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Sometimes science leads us to unexpected places. For example, work we started during the COVID lockdown, may help treating the "Curse of the Pharaohs".

Read all about it at Science Immunology.

PS, we don't support tomb-robbing of ancient Egyptian burial sites.

www.science.org/doi/10.1126/...

The best part is, because we only altered the immunology of the lung tissue, the anti-viral responses generated in the LN were intact, so we could reduce lung inflammation without giving the infection a free-pass.

This is why tissue immunology has such potential - only hit the site needed!

The system works great! AAV6.2.CC10 driving #IL2 production gives an expansion of #lung #Tregs without impacting other sites, even the draining LN of the lung.

And it is not just IL2 - in the same way we can drive #IL10 or #IL1RA in the lung without altering systemic levels. Pick your own cargo!

We have an exciting new story out at @science.org's Science Immunology! It is all about using #AAV-mediated cytokine delivery to change the lung environment. We can boost #lung #Tregs or delivery anti-inflammatory #cytokines, preventing fatal respiratory collapse

www.science.org/doi/10.1126/...

Morning squirrel visit

It took quite some trial and error, but eventually we found that intranasal delivery of AAV6.2 capsid with the CC10 promoter drove tight expression of our cargo by club cells, limited to the lung tissue.

Gorgeous imaging from the team of @regisjoulia.bsky.social ia.bsky.social

Gene delivery of immunomodulatory cytokines to the lung preserves respiratory function during inflammatory challenge @labliston.bsky.social @sciimmunology.bsky.social
@babrahaminst.bsky.social @drntombizodwa.bsky.social
www.science.org/doi/10.1126/...

Potentially! Just needs the right cargo combination

If you are interested in the people behind the science, Tombi started in rural Zimbabwe and James went from foster care to homelessness. Their stories "I won't become a Statistic", and "From the Streets to the Lab", in our book "Self-Doubt", are a real inspiration.

www.amazon.co.uk/Self-Doubt-A...

Thanks! Yes, no reason why it shouldn't work with pro-inflammatory cytokines. We've tried with our own engineered IL2 variants and the approach works great, letting us hit Treg vs CD8 T cells. Immune-modulating cargos tend to be small and suitable for delivery via AAV!

Becoming a Scientist | PDF to Flipbook Created with the Heyzine flipbook maker

A huge thanks to our team at @cam.ac.uk & @babrahaminst.bsky.social. Thanks also to the @kuleuvenuniversity.bsky.social team, especially Laura Seldeslachts and Lauren Michiels.
Funded by @erc.europa.eu, @wellcometrust.bsky.social & @fwovlaanderen.bsky.social 🙏

heyzine.com/flip-book/a1...

The best part is, because we only altered the immunology of the lung tissue, the anti-viral responses generated in the LN were intact, so we could reduce lung inflammation without giving the infection a free-pass.

This is why tissue immunology has such potential - only hit the site needed!

So we teamed up with @kuleuvenuniversity.bsky.social and tested our AAV-cytokine delivery approach in coinfected (IAPA) mice. Success! In every measure we tested, our treatment reduced severity down from fatal respiratory failure down closer to a regular flu infection.

But Aspergillus is a hidden killer.

The Wauters, Vande Velde and Humblet-Baron teams at @kuleuvenuniversity.bsky.social found that coinfection of influenza and aspergillus is extremely deadly, with an ICU mortality rate of >50%, >70% if immunocompromised. Likewise, coinfection in mice is lethal.

Aspergillus is a fungus common in decaying soil, that can infect the lung. For healthy individuals it is rarely a problem, and is easily cleared

Fun fact: Aspergillus may be the "Curse of the Pharaohs" as Egyptian tombs were full of spores, and tomb robbers would have breathed in very high doses

We never ended up testing it in SARS-CoV2 infection - by that point the #vaccine had come along. But COVID isn't the only important lung infection. You might not even have heard of one of the most deadly:

Influenza-Associated Pulmonary Aspergillosis (IAPA)

The system works great! AAV6.2.CC10 driving #IL2 production gives an expansion of #lung #Tregs without impacting other sites, even the draining LN of the lung.

And it is not just IL2 - in the same way we can drive #IL10 or #IL1RA in the lung without altering systemic levels. Pick your own cargo!

It took quite some trial and error, but eventually we found that intranasal delivery of AAV6.2 capsid with the CC10 promoter drove tight expression of our cargo by club cells, limited to the lung tissue.

Gorgeous imaging from the team of @regisjoulia.bsky.social ia.bsky.social

Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation - Nature Immunology Liston and colleagues design a gene-delivery system to specifically target astrocytes in the central nervous system to express IL-2 and thereby expand/maintain Treg cells to suppress neuroinflammation...

At the time we had been working on a system to boost #Tregs in the brain, as a way of combatting neuroinflammation. Our AAV system was working great, so we thought "what if we tried to do the same thing in the lung?"

www.nature.com/articles/s41...

<em>Clinical & Translational Immunology</em> | ASI Journal | Wiley Online Library Clinical presentation of patients infected with the new coronavirus SARS-CoV-2 is very variable and possibly due to differences in the immune response. To address this hypothesis, we investigated the...

We had only just moved to Cambridge, and I still had a team in Belgium. They were processing clinical samples from #COVID patients, so we already had a good idea that the respiratory failure was driven by excessive #inflammation rather than the virus itself

onlinelibrary.wiley.com/doi/10.1002/...

This story started during the COVID pandemic. Our first Cambridge PhD students joined during lockdown, and a talented student, @drntombizodwa.bsky.social, wanted to work on a potential therapeutic. Only essential people (James Dooley, not me!) could be in the lab, but they started on the problem

We have an exciting new story out at @science.org's Science Immunology! It is all about using #AAV-mediated cytokine delivery to change the lung environment. We can boost #lung #Tregs or delivery anti-inflammatory #cytokines, preventing fatal respiratory collapse

www.science.org/doi/10.1126/...

Spring garden

Unfortunately, in my write up of our new paper, I committed the cardinal sin of science communication:

I forgot to say we used #machinelearning!

Clearly I should have led with "Hidden disease solved by #AI"

www.nature.com/articles/s41...

No - none of them had the clinical signatures (e.g. salmon pink rash) of Still's disease at sampling/diagnosis or a year-long clinical follow-up.

So AI was a marginally-useful tool, which helped at the edges. But medical data is rarely of the right data structure to give the types of advantages you see in things like weather prediction, so the idea of AI transforming medicine is largely hype.

Will that ~2.6% increase in diagnostic discrimination be reproducible/useful? Hard to know - these effects are prone to over-fitting, so I'm not betting on that gain being reproducible

And actual clinical diagnostics are usually simplified, without research-grade complexity, removing the "AI boost"

Random Forests (the best performing AI approach) identified the same immunological signatures as MLR, so we didn't learn any new biology from AI.

It did improve diagnostic AUC by ~2.6% though. That's not nothing - incremental improvements are at the heart of clinical advances.