How mucus protects against infections

00:00:01: We

00:00:01: usually only notice mucus when it's causing a problem, with the runny nose or cold... ...or allergies.

00:00:09: That is where our nose runs…our airways feel congested and our body visibly produces more of it!

00:00:16: Yet mucus isn't just a symptom of illness – It's a permanent part of our mucous membranes AND an important protective barrier against infections.

00:00:26: Even when we're healthy, the body produces up to one point five liters of mucus a day.

00:00:31: It carries away dirt

00:00:33: bacteria

00:00:34: old cells and viruses And makes it harder for pathogens to make initial contact with our cells?

00:00:40: It is precisely this early phase of an infection that Professor Christian Sieben and his nano-infection biology research group at The HZi are studying.

00:00:50: using specialized microscopy His team investigates how individual viral particles interact with mucosal cells, how they bind to cells and what role the mucus barrier plays in this process.

00:01:03: The goal is to understand how viruses overcome this natural protective layer – And How This Process Can Be Specifically Disrupted.

00:01:12: In this episode of IN FACT our host Julia Dehmann talks to Professor Sieben about how this research could lead new approaches for vaccines antiviral drugs and better preparation for future waves of

00:01:43: infection.

00:01:46: extremely small particles.

00:01:47: You use a microscope to examine how individual viruses attack our cells and what individual proteins do in this process, why did you choose these challenges?

00:01:59: I think they are much easier things.

00:02:00: look at on the microscope!

00:02:03: Yeah that's true but we typically use microscopes to study smaller things.

00:02:08: so i've always looked at cells... So i started with plant cell biology and then started to work on mammalian cells, viruses.

00:02:17: And that was really a fascinating transition sort of to see a virus like little dot infecting alive cell.

00:02:27: looking under the microscope seeing how cells behave what they do is already quite interesting but once we infect them it's whole new kind fascination, and that's why we stuck to it.

00:02:42: And then we started to focus even on things that are smaller than viruses because that's what matters for them.

00:02:48: so we wanted to understand... We want to understand What happens at the scale of an infecting virus?

00:02:54: And viruses are small So they only have a few proteins to interact with the target cell.

00:02:59: and we want To understand exactly what happens in this little patch Of cells That is in contact With The Virus.

00:03:06: What magnifications do you use and what do you see there?

00:03:10: So we used light microscopes, so they have typically one or two thousand fold magnification.

00:03:16: For comparison maybe like a school microscope that you would have at home ago has a couple hundred fold magnifications may be four five hundreds.

00:03:25: That is already enough to see individual cells And that is enough, and then it's a sort of specific branch of light microscopy.

00:03:34: There are fluorescence microscopes where we label individual structures so they can see them with very high contrast like the carry-a little light torch.

00:03:43: That is what... So for example how we look at viruses?

00:03:47: They have a little light torches to which you can see in dark.

00:03:52: Then there will be some expertise on super resolution microscopy technologies and those allow us then to go even further down with conventional light microscopes, um...to see individual molecules basically.

00:04:08: Which is super cool!

00:04:08: So you can see the individual molecule kind of moving around inside life cells And we see the virus let's say in another color.

00:04:16: We can detect and quantify how individual receptor proteins for example interact with an infecting virus.

00:04:25: What happens next?

00:04:27: Yeah, and what happens next?

00:04:28: What happens when viruses enter the cell.

00:04:31: So that is also something we want to understand.

00:04:34: so if you look at a cell surface... The plasma membrane virus is binded to receptors And then there's somehow the virus needs signal into the cells right?

00:04:43: The virus need to tell this cell I'm here!

00:04:46: I want to enter!

00:04:47: The plasma membranes quite as a barrier virus cannot get over easily.

00:04:53: We wanna understand how these signals is transmitted and how the cell understands the virus.

00:04:58: It has never seen a virus before, right?

00:05:01: But from a molecular point of view these are signaling cascades so receptors become activated So they change They become modified.

00:05:10: The cell detects this modification And performs a certain action.

00:05:14: The viruses enter They deliver their genome Then make the cells basically produce viral proteins.

00:05:21: Which viruses are you examining then?

00:05:24: So, we work on respiratory viruses.

00:05:29: We have a long-standing expertise in influenza and we started to work on Respiratory Sensitiovirus recently here at HCI RSV And the more recent project since last year... ...we also worked on Marbook virus that is Hydepathogenic virus or Hydepatogenic Philovirus where safety model systems to study the cell biology of these viruses.

00:05:57: When we look at a larger scale, many researchers say that influenza viruses pose the highest risk for the next pandemic which makes influenza virus so dangerous.

00:06:08: So influenza viruses, they are very variable.

00:06:10: They have a very high genetic diversity and very high mutation rate.

00:06:15: so no virus is basically exactly identical to the other virus in nature.

00:06:20: And then the lab was a little bit different.

00:06:22: That's one aspect.

00:06:24: Our immune system needs to adapt every time it sees an influenza virus To this new strain or variant.

00:06:32: This is one aspect and there's a quite large animal reservoir where these viruses constantly circulate, again constantly evolve.

00:06:43: One needs to have close surveillance of this animal reservoirs to know which strains currently circulates in which animals they circulate because their might be spillover events on other populations also into livestock for example that are critical.

00:07:02: sort of risk or like characteristic of influenza is that it's a respiratory pathogen and those viruses just transmit easier than other viruses.

00:07:13: That need to kind of close contact means.

00:07:16: so, you know checks couple boxes could make the pandemic virus

00:07:26: Okay.

00:07:27: We have an annual flu vaccine, but you just said that they are very variable and I think this is one reason why the vaccine doesn't protect against all influenza viruses or strains isn't it?

00:07:45: Yes!

00:07:46: That's right.

00:07:46: so the virus are very dynamic... They mutate we say they drift ...they.

00:07:54: So when it comes to the seasonality of influenza, one has to make a certain kind of look into the future prediction on which virus strain might circulate in a certain area next winter and then make that respective vaccine.

00:08:11: There is some uncertainty there but there's research to overcome this.

00:08:17: so many people are working with vaccines prevent infection or disease of a large diversity of different influenza virus strains.

00:08:31: And they do this by focusing on sort-of conserved epitopes, so parts of the virus that are not so variable because it's only some part of the viruses to change all the time.

00:08:40: Some parts the viruses cannot changed and there wouldn't be infectious anymore.

00:08:44: So they keep at constant we say conserved.

00:08:48: And if we could target those conserved parts, We would have a very effective vaccine that will protect against the large number of different influenza virus strains.

00:08:59: Is it even possible to develop vaccines or medications for example against influenza virus infections?

00:09:07: quickly adapted in an emergency?

00:09:09: So vaccines, yes.

00:09:11: We have seen this also during corona for therapeutics is much harder because the development of therapeutics has already a quite long process and also the identification of targets... The identification of really antiviral mechanisms.

00:09:26: it's a much longer process so that I think group of people who work on antiviral development.

00:09:41: So we are also involved in projects to do this, there's one example where you have a collaboration with the partner institutes of HDI, The Hips and Saarbrücken.

00:09:51: We want to develop adhesion inhibitors or new sort-of glycan based inhibitors that for example could prevent virus cell binding.

00:10:01: so it is something kind of in advance against newly or upcoming viruses.

00:10:09: But yeah, otherwise it's hard to really specifically develop anti-viral drugs that could fit a new emerging virus.

00:10:22: so I think the vaccines are faster mechanism there.

00:10:28: And how do you know which structures the active ingredients need to target?

00:10:32: Yeah, so they're on the viral side.

00:10:35: Of course this can be sort of tested.

00:10:37: many antiviral drugs target viral enzymes for example or the replication machinery.

00:10:45: in our case as I said we focus on virus cell binding.

00:10:49: So try develop competitive binding inhibitors.

00:10:53: Try prevent synthetic particles that viruses like to bind and that bind more efficiently than the cell surface so we can prevent a very early interaction.

00:11:03: And when it comes to this cellular site, yeah... So there are also ongoing projects which have launched an EU-wide project last year called Combine which has the virus cell binding and cell entry phase in its sort of scientific focus.

00:11:22: And we want to develop new pipelines, too quickly identify virus interacting factors and cellular factors that are important for virus infection.

00:11:33: So this is one aspect.

00:11:35: there to be a new pathogen, let's say comes up.

00:11:39: Pathogen X. we have a pipeline under high bio-containment.

00:11:44: interrogate that specific pathogen and identify cellular factors involved in virus infection.

00:11:50: so then how can look maybe into catalog of drugs?

00:11:55: Do you something?

00:11:56: targets the particular protein against this virus or the disease.

00:12:05: And we have another sort of branch in this project where also identify antiviral drugs, small molecule drug.

00:12:14: that is an other collaboration here at HZI Where we use Marburg Virus as a model on his project.

00:12:20: we used Marburg virus because it's a highly pathogenic virus that is only handled under high biosafety containment.

00:12:26: We don't have here actually at HZi, so we use other model systems, surrogate systems.

00:12:31: but we want our pipelines and workflows to be ready for this biocontainment.

00:12:39: So all assays will develop are sort of ready-to-use in the biocontainment for PathogenX.

00:12:46: Very interesting But let us stay Respiratory viruses before such a virus can infect us.

00:12:56: They first have to pass through our mucus membranes, you are also looking into how they do that and in a brand new research project, you do this.

00:13:06: How did they get through these mucous?

00:13:09: That is an interesting point.

00:13:12: as you say our respiratory tract is lined with the thin layer of this mucus which kind by ciliary movements or our cells have kind of small extensions, little fingers and they move the mucous constantly.

00:13:29: So that's moved out off-the-way.

00:13:31: you can really trap particles anything we inhale to move it away from our respiratory cells.

00:13:38: so protect them.

00:13:39: It is a very effective barrier.

00:13:44: irritation and infections all the time.

00:13:46: So in this new project, which is called one MOOC that we started just here We want to understand this barrier from a zoonotic perspective.

00:13:54: so...we have a Zoonotic transmission.

00:13:57: so viruses that spill over form an animal reservoir like influenza..so there we want to study if the animal mucus Is different than human mucus adapted to interact and penetrate the respective mucous barrier more efficiently.

00:14:16: And ideally, then downstream which molecular characteristics in which molecular factors are responsible for a better or worse interaction with viruses so that we can ideally maybe test property of mucos or even change it in the future.

00:14:37: And this project you're working together with research group Dr.

00:14:41: Julia Pot, transmission immunology and I talked to her about viruses spread like Mpox.

00:14:50: feel free to give a listen.

00:14:52: season two episode two It was really interesting but back What is the goal of these studies?

00:15:00: Do we need more mucous?

00:15:02: More mucus probably isn't so good.

00:15:05: There are some diseases like cystic fibrosis, for example where the mucus is very thick and that's difficult to treat those patients.

00:15:15: but it's about the properties of the muco.

00:15:20: Those who want to understand from a molecular virology or biochemical point-of view what is in the mucos proteins, glycans, antibodies and what are the biophysical properties?

00:15:32: Viscosity or density.

00:15:35: These kind of things if these property sort-of affect virus penetration and virus infection.

00:15:43: so once we have this information We can probe for specific properties in a new virus animal population or even a specific person.

00:16:00: So this goes towards kind of diagnostics and toward the development of biomarker, so can we relate certain characteristics of mucus to more for the personal that the animal being more likely to be infected?

00:16:19: So basically saying, maybe your mucous is different from my mucose or you're mucoses more antiviral than mine mucos.

00:16:26: We might understand why that is and if we can change these properties on the big.

00:16:33: I think the bottom line Is that?

00:16:34: We want to understand at barrier how it works And How we Can Understand.

00:16:41: then Maybe focus On specific Properties To Make It More Efficient.

00:16:45: As we heard, you have many collaborative projects with national and international partners.

00:16:51: What does collaboration mean to you?

00:16:53: And what can we maybe learn from research for our society?

00:16:57: Collaboration is very central in the scientific community.

00:17:01: so this really starts here as a group.

00:17:03: So we collaborate with each other.

00:17:05: people have different projects, different interests, different expertise... ...and it's important that there be diversity because then we get new ideas We can really fill our knowledge gaps, we fill gaps in our projects where I don't know how to do this.

00:17:20: Can you help me?

00:17:22: So it starts here close by and then is transferred into the scientific community.

00:17:32: So let's say our group is good in microscopy, so we do that.

00:17:36: We need other groups that maybe can work with animals or people who work at the clinic to have contact with human patients and give us maybe human mucos for example.

00:17:47: These projects really live because of collaborations which are very central.

00:17:56: spirit also into our group, is also diverse and people work in diverse projects.

00:18:02: They have all kind of collaborations where they work with other disciplines so very interdisciplinary that you learn how to speak each others language really advance scientific project.

00:18:15: I think this very much the key.

00:18:17: Otherwise, we would not really move forward that quickly so we couldn't really entertain these projects I mentioned without having diverse interdisciplinary

00:18:29: collaborations.".

00:18:30: So this is something you could take with us for our society and living together?

00:18:38: It's being open to other ideas of what people think or have to say... and also what they are good at, so that we try to be open.

00:18:50: We don't judge.

00:18:52: That brings us forward – it allows these collaborations!

00:18:55: And this is really the fun in our daily life because there's a diverse group of people here on HZi.

00:19:03: There're many different people next door who just talk with each other during lunch.

00:19:09: And then, you know from one to the other things happen and suddenly we have maybe a new You know in your angle to study a certain aspect of infection biology that was not really able.

00:19:21: That what's not really possible before.

00:19:23: What is your long-term goal for research?

00:19:25: But do you like to have achieved someday

00:19:28: also?

00:19:29: our team is still fairly young.

00:19:30: an hour group is fairly young.

00:19:31: so We have developed some new concepts and we try to push those forward.

00:19:38: We talked about the nano infection biology, so we want to understand how viruses work at a scale of sort-of virus or single protein that we want establish in scientific community.

00:19:52: there will be one I think wish... And then it's the transfer also on translation!

00:20:02: stronger transnational aspect.

00:20:04: I think most of what we do is still very much basic science, understanding virus entry.

00:20:08: so if some of these aspects could manifest themselves in kind other directions maybe become either an antiviral or a new diagnostic tool things like that would be nice to have and may be five or ten years.

00:20:28: maybe will have a mucous chip.

00:20:30: You know, we can sample your mucous and my mucose.

00:20:32: And we can tell very quickly if you should get a flu vaccine or not?

00:20:37: I think there will be.

00:20:39: that would be nice goal to achieve.

00:20:41: Sounds really nice!

00:20:43: So when i'm talking to you... ...and listening to you.. ..I really hear in the voice of how you're talking That you are into research but need some Yeah, free time I think.

00:20:57: What do you do to relax from work?

00:21:00: My family is sort of the big counter pole so we spend a lot of time together.

00:21:06: We do things together with my wife and kids.

00:21:12: So I wouldn't say that i have really active hobbies at the moment, but i'm interested in sports.

00:21:16: so i do sports to work out... I am interested in comics or video games this kind of stuff.. I would not call it a hobby ,but its like interest where i try get away from put thoughts on other things.

00:21:30: But I think the big counter, though... The Big Pole is the counterpart.

00:21:33: It's a family that naturally brings you to other things or puts your mind on other things

00:21:40: at the end.

00:21:40: do You have yeah like take home message for us all?

00:21:45: Yeah i think it's important For Us To appreciate the world we live in In terms of infectious diseases that we live in this world together with other people, animals and our environment.

00:22:01: And it's important to keep an eye on all those so they are interconnected.

00:22:07: We have seen these spillover events for example.

00:22:11: if you think about zoonotic viruses This is one part just to appreciate how they affect eachother.

00:22:18: We haven't really talked about.

00:22:19: climate change is also part of this whole global environment that really determines how virus or infectious diseases spread.

00:22:32: So, it's maybe one thing just to think about and then appreciate.

00:22:38: there as a large scientific research community who tries understand these things work.

00:22:45: so we know what we are doing, we're good at this.

00:22:49: We have large centers like HCI which has really a large collaborative communities where we can very focus and very interdisciplinary drive projects forward to understand infectious diseases very quickly.

00:23:04: so it will help each one of us.

00:23:07: So I would hope that people just know they appreciate this.

00:23:15: Yeah, we'll try to make the next pandemic less severe or you know faster understand and develop countermeasures.

00:23:26: Thank you for your time!

00:23:27: And the exciting talk about viruses in mucus?

00:23:30: You're welcome.

00:23:31: thank you very much.

00:23:31: it was a lot of

00:23:32: fun.

00:23:32: Professor Christian Sieben researches how virus is interact with the cells on our mucous membrane to infect them so that they can get ahead maybe into future.