Pharmacological mechanism of immunomodulatory agents for the treatment of severe cases of COVID-19 infection

Abstract

Objective: Coronavirus disease 2019 (COVID-19) is a world-wide pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To date, treatment of severe COVID-19 is far from clear. Therefore, it is urgent to develop an effective option for the treatment of patients with COVID-19. Most patients with severe COVID-19 exhibit markedly increased serum levels of pro-inflammatory cytokines, including interferon (IFN)-α, IFN-γ, and interleukin (IL)-1β. Immunotherapeutic strategies have an important role in the suppression of cytokine storm and respiratory failure in patients with COVID-19.

Methods: A systematic search in the literature was performed in PubMed, Scopus, Embase, Cochrane Library, Web of Science, as well as Google Scholar preprint database using all available MeSH terms for Coronavirus, SARS-CoV-2, anti-rheumatoid agents, COVID-19, cytokine storm, immunotherapeutic drugs, IFN, interleukin, JAK/STAT inhibitors, MCP, MIP, TNF.

Results: Here, we first review common complications of COVID-19 patients, particularly neurological symptoms. We next explain host immune responses against COVID-19 particles. Finally, we summarize the existing experimental and clinical immunotherapeutic strategies, particularly anti-rheumatoid agents and also plasma (with a high level of gamma globulin) therapy for severe COVID-19 patients. We discuss both their therapeutic effects and side effects that should be taken into consideration for their clinical application.

Conclusion: It is suggested that immunosuppressants, such as anti-rheumatoid drugs, could be considered as a potential approach for the treatment of cytokine storm in severe cases of COVID-19. One possible limitation of immunosuppressant therapy is their inhibitory effects on host anti-viral immune response. So, the appropriate timing of administration should be carefully considered.

Keywords: Anti-rheumatoid agents; COVID-19; Cytokine storm; Immunotherapeutic drugs.

Fig. 1

Host immune responses against viral particles in a typical immune cell. The viral extracellular PAMPs and intracellular DAMPs detected by three sensors; (1) the endosomal TLRs, such as TLR-3 and TLR7/8, (2) the cytoplasmic NLR proteins, such as Pr1, Pr2, Pr3, and C4, (3) the cytoplasmic RNA sensors, such as RIG-I, MDA5, and LGP2. Activation of these sensors leads to downstream transduction pathways, including activation of TRAF3/6, NF-κB, IRF3/7, JAK/STAT. Then, activation of all these transduction pathways leads to generation and release of several pro-inflammatory cytokines (e.g., IL-1β, IL-6, TNF-α, type 1 IFNs). Additionally, IL-1β, IL-6, TNF-α and type I IFNs via their receptors (cytokine receptors and IFNAR) can increase their own generation via a positive feedback. These inflammatory, anti-viral responses increased clearance of viral pathogens. IL interleukin, IFN interferones, IFNAR type I IFNs receptor, ISG IFN-stimulated genes, PAMPs pathogen-associated molecular patterns, DAMPs danger-associated molecular patterns, TLRs Toll-Like Receptors, NLR nucleotide-binding domain leucine-rich repeat, RIG-I retinoic acid-inducible gene I, MDA5 melanoma differentiation-associated protein 5, LGP2 laboratory of genetics and physiology 2, TRAF TNF receptor-associated factors, NF-κB nuclear factor κB, IRF interferon regulatory factor, JAK Janus kinase, STAT signal transducer and activator of transcription, TYK tyrosine kinase, TNFα tumor necrosis factorα. Figure created using BioRender software

Fig. 2

Evasion mechanism of COVID-19 particles of host anti-viral responses in the early stage of infection. The COVID-19 particles similar to two previous CoV families (SARS-CoV1 and MERS-Cov) infection develops three important immune evasion strategies in the early stage of infection. The first immune evasion strategy is the isolation of viral PAMPs in the DMVs. The DMVs can shield viral PAMPs from recognition by TLRs. The second immune evasion strategy is suppression of TRAF3/6, NF-κB, JAK/STAT and IRF3/7 in the host immune cells. The third immune evasion strategy is inhibition of IFN induction via the anti-IFN proteins such as ORF3a and ORF6 proteins. These anti-IFN proteins can suppress the IFNAR function via degradation of its receptors (IFNAR), and disrupting nuclear translocation of STAT. Therefore, suppression of host anti-viral mechanisms in the early stage of infection, allow COVID-19 particles to replicate without turning on the host anti-viral immune machine. ACE2 angiotensin converting enzyme, DMVs double membrane vesicles, IL interleukin, IFN interferones, IFNAR type I IFNs receptor, ISG IFN-stimulated genes, TLRs Toll-Like Receptors, NLR nucleotide-binding domain leucine-rich repeat, RIG-I retinoic acid-inducible gene I, MDA5 melanoma differentiation-associated protein 5, LGP2 laboratory of genetics and physiology 2, TRAF TNF receptor-associated factors, NF-κB nuclear factor κB, IRF interferon regulatory factor, JAK Janus kinase, STAT signal transducer and activator of transcription, TYK tyrosine kinase, TNFα tumor necrosis factorα, ORF open reading frame. Figure created using BioRender software.

Fig. 3

Induction of cytokine storm in elderly or weak adults with COVID-19 in the late stage of infection. Several factors orchestrate induction of cytokine storm in some elderly adults with COVID-19. First, decreased antioxidant capacity during aging together with excess ROS generation, increasing pro-inflammatory cytokine secretion during aging and induce mild inflammatory condition. Additionally, excess ROS generation during aging can activate NLRs, leading to generation of inflammasomes. The inflammasomes convert procaspase-1 (inactive form) to the active form of caspase-1. Subsequently, caspase-1 converts pro-IL-1β to active IL-1β. Excess release of IL-1β is associated with pyroptosis and cytokine storm in elderly adults. Second, the decline of ACE2 receptor expression and vitamin D deficiency in aged-subjects can increase secretion of pro-inflammatory cytokines in elderly adults. Finally, pro-inflammatory cytokines can increase their own generation via an autocrine pathway. ACE2 angiotensin converting enzyme, IL interleukin, PAMPs pathogen-associated molecular patterns, DAMPs danger-associated molecular patterns, NLR nucleotide-binding domain leucine-rich repeat, NF-κB nuclear factor κB, STAT signal transducer and activator of transcription, Vit D vitamin D. Figure created using BioRender software

Fig. 4

The targets of anti-rheumatoid agents in the host inflammatory pathway in COVID-19 infection. The IL-1, IL-6, and IFNs bind to their own receptors (IL-1RI, sIL-6R, IFNAR, respectively) and trigger specific signaling cascades to activate the generation of multiple cytokines. IL-1 inhibitors, IL-6 inhibitors, and JAK inhibitors (ruxolitinib, tofacitinib, baricitinib, peficitinib, fedratinib, and upadacitinib) can limit cytokine storm and hyper-inflammation by suppressing these signaling cascades. IL interleukin, IFN interferones, IFNAR type I IFNs receptor, ISGF IFN-stimulated gene factor, R receptor, sIL-6R soluble interleukin receptor, JAK Janus kinase, STAT signal transducer and activator of transcription, NF-κB nuclear factor κB. Figure created using BioRender software