidays?

The hygiene hypothesis (https://en.wikipedia.org/wiki/Hygiene_hypothesis) is really fascinating and there is a lot of epidemiology that supports the idea that exposure to more dirt (which may be bacteria, bacterial products or something else entirely) in early life reduces the risk of asthma later in life.

The best studies have tried to take out the genetic background of people and focus only on the environment - for example East and West Germany before and after re-unification and the Amish and Hutterite communities https://news.uchicago.edu/story/growing-amish-farms-protects-children-against-asthma.

Both of these studies suggest that exposure to farmyard dust reduces the risk of asthma in later life. If we could identify a single component that could be sprayed into the lungs at an early age that trains the immune response away from asthma that would be fantastic, but we are a long way from this; in no small part because ‘asthma’ is a real mix of conditions not just one disease.

Taking off science hat and putting on wild speculative parenting hat, yes going to a barn, being outside and in contact with animals is probably going to be good for them, at least it will stop them playing Fortnite for a bit!

I've recently red that robotic cleaning of hospitals is more effective than human. What do you think of this from your view as an expert for infections? Could this reduce the high number of death from clinical related bacteria?

Hi RobertThorn2022. Sorry, this is outside my area of research.

Do you often encounter antivaxxers or the likes of PETA (or the like)? What is a way you deal with them?

I honestly live that you are working for the good of humanity...just curious on how you handle those types of situations.

Thanks for everything you do and are working towards!!

Thank you for the kind message of support. I think the best way is through open, informed discussion about the different issues.

We do not undertake animal research lightly and the work we do is under close scrutiny (https://wwwf.imperial.ac.uk/blog/imperial-medicine/2018/06/27/reducing-refining-and-replacing-the-use-of-animals-is-crucial-to-respiratory-research/).

Moreover in the UK there is a constant open discussion with anti-animal research groups and organizations like Understanding Animal Research (http://www.understandinganimalresearch.org.uk/) do work to promote the openness and transparency regarding the use of animals, and to improve communication with the general public about what happens in the lab and why it is important to use animals in research.

Hi, is there any similarities that you have found in the body's response and reaction to infections and how the body responds to other conditions like tracheomalacia or cronic lung disease in infants and young children?

Sorry, RandomHero1018, this is outside my areas of research.

What sort of drugs are you looking to develop? Drugs for prevention of infection in susceptible groups (e.g. COPD patients) or for treatment following contraction of an infection?

We are looking at both. We are looking at drugs to reduce infection by reducing the existing airway glucose, for example using the anti-diabetic drug metformin (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4897689/). But we are also thinking about ways in which we could stop bacteria accessing the glucose in the airways as a treatment approach.