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Understanding SARS-CoV-2-Mediated Inflammatory Responses: FromMechanisms to Potential Therapeutic To

Topic Cover

-Review of SARSCOV2 immunopathology

-Warnings about Antibody Dependent Enhancement of Infection (ADE).


Currently there is no effective antiviral therapy for SARS-CoV-2 infection, which frequently leads to fatal inflammatoryresponses and acute lung injury. Here, we discuss the various mechanisms of SARS-CoV-mediated inflammation. We alsoassume 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 FcRblocker, the use of intravenous immunoglobulin to block FcR activation may be a viable option for the urgent treatment ofpulmonary inflammation to prevent severe lung injury. Such treatment may also be combined with systemicanti-inflammatory drugs or corticosteroids. However, these strategies, as proposed here, remain to be clinically tested foreffectiveness.

Fig 1 Possible mechanisms of SARS-CoV-2-mediated inflammatoryresponses. Based on previous studies of SARS-CoV, we separate theinflammatory responses in SARS-CoV-2 infection into primary andsecondary responses. Primary inflammatory responses occur earlyafter viral infection, prior to the appearance of neutralizing antibodies(NAb). viral-mediated ACE2 downregulation and shedding, and host anti-viral responses. Secondary inflammatory responses begin with thegeneration of adaptive immunity and NAb. The virus-NAb complexcan also trigger FcR-mediated inflammatory responses and acute lunginjury.



Fig 2 Fc receptor-mediated antibody-dependent enhancement (ADE)of viral infection and inflammatory responses.AADE occurs whenantiviral neutralizing antibodies cannot completely neutralize thevirus. 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 andgreater disease severity.BVirus-NAb complex binding to FcR canalso activate proinflammatory signaling, skewing macrophageresponses to the accumulation of proinflammatory (M1 or classicallyactivated) macrophages in lungs. The M1 macrophages secreteinflammatory cytokines such as MCP-1 and IL-8, leading to lunginjury.CPotential therapeutics based on targeting the Fc receptors toblock SARS-CoV-2-induced inflammatory responses. From left toright, FcR can be blocked using anti-Fc specific antibodies, smallmolecules, or intravenous immunoglobulin (IVIG). The inhibitoryFcR, FccRIIB, may also be targeted to inhibit FcR activation. TheFcRn can also be blocked by specific antibodies or inhibitedcompetitively through IVIG binding.


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https://link.springer.com/content/pdf/10.1007/s12250-020-00207-4.pdf

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