Several studies are coming out saying that blood LDH (lactate dehydrogenase) levels early in #COVID19 disease correlates with severe disease progression. This is a clue that #pyroptosis may be a the core of this disease (1/n).

https://www.medrxiv.org/content/10.1101/2020.03.24.20040162v1
https://www.jci.org/articles/view/137244
Lactate dehydrogenase, a Risk Factor of Severe COVID-19 Patients

BACKGROUND The World Health Organization (WHO) has recently declared coronavirus disease 2019 (COVID-19) a public health emergency of global concern. Updated analysis of cases might help identify the...

https://www.medrxiv.org/content/10.1101/2020.03.24.20040162v1
What is LDH? It is an enzyme found within the cytosol of nearly all cells. Ed Miao's group showed that LDH release is a reliable way to monitor #pyroptosis, a form of cell death that depends on inflammasomes leading to plasma membrane rupture. (2/n) https://www.ncbi.nlm.nih.gov/pubmed/23852598 
Detection of pyroptosis by measuring released lactate dehydrogenase activity - PubMed

Pyroptosis is a form of programmed, inflammatory cell death that is dependent on the activation of a cysteine protease caspase-1. Following caspase-1 activation via inflammasomes (including NLRP3,...

https://www.ncbi.nlm.nih.gov/pubmed/23852598
LDH is not released by apoptosis or even hyperactivation of macrophages. It requires pyroptosis and membrane rupture shown by @jkagan1 's group. (3/n)

https://www.sciencedirect.com/science/article/pii/S1074761317305149
How might #SARSCoV2 induce pyroptosis? A study showed that #SARSCoV1's Orf8 triggers NLRP3 inflammasome activation and pyroptosis in macrophages. Whether #SARSCoV2 Orf8 also activate pyroptosis is unknown. (4/n) https://www.ncbi.nlm.nih.gov/pubmed/31231549 
SARS-Coronavirus Open Reading Frame-8b triggers intracellular stress pathways and activates NLRP3...

The SARS (severe acute respiratory syndrome) outbreak was caused by a coronavirus (CoV) named the SARS-CoV. SARS pathology is propagated both by direct cytotoxic effects of the virus and aberrant...

https://www.ncbi.nlm.nih.gov/pubmed/31231549
While LDH correlates well with disease severity, this may not be the reason for severe disease. However, pyroptotic (pyro=fire, ptosis=falling) death is very immunogenic, releasing intracellular contents and can lead to blood clotting. (5/n) https://www.ncbi.nlm.nih.gov/pubmed/31076358 
Inflammasome Activation Triggers Blood Clotting and Host Death through Pyroptosis - PubMed

Inflammasome activation and subsequent pyroptosis are critical defense mechanisms against microbes. However, overactivation of inflammasome leads to death of the host. Although recent studies have...

https://www.ncbi.nlm.nih.gov/pubmed/31076358
Blood clotting is also associated with poor prognosis in #COVID19. (6/n) https://www.ncbi.nlm.nih.gov/pubmed/32073213 
Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronav...

The present study shows that abnormal coagulation results, especially markedly elevated D-dimer and FDP are common in deaths with NCP.

https://www.ncbi.nlm.nih.gov/pubmed/32073213
There are other reasons why inflammasome inhibitors might be a promising approach - to increase host disease tolerance. Please see a nice thread by @padminipillai explaining this concept. (7/n) https://twitter.com/padminipillai/status/1243165595740385285
I believe inflammasome inhibitors should be tested for #COVID19 treatment. I've said this before but I believe it is worth repeating here. I hope pharma companies working on developing such inhibitors for other disease indications can help 🙏🏽 (end) https://www.nature.com/articles/d41573-019-00086-9
NLRP3 inhibitors stoke anti-inflammatory ambitions

Inhibitors of the innate immune system’s NLRP3 inflammasome promise potential in Parkinson disease, Alzheimer disease, non-alcoholic steatohepatitis, gout and much more, catching the eye of Novartis,...

https://www.nature.com/articles/d41573-019-00086-9
You can follow @VirusesImmunity.
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