How mucus protects against infections

00:00:01: We usually only notice mucus when it's causing a problem

00:00:04: with a runny nose or cold or allergies.

00:00:09: That's when our nose runs, our airways feel congested

00:00:12: and our body visibly produces more of it.

00:00:16: Yet mucus isn't just a symptom of illness.

00:00:19: It's a permanent part of our mucous membranes

00:00:22: and an important protective barrier against infections.

00:00:26: Even when we're healthy, the body produces up to 1.5 l of mucus a day.

00:00:31: It carries away dirt, bacteria, old cells and viruses

00:00:36: 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

00:00:44: Christian Sieben and his Nanoinfection- Biology research group at the HZI

00:00:48: are studying using specialized microscopy.

00:00:52: His team investigates how individual viral particles interact with mucosal cells,

00:00:58: 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,

00:01:08: and how this process can be specifically disrupted.

00:01:11: In this episode of InFact, our host Julia Demann talks to Professor Sieben

00:01:17: about how this research could lead to new approaches for vaccines,

00:01:21: antiviral drugs, and better preparation for future waves of infection.

00:01:29: I'm sitting

00:01:30: here in Cologne, and I'm talking now to Professor

00:01:34: Christian Sieben in Braunschweig, at the HZI.

00:01:39: Hi. Hi.

00:01:40: You're Christian.

00:01:43: Nanoinfection Biology involves working with extremely small particles.

00:01:47: You use a microscope to examine how individual viruses attack our cells

00:01:52: and what individual proteins do in this process.

00:01:57: Why do you choose this challenge?

00:01:59: I think there are much easier things to look at.

00:02:01: Under a microscope.

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

00:02:08: So I've always looked at cells.

00:02:11: So I started with plant cells, plant cell biology

00:02:14: and then started to work on mammalian cells and viruses.

00:02:17: And that was really a fascinating transition, sort of

00:02:21: to see a virus like a little dot infecting a live cell.

00:02:26: So looking under the microscope and seeing how cells,

00:02:31: you know, behave and what they do is already quite interesting.

00:02:35: But once we infect them, it's a whole new kind of fascination.

00:02:40: And that's why we stuck to it.

00:02:42: And then we started to to focus even on things

00:02:45: that are smaller than viruses, because that's what matters for them.

00:02:48: So we wanted to understand.

00:02:50: So we want to understand what happens at the scale of an infecting virus.

00:02:54: And viruses are small,

00:02:56: so they only have a few proteins to interact with the target cell.

00:02:59: And we want to understand exactly what happens

00:03:01: in this little patch of cell that is in contact with the virus.

00:03:05: And what magnifications do you use and what do you see there.

00:03:10: So our we use light microscopes.

00:03:12: So they have typically 1,000- or 2,000-fold magnification.

00:03:16: So for comparison

00:03:17: maybe like a school microscope or one that you would have at home,

00:03:21: they all have a couple hundred- fold magnification, maybe 400 or 500.

00:03:25: So that is already enough to see individual cells.

00:03:28: So we have a bit more and that is enough.

00:03:31: And then it's sort of a specific branch of light microscopy

00:03:35: that is fluorescence microscopy

00:03:36: where we label individual structures so that we can see them

00:03:39: with very high contrast, like they carry a little light torch.

00:03:43: And that is what sort of, for example, how we look at viruses.

00:03:47: So they have a little light torch so we can see them in the dark.

00:03:51: And then we have a specific sort of

00:03:55: expertise on super-resolution microscopy technologies.

00:03:59: And those allow us then to go even further down with conventional light

00:04:04: microscopes to see individual molecules basically, which is super cool.

00:04:08: So you can see individual molecules kind of moving around inside live cells.

00:04:13: And then we see the virus, let's say, in another color.

00:04:16: And we can detect and quantify how individual receptor

00:04:20: proteins, for example, interact with an infecting virus.

00:04:25: And what happens next. Yeah.

00:04:27: And what happens next.

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

00:04:31: Yeah.

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

00:04:34: So we look at the cell surface the plasma membrane viruses bind to receptors.

00:04:39: And then there's somehow the virus needs to signal into the cell right.

00:04:43: The virus needs to tell the cell

00:04:45: look, I'm here I want to enter the plasma membrane is quite is a barrier.

00:04:50: Virus cannot get over so easily.

00:04:52: So we want to understand

00:04:53: how this signal is transmitted and how the cell understands the virus.

00:04:58: It has never seen a virus before.

00:04:59: Right. So.

00:05:01: But from a molecular point of view

00:05:03: these are signaling cascades or receptors become activated.

00:05:07: So they change they become modified.

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

00:05:14: And the viruses enter.

00:05:15: They deliver their genome

00:05:17: and then make the cell basically to produce viral proteins.

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

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

00:05:28: So we have a long- standing expertise on influenza.

00:05:32: And we started to work on respiratory syncytial virus recently, RSV.

00:05:38: And in a more recent project since last year we also work on

00:05:42: Marburg virus that is a highly

00:05:46: pathogenic virus, highly pathogenic filovirus that where we have

00:05:52: low biosafety model systems to study the cell biology of these viruses.

00:05:57: When we look at larger scale, many researchers say that

00:06:01: influenza viruses pose the highest risk for the next pandemic.

00:06:05: What makes influenza viruses so dangerous?

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

00:06:10: They have a very high genetic diversity, 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 is a little bit different.

00:06:22: So that is one aspect.

00:06:24: So that our immune system needs to adapt every time

00:06:28: it sees an influenza virus to this new strain or new variant.

00:06:32: This is one aspect.

00:06:33: And there's of a quite a large animal reservoir

00:06:36: where these viruses constantly circulate and again constantly evolve.

00:06:42: And so one needs to have a close kind of surveillance

00:06:46: of these animal reservoirs to know which strains currently circulate

00:06:50: and in which animals they circulate,

00:06:52: because there might be the spillover events in other populations

00:06:56: and also into livestock, for example, which is quite critical.

00:06:59: And then maybe the third sort of risk

00:07:04: or like a characteristic of influenza, is that it is a respiratory pathogen,

00:07:08: and those viruses just transmit easier

00:07:12: than other viruses that need to kind of close contact or other means.

00:07:17: So it has it, you know, it checks a couple of boxes

00:07:21: that would make it an could make it a pandemic virus.

00:07:26: Okay.

00:07:27: And we have an annual vaccine flu vaccine.

00:07:31: But yeah you just said that they are very variable.

00:07:36: And I think this is one reason why the vaccine doesn't

00:07:40: protect against all influenza viruses or strains, isn't it?

00:07:45: Yes that's right.

00:07:46: So the viruses are very dynamic.

00:07:49: They mutate.

00:07:50: We say they drift.

00:07:52: They have a genetic drift.

00:07:54: So when it comes to the seasonality of influenza, one has to make a certain

00:07:59: kind of yeah, look into the future prediction of which virus strain

00:08:03: might circulate in a certain area in the next winter season

00:08:07: and then make that respective vaccine.

00:08:11: So that is there's some uncertainty there.

00:08:13: But there's research to overcome this, of course.

00:08:17: So there's many people working on vaccines that try to.

00:08:21: Prevent infection

00:08:26: 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

00:08:35: or parts of the virus that are not so variable,

00:08:37: because only some parts of the viruses that change all the time, some parts

00:08:41: the viruses cannot change and there wouldn't be infectious anymore.

00:08:44: So they keep it constant.

00:08:46: We say conserved, and if we could target those conserved

00:08:50: parts, we would have a very effective vaccine

00:08:53: that would protect against a large number of different influenza virus strains.

00:08:59: Is it even possible

00:09:00: to develop vaccines or medications, for example, against influenza

00:09:05: virus infections that can be quickly adapted in an emergency?

00:09:09: So vaccines yes, we have seen this also during corona

00:09:13: for therapeutics is much harder because the development of therapy

00:09:17: is already a quite long process

00:09:20: and also the identification of targets,

00:09:23: the identification of really antiviral mechanisms is a much longer process.

00:09:28: So that is I think it is harder.

00:09:31: But yes, there is of course a large, you know,

00:09:34: group of people who work on

00:09:38: antiviral development.

00:09:41: So we we also involved in projects to do this is one example.

00:09:46: We have one collaboration

00:09:47: with one of the partner institutes of HZI, the HIPS in Saarbrücken,

00:09:51: where we want to develop adhesion inhibitors or new sort of glycan-based

00:09:56: inhibitors that, for example, could prevent virus cell binding.

00:10:01: So that is something that could be prepared kind of in advance

00:10:05: against newly or upcoming viruses.

00:10:09: But yeah, otherwise it's it's hard

00:10:11: to really specifically or in advance develop

00:10:15: kind of antiviral drugs that could fit to a newly emerging virus.

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

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

00:10:32: Yeah.

00:10:32: So on the virus side, this can of course this can be sort of tested.

00:10:37: Many antiviral drugs target viral

00:10:41: enzymes for example, or the replication machinery.

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

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

00:10:53: So try to prevent kind of synthetic particles

00:10:56: that viruses like to bind and that bind more efficiently than the cell surface.

00:11:00: So we can prevent very early interaction.

00:11:03: And when it comes to the cellular side.

00:11:06: Yeah.

00:11:07: So there we have also ongoing projects.

00:11:11: We have launched an EU-wide project last year.

00:11:14: It's called COMBINE which has the virus cell binding and cell entry phase.

00:11:20: And it's sort of a scientific focus.

00:11:22: And we want to develop new pipelines to quickly identify virus

00:11:27: interacting factors and cellular factors

00:11:30: that are important for virus infection.

00:11:33: So this is one aspect there to be

00:11:37: when a new pathogen, let's say, comes up, pathogen X.

00:11:40: We have a pipeline to under high biocontainment, interrogate that specific

00:11:46: pathogen and identify cellular factors that are involved in virus infection

00:11:50: so that we know how we can look maybe into a catalog of drugs.

00:11:55: Do we have something that targets that particular protein.

00:11:59: We can use that against this this virus or against the disease.

00:12:05: And we have another sort of branch in this project where we want to

00:12:09: we want to also identify antiviral drugs, small molecule drugs.

00:12:14: That is another collaboration here at HZI where we use Marburg virus as a model.

00:12:19: So on this project we use Marburg virus because it's a highly pathogenic virus

00:12:24: that is only handled under high-biosafety containment that we don't have here

00:12:27: actually at HZI.

00:12:28: So we use other model systems, surrogate systems.

00:12:31: But we want our pipelines and our workflows to be ready

00:12:35: for this bio, for this high biocontainment.

00:12:38: So all assays, we develop a sort of ready

00:12:42: to use in this biocontainment for pathogen X.

00:12:46: Very interesting.

00:12:47: But let's say at the respiratory

00:12:52: viruses, before such a virus can infect us

00:12:56: they first have to pass through our mucous membranes.

00:12:59: You are also looking into how they do that.

00:13:02: And in a brand new research project you do this.

00:13:06: How do they get through this mucus?

00:13:09: That is a very interesting point.

00:13:11: So yeah, as you say, our respiratory tract is lined

00:13:15: with a thin layer of this mucus, which is kind of a viscous gel

00:13:19: that is kept under flow by ciliary movements.

00:13:23: Or our cells have kind of small extensions,

00:13:26: little fingers, and they move the mucus constantly.

00:13:29: So that's kind of moved out of the way.

00:13:31: And it can really trap particles.

00:13:33: Anything that we inhale and move it away from our respiratory cells to protect.

00:13:39: So and it is a really effective barrier that prevents really.

00:13:43: Yeah.

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

00:13:46: So in this new project, which is called ONEMUC that we started

00:13:49: just this year, we want to understand this barrier from a zoonotic perspective.

00:13:54: So we have a zoonotic

00:13:57: transmission.

00:13:57: So viruses that spill over from an animal reservoir like influenza.

00:14:01: So there we want to study if the animal mucus is different from the human mucus.

00:14:08: And if viruses are sort of adapted to interact and penetrate

00:14:13: the respective mucus barrier more efficiently and ideally

00:14:17: then downstream, which molecular characteristics

00:14:21: and which molecular factors are responsible for,

00:14:25: you know, a better or worse interaction with viruses

00:14:29: so that we can ideally maybe test for this

00:14:33: specific property of mucus or even change it in the future.

00:14:37: And in this project you are working together with, with the research

00:14:40: group of Dr. Port, Transmission Immunology.

00:14:45: And I talked to her about virus spread, like mpox.

00:14:50: Feel free to give it a listen.

00:14:52: Season two, episode two.

00:14:53: It was really, really interesting.

00:14:56: But back to the mucus.

00:14:58: What is the goal of these studies?

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

00:15:02: So more mucus is is probably not so good.

00:15:05: So there are some kind of diseases like cystic fibrosis for example,

00:15:09: where the mucus is very thick and that is very difficult for those patients.

00:15:15: But it's more about the, the, the properties of the mucus.

00:15:19: So those we want to understand

00:15:21: from a, from a molecular virology and then biochemical point of view.

00:15:25: So what is in the mucus proteins glycans antibodies

00:15:29: and what are the biophysical properties

00:15:32: viscosity density these kind of things.

00:15:36: And if then if these properties sort of affect

00:15:39: virus penetration and virus infection.

00:15:43: So once we have these this information

00:15:45: we can probe for these specific properties

00:15:49: in, in sort of

00:15:52: for a new virus or for a specific

00:15:56: animal population or even a specific person.

00:16:00: So this goes towards kind of diagnostics and towards

00:16:03: the development of a biomarker.

00:16:05: So can we relate certain characteristics of mucus

00:16:08: to, you know, more.

00:16:13: For the person or the animal being more likely to be infected.

00:16:19: So basically saying maybe your mucus

00:16:21: is different from my mucus or your mucus is more antiviral than my mucus.

00:16:25: We might understand why that is.

00:16:28: And if we can change these properties on.

00:16:31: Yeah, the the big I think the big bottom line is that we want to understand

00:16:35: that barrier, how it works and how we can understand

00:16:41: and maybe focus on specific properties to make it more efficient.

00:16:45: As we heard,

00:16:46: 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 in the group.

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

00:17:05: People have different projects, different interests, different expertise.

00:17:09: And that is very important

00:17:10: to have this diversity because then we really get new ideas.

00:17:14: We can really fill our knowledge gaps.

00:17:17: We fill gaps in our projects.

00:17:19: I don't know how to do this. Can you help me?

00:17:22: So this really starts, you know, here close by and then it is really transferred

00:17:27: into the scientific community where we need really dedicated expertise.

00:17:31: So let's say our group is good in microscopy.

00:17:35: So we do that.

00:17:35: We we need other groups that maybe can work with animals or people

00:17:40: that work in the clinics, or they have contact with human patients

00:17:43: and can give us maybe human mucus, for example.

00:17:46: So these projects really live and only live because of collaborations.

00:17:51: And that is very central.

00:17:53: And I try to give this this kind of spirit also into our group.

00:17:58: Our group is also diverse and people work in diverse projects.

00:18:02: They have all kinds of collaborations where they work with other people

00:18:05: from other disciplines also so very interdisciplinary, so that you learn

00:18:10: how to speak each other's language and really advance scientific projects.

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

00:18:17: Otherwise we would not really move forward that quickly.

00:18:22: So we couldn't really entertain these projects that I mentioned

00:18:26: without having, you know, diverse interdisciplinary collaborations.

00:18:30: So this is something that we could take with us for our society, for our.

00:18:35: Yeah, living together.

00:18:37: I think, you know, it's being open to other ideas,

00:18:41: to what other people think, what they have to say,

00:18:44: and also what they are good at and what they know.

00:18:47: So that we yeah, we try to be open, communicate, open.

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

00:18:51: And that brings us forward, that allows these collaborations.

00:18:55: And that's really what brings the. Yeah.

00:18:57: Also the fun in our daily life because we can we have a diverse

00:19:01: group of people, you know, here at HZI we have a number of different people

00:19:05: next door. We just talked to each other.

00:19:07: We see each other at lunch

00:19:09: and then, you know, from one to the other things happen.

00:19:12: And suddenly we have maybe a new, you know, a new angle

00:19:16: to study a certain aspect of infection biology

00:19:19: that was not really able, that was not really possible before.

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

00:19:25: What do you like to have achieved someday?

00:19:28: Yeah.

00:19:28: So our our team is still fairly young and our group is fairly young.

00:19:32: So we have developed some new concepts and we push we try to push those forward.

00:19:38: You know we talked about Nano Infection Biology.

00:19:41: So we want to understand how viruses work

00:19:44: at the scale of sort of of a virus and of single proteins.

00:19:47: So that we want to establish that in the scientific community.

00:19:52: There will be one, I think, wish and then it's the transfer.

00:19:56: Also on the translation, we have talked a lot

00:19:58: about the mucus project, which is a very translational project,

00:20:01: or it has sort of stronger translational aspect.

00:20:04: I think most of what we do

00:20:05: is still very much basic science understanding virus entry.

00:20:08: So some of these aspects could manifest themselves in kind of,

00:20:14: you know, other directions, maybe become either an antiviral

00:20:18: or a new diagnostic tool or things like that.

00:20:23: That will be that would be nice to have in maybe 5 or 10 years,

00:20:28: maybe we'll have a mucus chip, you know, we can sample your mucus and analyze it

00:20:32: and we can tell, you know, very quickly if we should get a flu vaccine or not.

00:20:37: I think that will be there will be a nice goal to achieve science.

00:20:42: Really nice.

00:20:42: So when I'm talking to you and when I'm listening to you,

00:20:46: I really hear in your voice and how you're talking

00:20:50: that you're really into your research, but you need to have some.

00:20:54: Yeah. Free time, I think.

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

00:21:00: My family is sort of the big counterpole.

00:21:02: So we spend a lot of time together.

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

00:21:11: And so I wouldn't say I have really active hobbies at the moment.

00:21:15: I'm interested in sports, so I do sports to to work out.

00:21:19: I'm interested in comics and video games, this kind of stuff.

00:21:22: I wouldn't call it a hobby, but it's like interest where I try to get,

00:21:25: you know, away from or put the thoughts on other things.

00:21:29: But I think the big counter, the big pole is the counterpart is the

00:21:33: is the family that naturally brings us, brings you to other,

00:21:37: you know, things or puts your mind on other things at the end.

00:21:40: Do you have a yeah like take-home message for us all?

00:21:45: Yeah.

00:21:45: I think it's it's important for us to, to appreciate the world we live in,

00:21:51: you know, in terms of infectious diseases for now and that, you know, we live

00:21:56: in this world together with other people, with animals and our environment.

00:22:01: And it's important to keep an eye on all those

00:22:04: and that they are interconnected and that we have seen this, you know,

00:22:08: we have these spillover events, for example, if we think about viruses.

00:22:13: So this is one part just to appreciate this

00:22:16: and how they affect each other.

00:22:18: We haven't really talked about climate change for example.

00:22:21: So environment you know, is also part of this whole global

00:22:26: environment that really determines how virus or infectious diseases spread.

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

00:22:35: and then also to appreciate that there is a large scientific

00:22:40: research community that tries to understand how these things work.

00:22:44: So we know what we are doing.

00:22:48: We are good at this.

00:22:49: We have large centers like HZI, which have really a large collaborative

00:22:54: communities where we can be very focused and very interdisciplinary drive

00:22:59: projects forward to understand infectious diseases very quickly.

00:23:04: So to really help each and every one.

00:23:07: So I would hope that people yeah, just know this, appreciate this

00:23:12: and have trust in what we do and that we

00:23:17: yeah, we'll try to make the next pandemic

00:23:21: less severe or, you know, faster, understand and develop countermeasures.

00:23:25: Thank you for your time and the exciting talk about viruses and mucus.

00:23:30: No, you're welcome.

00:23:31: Thank you very much.

00:23:31: It was a lot of fun.

00:23:32: Professor Christian Sieben researches how viruses interact with the cells

00:23:37: of our mucous membrane to infect them so we can get ahead of them,

00:23:41: maybe in the future.