Lessons Learned to Date on COVID-19 Hyperinflammatory Syndrome: Considerations for Interventions to Mitigate SARS-CoV-2 Viral Infection and Detrimental Hyperinflammation

Abstract

The first case of human transmission of SARS-CoV-2 was reported in China in December 2019. A few months later, this viral infection had spread worldwide and became a pandemic. The disease caused by SARS-CoV-2, termed COVID-19, is multifactorial and associated with both specific antiviral as well as inflammatory responses, the extent of which may determine why some individuals are asymptomatic while others develop serious complications. Here we review possible life-threating immune events that can occur during disease progression to uncover key factors behind COVID-19 severity and provide suggestions for interventions with repurposed drugs in well-controlled and randomized clinical trials. These drugs include therapeutics with potential to inhibit SARS-CoV-2 entry into host cells such as serine protease inhibitors of the cellular protease TMPS2 and drugs targeting the renin-angiotensin system; antivirals with potential to block SARS-CoV-2 replication or factors that could boost the antiviral response; monoclonal antibodies targeting pro-inflammatory cytokines that drive the hyperinflammatory response during COVID-19 progression toward the severe stage and therapeutics that could ameliorate the function of the lungs. Furthermore, in order to help make more informed decisions on the timing of the intervention with the drugs listed in this review, we have grouped these therapeutics according to the stage of COVID-19 progression that we considered most appropriate for their mechanism of action.

Keywords: 2019-nCoV; SARS-CoV-2; antiviral immune response; coronavirus; cytokine release syndrome; hyperinflammation; severe COVID-19; treatment strategies.

Figure 1

Viral entry and replication, and host antiviral immune response—SARS-CoV-2 (Spike (S)-protein) recognizes cell surface proteins (ACE2, TMPS2, and CD147) which facilitate the endocytosis of the virus particle. Viral genome (ssRNA) exits the endosomal vesicles and starts the replication cycle generating dsRNA intermediates, protein translation, encapsidation and generation of new viral particles. New virions can subsequently infect neighboring cells. DAMPs are being released by the dying cells into the extracellular space. Innate immune receptors such as TLR3, RIG-I and MDA-5 or TLR7 can sense viral RNA (dsRNA or ssRNA, respectively) and initiate a signaling cascade for the production of IFNα/β and pro-inflammatory cytokines. Interferon-induced genes (IIG) will be expressed as a result of this type I IFN feedback loop, blocking viral replication. SARS-CoV and MERS-CoV structural and non-structural proteins can interfere with the cells' innate immune response [see proteins in red; for further information refer also to the Kindler et al. (29)], delaying the production of sufficient levels of antiviral cytokines to prevent control of viral replication at the early stages. SARS-CoV-2 might utilize similar evasion mechanisms, although no data have yet been reported. Pharmacological interventions (blue-background boxes) are being proposed to block both the entry and genomic replication of SARS-CoV-2, as well as to boost the innate immune response.

Figure 2

Cause and consequences of the CRS—Constant exposure to DAMPs from dying infected cells and to high viral titers (pathogen associated molecular patterns, PAMPs) lead to the enhancement of pro-inflammatory cytokine pathways in immune cells and tissue resident cells. In addition, complement activation leads to macrophages activation and cytokine release. Of importance is the induction of the IL-1β autocrine loop, involving the activation of the inflammasome complex that results in high levels of this cytokine being secreted to the extracellular space. Release of IL-1β and subsequent engagement with its receptor will enhance the production of other pro-inflammatory cytokines by the activated cells, leading to a massive release of cytokines, chemokines and growth factors. This cytokine storm creates an inflammatory microenvironment in the tissue, already experiencing elevated inflammation due to the dysregulation of angiotensin II levels, that will feedback into hyperactivation of resident immune cells, as well as mobilization of peripheral immune cells into the tissue. The end result of the dysregulation of the host immune response will be tissue damage and organ failure with the possibility of patient death as severity increases. Pharmacological interventions (blue-background boxes) are being proposed to control or manage the tissue and systemic hyperinflammation detected in moderate and severe cases of COVID-19, by agents that can block the binding of cytokines to their receptors as well as drugs that inhibit the synthesis of hyaluronic acid to prevent pulmonary edema.