Pathology of Germ-Induced Damage: Distinguishing Direct Action from Inflammation

[mktsgm]

TL;DR Summary

Analyzing the damage due to the direct infection of virus and due to the inflammation?

When a bacteria/virus infects a human, they damage the infected tissues and cells.

Also further damage is seen in case of body's own inflammatory response in fighting the germs.

How do we distinguish the damage due to germ's direct action/invasion from the damage caused due to the body's excessive immune reaction (such as cytokine storm)?

Is there a way to differentiate the injury caused by them separately? Can the pathologists identify that a 'particular damage is due to the virus itself' while 'another damage is due to the inflammation' etc, by analyzing them?

 

[jim mcnamara]

This whole post is limited technically so anyone can get most of it. I probably overdid it.

Think of collateral damage. If you fire a weapon into crowd of people someone you do not want to hurt inadvertently gets hurt.

Have you heard of a biochemical cascade? Example: add a tiny bit of glucose to a lightning bug cell culture and all of a sudden the quiescent cells start to fluoresce. The presence of glucose "flipped a chemical switch" which flipped other switches and all of a sudden there are literally hundreds of biochemical pathways all running full tilt.

Inflammation works like that. So a virus can tweak some pathway, turn it off or make it run overtime and all hell breaks loose. It can do it either as a single switch or through multiple ones. It can do this nasty trick in one tissue or many. Covid can attack any place where there are cells with ACE receptors. Nose, gut, lungs, etc.

One of the primary switches in Covid wherever it starts working:
SARS-CoV-2 induces fatal oxidative stress in cells. Especially alveolar cells in your lungs. Covid-19 breaks the Citric Acid cycle.
https://en.wikipedia.org/wiki/Citric_acid_cycle

Reactive Oxygen Species (ROS, example $H_2O_2$) build up from the broken Citric Acid cycle. It damages that cell and it dies and it kind of falls apart because it sent out the switch to turn on IL6. Macrophages come in and make the whole deal worse. and viola a whole series of inflammatory biochemical cascades turn on when they should not have.

The answer is all of the out of control damage is ultimately from the pathogen. If this happens in other ACE receptors sites like in your nose you can lose your sense of smell.

So what you see as a symptom may not really be helpful.

Also inflammation involves a lot of immune system cells. When that system is out of control, blood analysis can spot the cell type imbalances, either by seeing the cells under the microscope or looking for chemical markers like ferritin levels. These are changed when immune systems get out of whack.
https://pubmed.ncbi.nlm.nih.gov/8528049/

Short answer is no, not the way you want.

Think of a perfectly still pond. Now lob a big rock out into the middle. Every part of the pond gets waves that make changes in the water column. Covid-19 is a rock.

 

[mktsgm]

I understand that distinguishing becomes fudgy, as your post makes it very clear. Thank you very much.

The major problem with Covid is the cytokine storm or the excessive immune reaction.

What would have happened, if an immunocompromised person got infected? Would he also have experienced such severe Covid effects? I doubt it.

In such cases, how would be the outcome?

 

[Ygggdrasil]

I understand that distinguishing becomes fudgy, as your post makes it very clear. Thank you very much.

The major problem with Covid is the cytokine storm or the excessive immune reaction.

What would have happened, if an immunocompromised person got infected? Would he also have experienced such severe Covid effects? I doubt it.

In such cases, how would be the outcome?

Certain immunocompromising conditions (which hamper the body's interferon responses to viral infection) are behind a significant fraction of severe COVID-19 cases (maybe up to 14% of the severe cases worldwide are associated with flawed interferon responses).

See:
https://www.physicsforums.com/threads/flawed-interferon-response-spurs-severe-covid-19.994080/
https://science.sciencemag.org/content/369/6511/1550

 

[Ygggdrasil]

A new paper published just yesterday suggests that individuals who showed signs of early antibody responses in the course of the disease had much better survival than those who did not, further giving evidence that early immune responses to the virus are key to preventing the infection from evolving into severe, life-threatening disease:

Compromised humoral functional evolution tracks with SARS-CoV-2 mortality
https://www.cell.com/cell/fulltext/S0092-8674(20)31459-8

Abstract:

The urgent need for an effective SARS-CoV-2 vaccine has forced development to progress in the absence of well-defined correlates of immunity. While neutralization has been linked to protection against other pathogens, whether neutralization alone will be sufficient to drive protection against SARS-CoV-2 in the broader population remains unclear. Therefore, to fully define protective humoral immunity we dissected the early evolution of the humoral response in 193 hospitalized individuals ranging from moderate-to severe. Although robust IgM and IgA responses evolved in both survivors and non-survivors with severe disease, non-survivors showed attenuated IgG responses, accompanied by compromised Fcɣ-receptor binding and Fc-effector activity, pointing to deficient humoral development rather than disease-enhancing humoral immunity. In contrast, individuals with moderate disease exhibited delayed responses that ultimately matured. These data highlight distinct humoral trajectories associated with resolution of SARS-CoV-2 infection and the need for early functional humoral immunity.

Another paper published at the same time also notes differing trajectories for the antibody responses of those who recover rapidly from COVID-19 vs those who don't:

Quick COVID-19 Healers Sustain Anti-SARS-CoV-2 Antibody Production
https://www.cell.com/cell/fulltext/S0092-8674(20)31458-6

Abstract:

Antibodies are key immune effectors that confer protection against pathogenic threats. The nature and longevity of the antibody response to SARS-CoV-2 infection is not well defined. We charted longitudinal antibody responses to SARS-CoV-2 in 92 subjects after symptomatic COVID-19. Antibody responses to SARS-CoV-2 are unimodally distributed over a broad range, with symptom severity correlating directly with virus-specific antibody magnitude. Seventy-six subjects followed longitudinally to ∼100 days demonstrated marked heterogeneity in antibody duration dynamics. Virus-specific IgG decayed substantially in most individuals, whereas a distinct subset had stable or increasing antibody levels in the same timeframe despite similar initial antibody magnitudes. These individuals with increasing responses recovered rapidly from symptomatic COVID-19 disease, harbored increased somatic mutations in virus-specific memory B cell antibody genes, and had persistent higher frequencies of previously activated CD4+ T cells. These findings illuminate an efficient immune phenotype that connects rapid symptom clearance to differential antibody durability dynamics.