Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2

Abstract

To date, no vaccines or effective drugs have been approved to prevent or treat COVID-19 and the current standard care relies on supportive treatments. Therefore, based on the fast and global spread of the virus, urgent investigations are warranted in order to develop preventive and therapeutic drugs. In this regard, treatments addressing the immunopathology of SARS-CoV-2 infection have become a major focus. Notably, while a rapid and well-coordinated immune response represents the first line of defense against viral infection, excessive inflammatory innate response and impaired adaptive host immune defense may lead to tissue damage both at the site of virus entry and at systemic level. Several studies highlight relevant changes occurring both in innate and adaptive immune system in COVID-19 patients. In particular, the massive cytokine and chemokine release, the so-called "cytokine storm", clearly reflects a widespread uncontrolled dysregulation of the host immune defense. Although the prospective of counteracting cytokine storm is compelling, a major limitation relies on the limited understanding of the immune signaling pathways triggered by SARS-CoV-2 infection. The identification of signaling pathways altered during viral infections may help to unravel the most relevant molecular cascades implicated in biological processes mediating viral infections and to unveil key molecular players that may be targeted. Thus, given the key role of the immune system in COVID-19, a deeper understanding of the mechanism behind the immune dysregulation might give us clues for the clinical management of the severe cases and for preventing the transition from mild to severe stages.

Fig. 1

Schematic representation of SARS-CoV-2-driven signaling pathways and potential drug targets. Schematic representation of host intracellular signaling pathways induced by SARS-CoV-2 infection. Selected drugs, acting on these pathways, are repurposed to manage the cytokine storm induced by the viral infection. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; IκB, inhibitor of nuclear factor κB; NF-κB, p65-p50, nuclear factor κB; IL-6, interleukin 6; IL-1β, interleukin 1β; IL-2, interleukin 2; IL-8, interleukin 8; IL-17, interleukin 17; G-CSF, granulocyte-colony stimulating factor; GM-CSF, granulocyte macrophage-colony stimulating factor; IP-10, IFN-γ-induced protein 10; MCP-1, monocyte chemoattractant protein 1; CCL3, chemokine (C-C motif) ligand 3; TNFα, Tumor necrosis factor α; JAK, Janus kinase; STAT, signal transducer and activator of transcription; S1P, sphingosine-1-phosphate; S1PR₁, sphingosine-1-phosphate receptor 1; MyD88, myeloid differentiation primary response gene 88; TRIF, TIR-domain-containing adapter-inducing IFN-β

Fig. 2

Hypothetical mechanism by SARS-CoV-2 in establishing an inflammatory feedback loop between IL-6 and angiotensin II. Cytokine IL-6 has been found increased in COVID-19 patients, thus suggesting a direct role of SARS-CoV-2 in a massive cytokine release. IL-6 is able to activate a soluble form of IL-6 receptor interacting with gp130, thereby promoting the downstream activation of JAK/STAT signaling, and thely production of IL-6. Moreover, SARS-CoV-2 has been directly related with the occurrence of cardiovascular implications, such as coronary atherosclerosis, inflammation in the vascular system and diffuse microangiopathy with thrombosis. Synthesis and secretion of IL-6 are directly implicated in cardiovascular damages. Indeed, IL-6 production is also induced by angiotensin II in AT₁/JAK/STAT-dependent manner. As observed in SARS-CoV, also SARS-CoV-2 may be hypothesized to downregulate ACE2 expression, thus resulting in over-production of angiotensin II by the related enzyme ACE. In turn, increased angiotensin II enhances IL-6 production via JAK/STAT pathway, thus establishing a positive inflammatory feedback loop, ultimately resulting in the exacerbation of vascular and lung injuries. Moreover, the angiotensin II/AT₁ receptor axis activates ADAM17 that cleavages and inactivates ACE2, enhancing angiotensin II retention. In addition, ADAM17 induction has been found to process the membrane form of IL-6Rα to the soluble form (sIL-6Rα), followed by the gp130-mediated activation of STAT3 via the sIL-6Rα-IL-6 complex in a variety of IL-6Rα-negative non-immune cells. The IL-6 amplifier promotes the production and secretion of several pro-inflammatory cytokines and chemokines, such as IL-6, sustaining the IL-6 amplifier-driven positive feedback. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; IL-6, interleukin 6; ACE2, angiotensin-converting enzyme 2; AT₁, angiotensin II receptor type 1; JAK, Janus Kinase; STAT, Signal Transducer and Activator of Transcription; ADAM17, A Disintegrin And Metalloproteinase domain-containing protein 17