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1 approach to understanding #covid19 infection is to examine co-morbidities & ask what's common?

Most prevalent Cov19 co-morbs:

1)↗️age
2)Hypertension
3)Diabetes
4)Cardiovascular disease
5)Kidney disease
6)Chronic respiratory disease (esp COPD)
8)Cancers
9)BMI>40
10)♂️>♀️
2/
These are diverse diseases & increasing age technically not a disease at all. However, there is at least 1 factor in common among all of the co-morbidities identified thus far:

INFLAMMATION
3/
A survey of the co-morbidities revealed another commonality; a close association w/ dysregulation of the pro-inflammatory, neutrophil-recruiting cytokine, IL-17A.

IL-17A is made by multiple immune cell types, including lung-resident innate lymphoid cells (ILC3s).
4/
While this isn't place for a comp review, I'll include 1+ reference highlighting relationship between IL-17A & each CoV19 co-morb.

Useful resources for info about IL-17A:
doi.org/10.4267/2042/5…
ncbi.nlm.nih.gov/pubmed/28254169
ncbi.nlm.nih.gov/pubmed/31745337
Also PMID 31337278 & 28620097
1)↗️age
The increase inflammation that occurs with age (aka "inflammaging") is well-documented.

This paper shows how during viral infection, aged mice overproduce IL-17A (relative to young control), leading to neutrophil-mediated organ damage/death.

Rescued by anti-IL-17A Ab
6/
Close relationship of hypertension/kidney disease/diabetes, so some overlap in refs

2)hypertension

In short, Angiotensin II (produced by ACE) leads to elevated IL-17A & inflammation and hypertension. Targeting IL-17A lowers blood pressure.

PMID 29952002 (recent review)
7/
3)Diabetes

Due to the close relationship between hypertension, obesity, kidney disease, & diabetes, unclear if this is a separate co-morbidity.

Increased IL-17A is associated with secondary diabetic diseases and anti-IL-17A antibodies are being considered as therapeutics
8/
4) Cardiovascular disease

This co-morbidity should perhaps be classified as vascular disease; Chinese CoV19 patients were much more likely to have cerebrovascular disease than CV disease.

Also, overlap with hypertension. This is an older review.
9/
5)Kidney disease

Impossible to decouple from hypertension - see /6
10/
6)Chronic respiratory disease (esp COPD)

COPD & neutrophilic asthma have much in common. For both, IL-17A levels are elevated in BAL, implicated in pathology, & anti-IL-17A is being explored as a therapeutic

PMID 30383540/20565710/32172346 and many more
11/
8)Cancers
IL-17A producing cells are closely associated w/cancer. Depending on cancer type, IL-17A may have pro or anti-tumorigenic effects.

ncbi.nlm.nih.gov/pmc/articles/P…

Chronic inflammation contributes to cancer development, growth, therapy resistance & metastasis (31315034)
12/
9)BMI>40

see 2-11. Obesity/metabolic syndrome increases chances of all of these conditions.
Couple IL-17A SNPs associated w/ ⬆️susceptibility 2 ARDS, cerebrovascular disease, asthma, flu etc... May/may not be relevant 2 #covid19 . I lack expertise to critically evaluate GWAS lit, but putting here 4 someone else to investigate.
snpedia.com/index.php/Rs22…
Metasite very useful for summarizing/aggregating references on polymorphisms.

If you did @23andMe sequencing, you can see pull your own data through these links:
geneticlifehacks.com/increased-infl…
geneticlifehacks.com/are-you-geneti…
15/
How might chronic inflammation (& elevated IL-17A) contribute to #covid19 1) susceptibility and/or 2) severity?

IL-17A inhibits IFN-λ , the first line of defense against respiratory viruses!
17/
"•IFNλs are the 1st IFNs produced that suppress initial viral spread
•IFNλs exhibit potent antiviral functions w/o activating inflammation
•Type I IFNs come up later to enhance antiviral & pro-inflammatory responses"
doi.org/10.1016/j.immu…
18/
This leads to 1st hypothesis:

Individuals w/inflammation that affects the airways (including the vasculature) are less able to activate an effective first line defense against CoV-2. This would mean that more virus can get past upper airway & into alveolar spaces of lungs.
19/
VIRAL LOAD appears 2 CORRELATE w/DISEASE severity (32199493). Severe patients in 1 study avg ~60X higher viral loads than mild cases. IF disease severity also correlates w/exposure load, then HEALTHCARE WORKERS ARE ESPECIALLY VULNERABLE. We're already seeing evidence of that.
20/
IFN-λ allows neutrophils 2 respond w/o promoting inflammation (24952503) BUT IFN-λ requires IRF3 for expression ncbi.nlm.nih.gov/pmc/articles/P…

SARS ORF1ab inhibits IRF3 activity (PMID25481026/19369340/others)

CoV19 also has ORF1ab & likely does same =
major neutrophilic response
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