All right. So, we can only hope that this course isn't a major source of stress for any of you. Sometimes [LAUGH] it's a source of stress for us but we hear a lot of messaging about stress and health and the potential interactions between stress and infectious disease. And a lot of people have been asking questions about this. This is particularly come up in in a lot of the understanding about herpes viruses where people have, to tend to see flare-ups of herpes viruses when they're under acute stress because of things in their life and what-have-you. Right? So I want to open up the broader question of how does stress impact both susceptibility? So you're likely to becoming infected, and the expression of disease symptoms. So, how severe the infection with the pathogen can be. So do you want to start with herpes viruses? I want to start with herpes viruses. That's a good one. Yes. So, to start with herpes viruses, herpes simplex virus is certainly a classic one where we know that symptomatically genes are frequently induced after an extremely stressful experience. So, to give examples, that would be something like a long bout of drinking, [INAUDIBLE] work. Preparing for an exam. Even sitting in a hot tub, which feels relaxing, is actually a physical bodily stress. So it doesn't have to be something unpleasant, but something that really changes your body chemistry, or your body environment and your physiology. For a herpes virus, that is the type of thing that can wake it up out of this quiescent latent state. And it's not that your body in particular releases a molecule that would directly bind to the viral genome or a protein there. But more that there's a signaling cascade of steps in between your body's response to a stressor and the immune system, which is normally providing surveillance on the one hand. And also the neurons that this virus in particular goes latent in. So for the viruses that I study, you think about both of those. But I think for many of the other pathogens that we even comment on, we're really mostly talking about suppression of the immune response or transient depression of the immune response that allows a flare up to take place. Or an infection to get through a barrier that should of otherwise stopped it. Can I ask you another herpes related question? So one thing which I've found really puzzling is, so with the simplex virus, it seems very clear that the quiescence and reactivation is a, it's a great strategy because, and they come out of, of dormancy. I don't know every few months or every half a year I don't know, I don't know quite how often it happens, but it's clear that it's, it's very good for transmission, maintaining the general of transmission. But now I've been always wondering about chicken pox. Mm-hm. Since so it's chicken pox is acute and transmits very well, but then. The crescent face can last for decades. It does. And so, do you think is my question is so to what extent do you think shingles an important epidemic, so it's clearly medically very important because it's painful and horrible. But epidemiologically you, how important do you, do you think Shingles is for, for a virus? So the, the folks who spend their whole labs and their lives studying VZV think that the, the theory for why this happens is that it's actually grandparent to grandchild transmission. That's the cycle. Isn't that neat? When when this was first suggested I thought oh, that's, what a neat and different strategy, right? It's unfortunate that this is the case, medically speaking. But from the virus's perspective, shingles and the reactivation that happens in that upper level generation, provides a great opportunity to get past the immunity that most adults of our age have and reach the non-immune children of, you know, that of course in essence, the grandchildren. So there's infectiousness going on with shingles? Yes. Oh yes. Skin. Mm-hm. So the, the painful difficult nature of shingles is the part that lingers on afterwards. It's often called neuropathic pain. But that initial moment where you have this dermatome that comes out with a visible lesion, people are extremely infectious. And it can, it doesn't always happen in people of the grandparent's age. I know plenty of people my own age who can have shingles and outbreaks. But they'll literally advise you to stay away from your own young children, or from other people's young children during that stage so you don't infect them. And once it's in young children, they also transmit horizontally. So in, in evolution terms, grandparents are a bit of a conundrum. So, so most organisms die after reproducing, and you don't have this long period of time after say, menopause in women where you have a very active life. In terms of evolution biology, we've come around to understanding with all data from [COUGH] excuse me, long-term studies of Finnish populations over many hundreds of years that grandmothers perform a very essential duty, it's called the Grandmother Effect. They help their daughters raise their own, their granddaughters. And because of kin selection this is beneficial. And you can see that the benefit of grandmother when the mother is having male offspring ,versus twin male offspring, versus female offspring, because males are more expensive. The grandmothers allow those offspring to grow up. So my question is do we know if shingles is more present in females, grandmothers versus grandfathers? You know, I don't know the answer to that question. I'll have to look it up afterwards. I can certainly say that it's an unusual strategy. I agree with you. The grandparents strategy for that as a virus to reactivate there and move on, but something that's useful to reflect on for herpes virus's. They're very species specific, so this human one didn't cross over into humans anytime recently. It's been millennia, so as long as it took to evolve the Grandmother Effect. Yeah. That's how long Barre Oster virus had, to evolve this parasitism of grandmothers to their grandchildren. That's, I'm not sure it's. So does that suggest that this is not a, this is a strategy that we don't see in, in other, in other mammals? Or, are other examples outside of human systems where this kind of, you know, multigenerational transmission effect happens? There wouldn't be any reason to believe that this wouldn't be happening in the primate alpha herpes viruses, for instance, or the ones that happen in bovines, but I'm not sure if anyone's looked. But, but, To find that age of. Yeah, but the very long latent period that seemed to be quite unusual for. Yes. For shingles, isn't it? Because of the decades thing. Yes. If you were a virus of a. Mm-hm. Of a rat or something, then being quiescent for, for a decade wouldn't give you much bang for the bucks. [LAUGH]. Yes, I, I agree. There might be corollary examples in the animal kingdom, but it may be that the humans are the most exaggerated because our lifespan is among the longest.