Abstract
SARS-CoV-2 might directly activate NLRP3 inflammasome resulting in an endogenous adjuvant activity necessary to mount a proper adaptive immune response against the virus. Heterogeneous response of COVID-19 patients could be attributed to differences in not being able to properly downregulate NLRP3 inflammasome activation. This relates to the fitness of the immune system of the individual challenged by the virus. Patients with a reduced immune fitness can demonstrate a dysregulated NLRP3 inflammasome activity resulting in severe COVID-19 with tissue damage and a cytokine storm. We sketch the outlines of five possible scenarios for COVID-19 in medical practice and provide potential treatment options targeting dysregulated endogenous adjuvant activity in severe COVID-19 patients.
Highlights
SARS-CoV-2 might directly activate NLRP3 inflammasome resulting in an endogenous adjuvant activity necessary to mount a proper adaptive immune response against the virus
In one of the first analyses of patient characteristics of SARS-CoV-2 infection in Wuhan, China resulting in COVID-19, it was described that the virus affects largely adult age groups
In search for a pathway to relate sustained NLRP3 inflammasome activation in aging we found a microRNA that has Pyrin-only protein 1 (POP1) as its target [33]
Summary
The discrimination into two phases of the clinical disease requires the need for a dual treatment approach [2]. Chloroquine [58], Methotrexate [59], anti-oxidants [60,61,62], traditional Chinese medicine [63, 64], thrombomodulin [65], and others [66,67,68] are listed as potential therapeutic strategies to diminish HMGB1 Another option to limit severe damage would be to reduce the number of neutrophils. 1https://www.globenewswire.com/news-release/2020/04/09/2014265/0/en/FDAGrants-CalciMedica-Permission-to-Begin-Dosing-CM4620-IE-in-Patientswith-Severe-COVID-19-Pneumonia-under-a-Newly-Opened-IND.html from pre-clinical work can be distinguished, Galactin-9 inhibits the infiltration of neutrophils and decreases MMP levels and down-regulates Th1 and Th17 T cells [70] and exogenous carbon monoxide delivered from carbon monoxidereleasing molecule 2 inhibits neutrophil infiltration [71] This treatment inhibited NLRP3 activation in vitro [72] and HMGB1 in an in vivo model [73] and a suggestion is made that this could be of use in the current ICU [74]. Blocking the downstream mediators of NLRP3 inflammasome activation caspase-1 and cytokines IL-1β and IL18 and their receptors are potential options for treatment for COVID-19-related pneumonia [75,76,77]
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