Fungal glucans reprogram an inflammatory state in sepsis

Scientists in Canada have hit upon a new way in which severe systemic inflammation - states like sepsis - can lead to secondary, acute injury in the lungs; this is often a problem in patients being managed in intensive care settings, for instance. The findings hinge on a substance called beta glucan, which is released from the cell walls of fungi. Exposure at low levels, akin to the stimulus we all receive from the fungi naturally present within our microbiomes and environments, seems to be a good thing: it promotes a healthy immune tone that defends us better against a range of infectious threats. But higher level exposure seems to have the ability to reprogram a class of cells called alveolar macrophages, which normally sit quietly in the airways, mopping up inhaled debris and wannabe infective agents. Pre-stimulated by high levels of beta-glucan, though, these cells switch to a far more reactive state, which in the context of a severe inflammatory condition like sepsis, can lead to secondary devastating lung damage. As he explains to Chris Smith, Maziar Divangahi, from McGill University, has been wondering whether different levels of beta-glucan exposure could account for why some patients end up with this condition…

Maziar - We know that this fragment of fungi, which comes from the cell wall of the fungi, is able to benefit the host and enhance host defense against infection. But in this particular study that we did, and we were looking at the systemic inflammatory responses like sepsis model, we found that actually beta-glucan was not beneficial. And it was detrimental to the host immunity.

Chris - This sounds like it's contradicting itself. So can you just clear that up for me? Why, on the one hand, we've got something that appears to be quite useful, but can also be quite a pain?

Maziar - Yeah. The reasoning, it really depends on how we re-stimulate the immune system that has been already stimulated with the beta-glucan. So if it's too much inflammatory responses, then I think what would happen is that the beta-glucan will enhance these responses and under condition like sepsis that you want to dampen the inflammatory responses, then it becomes detrimental.

Chris - So the context matters then, is what you're saying? If we've got low grade exposure to this stuff, the kind of thing on a level that we would run into going about our lives healthily, it's a good thing having beta-glucan, this component of fungi, when they grow, they make it in their cell walls, don't they? The immune system is seeing that and that's translating into a good, well-modulated immune response. But when things get out of hand and there's inflammation and sepsis somewhere remote in the body, under those circumstances, the reaction to beta-glucan is quite different...

Maziar - Yeah. This is context dependent because it really also depends on type of the inflammatory responses you have. If you have a chronic bacterial infection, such as mycobacterium tuberculosis, or if you have immune response toward influenza, viral infection, these are very different kind of infectious diseases and beta-glucan in that respect is playing a beneficial role. But in terms of systemic inflammatory responses, like sepsis, that you have inflammation in multiple organs, beta-glucan is not certainly beneficial.

Chris - Talk us through then the experiments that you've done to test this out and show that that appears to be the case. How did you do it?

Maziar - So what we did, we used a mouse model of sepsis, a fragment called LPS, a gram-negative bacteria that has been clearly shown to really cause systemic inflammatory responses. We basically pre-treat that mouse with the beta-glucan and then after seven days, we induce sepsis by giving LPS.

Chris - When you say you pre-treat them with beta-glucan, what is that, by allowing them to be colonised with fungi or do you feed it to them? How are they exposed? What's the context there?

Maziar - In this case, we give beta-glucan intra-peritoneally because it goes systemically then. And then that will prime your immune system already with the beta-glucan, so your immune cells will be ready to react to the second stimuli, which in this case is the LPS. Because the magnitude of inflammatory responses is very big in LPS model, then of course your immune cells that have already been primed by beta-glucan will overreact to the LPS and it makes this whole entire systemic inflammatory response worse.

Chris - Which cells are particularly responsive to that beta-glucan? So when you put that exposure into the mouse and it goes systemically, which cells are seeing it and which cells are then changing their level of reactivity so that when the sepsis comes along subsequently, they're the ones that kick-start the process?

Maziar - In this model system, what we found is there are particular immune cells in your lung called alveolar macrophages. And because we are constantly exposed to the environment by breathing air, these cells are sitting in the lower part of the airway and they're responsible for reacting to pathogens or microbes or antigen that are coming into the lung and deal with them without causing inflammatory responses. So these alveolar macrophages appears to be really a major, they were the major cells that are overreacting now after beta-glucan treatment to LPS. And somehow these alveolar macrophages, we call it, they've been reprogrammed toward inflammatory macrophages and they are overreacting and then they ask for more immune cells to coming into the lung. And of course, then you have these massive inflammatory responses in the lung that causing enhanced the severity of the disease.

Chris - Why is the big question though, isn't it? Why should those cells respond in that way? Is this just basically a bastardization of a process that's supposed to be there, that's actually really useful, but then it gets carried away? Or is there something else going on that shouldn't, and this trips you over into a hyper-inflammed state under these abnormal conditions?

Maziar - Yeah. So these cells that are not inflammatory, somehow beta-glucan is able to change their phenotype and make them inflammatory. And now when you stimulate these cells, these cells that already inflammatory become hyper-inflammatory and detrimental.

Chris - Do you think this really happens in life like this though, because you've given very big doses of beta-glucan to your mice and then you're giving them a really profound immunological kick up the backside with the LPS. So is this just an artifact of a model or do you think in a person, this is really what's going on?

Maziar - Fungi are part of a microbiome and they are really important for regulating our immune system. So one hypothesis that we have is that because of that, we have certain level of the beta-glucan in circulation. So most likely the level of the beta-glucan that you have in your circulation, or I do have in my circulation in Canada, is very different than the level that people leave in India or other countries. So does this make a difference? As I mentioned, beta-glucan could be beneficial against certain infectious diseases, but in this case is detrimental. So the reasoning that people will develop sepsis, is that related to the level of the beta-glucan in their circulation? And we would like to know if this has anything to do with this overreacting of immune response under those conditions.