Peter Openshaw

So in terms of what we know about the pathogenesis of this disease, it's very early days.

But I think from what we know about other severe infections, we can begin to speculate.

And we think that what happens initially is that the virus must enter through the epithelium.

We're assuming through the respiratory epithelium, but it's possible also that it might get in through the gastrointestinal tract.

Many coronaviruses have dual tropism both for the respiratory and the gastrointestinal epithelium.

In some of these cases there is a bit of diarrhoea and maybe even in those without diarrhoea there may be secretion of virus by the stool.

So we're assuming that there is a bit of interplay between the gastrointestinal and the respiratory tract.

So the virus gets in, it starts to multiply in the absence of any sort of initial host defence because there doesn't seem to be any cross-reactivity between the known human coronaviruses to which we are all exposed as common cold agents and this novel coronavirus.

So once it gets in, it multiplies, and probably that initial phase is mostly controlled by the innate immune response because there is no specific immunity in terms of B cells, T cells.

So I'm speculating here, but what we saw in our very detailed analysis of pandemic H1N1 in 2009-2010 via the Mosaic study, which was a national study which I led on here from

from Imperial, we saw an initial phase when the response was more or less an antiviral response with interferon and so on.

That then diminished after a few days and was replaced by a very powerful inflammatory response in those with more severe disease.

And that inflammation, as I say, was quite nonspecific.

It included a lot of different cytokines.

It included cells migrating into the site of infection and releasing their mediators, the cytokines, the chemokines.

And an outpouring of many, many mediators, including things like tumor necrosis factor IL-6,

aisle one, you name it, it comes out into the secretions and into the blood.

So that's the cytokine storm, the immunological storm phase.

And that was much more severe in those who went on to have bad disease and need ventilating.

What I'm speculating is that the deterioration that we're seeing after the initial relatively mild phase, it reflects the cutting in of that innate powerful immune response which is pro-inflammatory and which may be