Understanding SARS-CoV-2-Mediated Inflammatory Responses: From Mechanisms to Potential Therapeutic Tools

Abstract

Currently there is no effective antiviral therapy for SARS-CoV-2 infection, which frequently leads to fatal inflammatory responses and acute lung injury. Here, we discuss the various mechanisms of SARS-CoV-mediated inflammation. We also assume that SARS-CoV-2 likely shares similar inflammatory responses. Potential therapeutic tools to reduce SARS-CoV-2-induced inflammatory responses include various methods to block FcR activation. In the absence of a proven clinical FcR blocker, the use of intravenous immunoglobulin to block FcR activation may be a viable option for the urgent treatment of pulmonary inflammation to prevent severe lung injury. Such treatment may also be combined with systemic anti-inflammatory drugs or corticosteroids. However, these strategies, as proposed here, remain to be clinically tested for effectiveness.

Keywords: Antibody-dependent enhancement (ADE); Fc receptors (FcR); Inflammatory response; SARS-CoV-2.

Fig. 1

Possible mechanisms of SARS-CoV-2-mediated inflammatory responses. Based on previous studies of SARS-CoV, we separate the inflammatory responses in SARS-CoV-2 infection into primary and secondary responses. Primary inflammatory responses occur early after viral infection, prior to the appearance of neutralizing antibodies (NAb). These responses are mainly driven by active viral replication, viral-mediated ACE2 downregulation and shedding, and host anti-viral responses. Secondary inflammatory responses begin with the generation of adaptive immunity and NAb. The virus-NAb complex can also trigger FcR-mediated inflammatory responses and acute lung injury.

Fig. 2

Fc receptor-mediated antibody-dependent enhancement (ADE) of viral infection and inflammatory responses. A ADE occurs when antiviral neutralizing antibodies cannot completely neutralize the virus. Instead, the virus-NAb complex attaches to the Fc receptor (FcR), leading to viral endocytosis and infection of the target cells. The outcome is an increase in the overall replication of the virus and greater disease severity. B Virus-NAb complex binding to FcR can also activate proinflammatory signaling, skewing macrophage responses to the accumulation of proinflammatory (M1 or classically activated) macrophages in lungs. The M1 macrophages secrete inflammatory cytokines such as MCP-1 and IL-8, leading to lung injury. C Potential therapeutics based on targeting the Fc receptors to block SARS-CoV-2-induced inflammatory responses. From left to right, FcR can be blocked using anti-Fc specific antibodies, small molecules, or intravenous immunoglobulin (IVIG). The inhibitory FcR, FcγRIIB, may also be targeted to inhibit FcR activation. The FcRn can also be blocked by specific antibodies or inhibited competitively through IVIG binding.