DAMPening COVID-19 Severity by Attenuating Danger Signals

Abstract

COVID-19 might lead to multi-organ failure and, in some cases, to death. The COVID-19 severity is associated with a "cytokine storm." Danger-associated molecular patterns (DAMPs) are proinflammatory molecules that can activate pattern recognition receptors, such as toll-like receptors (TLRs). DAMPs and TLRs have not received much attention in COVID-19 but can explain some of the gender-, weight- and age-dependent effects. In females and males, TLRs are differentially expressed, likely contributing to higher COVID-19 severity in males. DAMPs and cytokines associated with COVID-19 mortality are elevated in obese and elderly individuals, which might explain the higher risk for severer COVID-19 in these groups. Adenosine signaling inhibits the TLR/NF-κB pathway and, through this, decreases inflammation and DAMPs' effects. As vaccines will not be effective in all susceptible individuals and as new vaccine-resistant SARS-CoV-2 mutants might develop, it remains mandatory to find means to dampen COVID-19 disease severity, especially in high-risk groups. We propose that the regulation of DAMPs via adenosine signaling enhancement might be an effective way to lower the severity of COVID-19 and prevent multiple organ failure in the absence of severe side effects.

Keywords: COVID-19; DAMPs; SARS-CoV2; TLRs; adenosine; cytokine storm.

Figure 1

The proposed role of DAMPs/TLRs in the risk factors of COVID-19 severity. In males (compared to females) a lower (⇓) expression of toll-like receptor (TLR) 7 might (⇓) reduce the viral clearance. On the other hand, higher (⇑) TLR4 in males might lead to higher (⇑) sensitivity to danger-associated molecular patterns (DAMPs). Furthermore, obesity and aging are conditions associated with a proinflammatory state characterized by increased (⇑) DAMPs, interleukin 6 (IL-6), and tumor necrosis factor alpha (TNFα). After SARS-CoV-2 infection, an exacerbated (⇑⇑) accumulation of DAMPs and proinflammatory cytokines might explain the higher (⇑) COVID-19 severity in these individuals.

Figure 2

Integration between DAMPs signaling and adenosine signaling. (A) Different danger-associated molecular patterns (DAMPs) molecules are released by the cells and can be sensed by toll-like receptors (TLRs) leading to the activation of nuclear factor kappa B (NF-κB) and the production of proinflammatory cytokines. Similarly, adenosine triphosphate (ATP) is actively or passively released from damaged cells and activates purinergic ATP receptors (P2X) activating proinflammatory responses in the cells. ATP can be broken down by ectonucleotidases producing adenosine. (B) Adenosine activates adenosine receptors (ARs) and inhibits (dotted green line) TLR and P2X signaling by downregulating the NF-κB-mediated production of proinflammatory cytokines.

Figure 3

Adenosine in the reduction of COVID-19 severity. Pharmacological regulation of adenosine level and signaling, for instance by adenosine uptake inhibition or adenosine receptor agonists, will lead to adenosine signaling enhancement (⇧) resulting in a decreased (⇩) danger-associated molecular patterns (DAMPs) signaling and “cytokine storm”. All this together might result in a decreased severity and better prognosis for COVID-19 patients.