Molecular mechanisms of stress-induced reactivation in mumps virus condensates, 2023, Xiaojie Zhang et al

Highlights•

• Cellular stress provokes activation of viral replication in an RNA virus model
• The viral replication factories are liquid-like condensates that coarsen under stress
• Stress-triggered IDR phosphorylation stabilizes the viral replication machinery
• In-cell nucleocapsid structures reveal changes in genomic RNA and IDR accessibility

Summary
Negative-stranded RNA viruses can establish long-term persistent infection in the form of large intracellular inclusions in the human host and cause chronic diseases. Here, we uncover how cellular stress disrupts the metastable host-virus equilibrium in persistent infection and induces viral replication in a culture model of mumps virus.

Using a combination of cell biology, whole-cell proteomics, and cryo-electron tomography, we show that persistent viral replication factories are dynamic condensates and identify the largely disordered viral phosphoprotein as a driver of their assembly. Upon stress, increased phosphorylation of the phosphoprotein at its interaction interface with the viral polymerase coincides with the formation of a stable replication complex.

By obtaining atomic models for the authentic mumps virus nucleocapsid, we elucidate a concomitant conformational change that exposes the viral genome to its replication machinery. These events constitute a stress-mediated switch within viral condensates that provide an environment to support upregulation of viral replication.

https://www.cell.com/cell/fulltext/...m/retrieve/pii/S0092867423002763?showall=true

 

I wanted to know what specifically they mean by stress (definitely not psychosocial stress) and unless I missed something it's oxidative stress that promotes viral replication:

Our culture model recapitulated hallmarks of persistent benign infection: cells did not exhibit stress as indicated by the absence of stress granules, and cell division was maintained at normal levels (Figures 1A and 1C), although released virions were capable of infecting naive cells, indicating basal levels of viral replication (Figure 1D). However, when cells were challenged with established conditions of oxidative stress, viral replication increased by 2- to 4-fold

Prolonged mild oxidative stress (30 μM arsenite; As(III)) also increased viral transcription and replication, albeit at a lower rate or magnitude​

And by "stress granules" they mean:

We established a culture model of persistent MuV infection in a HeLa cell line (HeLa-MuV) stably expressing the stress granule protein mCherry-G3BP1 (Ras GTPase-activating protein-binding protein 1) as a marker of cellular stress​

I can't say I know enough about oxidative stress to understand what this means, but oxidative stress comes up a whole lot in ME studies, and if low level sustained oxidative stress is capable enough of promoting viral replication, this starts like sounding like a model, at least as far as I don't know much about biology.

Seems very interesting. Viral reservoirs, stable and, as they write in the highlights "The viral replication factories are liquid-like condensates that coarsen under stress", change morphology in response to oxidative stress. Sounds a lot like a stalemate that takes every opportunity it gets to breach the defenses. And with viruses, it only takes a few virions to mass produce, reservoirs can be small.

That was always the model that made the most sense here. But making sense is not exactly a feature of immunology so who knows?

 

Given that G3BP1 is a well-described target for many viruses with a clear functional role during infection could also offer novel therapeutic opportunities.

 

Maybe it's only part of the answer, but the intensity with which latent infections have been denied and dismissed, despite being common and well-documented, as a potential source of illness, and contrasting with the conditions where 1) viral particles are as small compared to a human body as a human body is to the volume of the entire damn planet Earth and 2) it only takes a handful of particles for a full infection.

The hubris. It's just staggering. I'm pretty convinced that this is the main explanation for most diseases, even most of those wrongly attributes to "lifestyles". Even most aging is probably a consequence of accumulated injuries and stalemates with various infections that found a niche somewhere.

As in this is probably the most important idea in all of medicine, or one of the top 5. And it's dismissed with the same ease as flat earth, even though it's common and well-documented. This feels as bad as having completely missed electricity, having dismissed it as of no interest and made taboo, turned into superstition and described as magical.

 

Or, as our immune systems degrade, losing the ability to control the deleterious effects of those latent infections. I think the partial reactivation of herpesviruses will be key and the mechanisms are starting to come in to focus. Eg if HHV6 partial reactivation prevents the host cell's own microRNA machinery that could have systemic consequences, losing more and more ability to maintain homeostasis through mechanisms that rely on those microRNAs.

 

As best as I can tell, this hypothesis is mostly brushed off because there is basically nothing we can do about it. No lifestyle changes can change the fact that we regularly get exposed with stuff that can cause health issues. And it's not just pathogens, so many toxins, metals, now plastics everywhere. It's everywhere, in the air we breathe, the water we drink, pathogens in food from faraway. Medicine massively struggles when they don't know the source of a problem, and this is basically a medical uncertainty principle, they can't ever really know for sure.

It removes control. If regular, even mild, infections can cause lifelong disease like this, barely possible to detect, it just makes everything so much harder. And it really seems like the ignorant bliss is simply preferred, mostly in favor of BS "adjust your lifestyle and nothing can touch you" woo. Even though it's mostly BS. There are centenarians who never exercised a day in their life, drank every day, smoked for decades. And then there are people like my aunt, one of the fittest and healthiest person you could find, died before 40. Did everything right, and still lost the biological lottery.

Everything I see out of medicine confirms this. It makes them powerless against it, at least temporarily, and that's just unacceptable. It's best to have the flawed perception of being in control, even if it's just an illusion. Even though swallowing the hard pill, working at it, would change everything. Very defeatist.