On the role of bacterial metalloproteases in COVID-19 associated cytokine storm

Abstract

The cytokine release syndrome or cytokine storm, which is the hyper-induction of inflammatory responses has a central role in the mortality rate of COVID-19 and some other viral infections. Interleukin-6 (IL-6) is a key player in the development of cytokine storms. Shedding of interleukin-6 receptor (IL-6Rα) results in the accumulation of soluble interleukin-6 receptors (sIL-6R). Only relatively few cells express membrane-bound IL-6Rα. However, sIL-6R can act on potentially all cells and organs through the ubiquitously expressed gp130, the coreceptor of IL-6Rα. Through this, so-called trans-signaling, IL-6-sIL-6R is a powerful factor in the development of cytokine storms and multiorgan involvement. Some bacteria (e.g., Serratia marcescens, Staphylococcus aureus, Pseudomonas aeruginosa, Listeria monocytogenes), commonly considered to cause co-infections during viral pneumonia, can directly induce the shedding of membrane receptors, including IL-6Rα, or enhance endogenous shedding mechanisms causing the increase of sIL-6R level. Here we hypothesise that bacteria promoting shedding and increase the sIL-6R level can be an important contributing factor for the development of cytokine storms. Therefore, inhibition of IL-6Rα shedding by drastically reducing the number of relevant bacteria may be a critical element in reducing the chance of a cytokine storm. Validation of this hypothesis can support the consideration of the prophylactic use of antibiotics more widely and at an earlier stage of infection to decrease the mortality rate of COVID-19. Video abstract.

Keywords: Bacteria; COVID-19; Cytokine storm; IL-6; Metalloprotease.

Fig. 1

The mode of action of IL-6. a IL-6 binds to membrane-bound IL-6Rα (gp80). The IL-6–IL-6Rα complex binds to gp130 membrane receptor, which is responsible for signaling. IL-6 acts on cells expressing IL-6Rα. b Metalloproteases are able to cleave the exodomain of membrane-bound IL-6Rα (gp80). Bacterial exogenous metalloproteases are directly capable of IL-6Rα shedding. In addition, bacteria are able to solubilize IL-6Rα by activating endogenous metalloproteases. The resulting soluble sIL-6R binds IL-6 with the same affinity as membrane-bound IL-6Rα. The IL-6–sIL-6R complex is also able to bind to the gp130 membrane receptor on cells that do not express IL-6Rα, thus affecting organs that would not be affected by IL-6 and the cytokine storm. This mechanism may contribute to the development of multiorgan involvement in the cytokine storm