Immune asynchrony in COVID-19 pathogenesis and potential immunotherapies

Abstract

The outbreak of coronavirus disease 2019 (COVID-19) is an unprecedented global health crisis. Tissue and peripheral blood analysis indicate profound, aberrant myeloid cell activation, cytokine storm, and lymphopenia, with unknown immunopathological mechanisms. Spatiotemporal control of the quality and quantity of the antiviral immune responses involves synchronized cellular and molecular cascades and cross-talk between innate and adaptive immunity. Dysregulated responses in immunity, such as at the stages of immune sensing, alarming, polarization, and resolution, may contribute to disease pathology. Herein, we approach SARS-CoV-2 through an immunomodulatory lens, discussing possible mechanisms of the asynchronized antiviral immune response and proposing potential therapeutic strategies to correct the dysregulation.

Figure 1.

Asynchronized immune responses in SARS-CoV-2 infection. Virus infection normally leads to a coordinated immune response (left), from immune activation via PAMPs or DAMPs and numerous cytokines and chemokines, to immune resolution via secretion of natural antagonists, and the down-regulation of innate immunity by adaptive immunity as well as by regulatory immune cells. In SARS-CoV-2 infection (right), aberrant innate sensing, alarming, cytokine production, and hyperactivation of myeloid cells triggered through viral–host interactions lead to immunopathology and lymphopenia.

Figure 2.

Potential mechanisms of SARS-CoV-2–induced lymphopenia. Lymphopenia is a hallmark of SARS-CoV-2 infection and is influenced by many factors, ranging from those affecting generation to recruitment, function, and survival. AICD, activation-induced cell death; DC, dendritic cell.

Figure 3.

Strategies for COVID-19 therapeutic intervention. Dysregulations at every stage of the antiviral response can be corrected but must carefully balance viral clearance with host toxicity. In early stages of the disease, the focus should be on prophylactic vaccines and antiviral drugs, while in late stages of the disease, various immunomodulatory agents should be considered to calm a hysteric innate immune response, down-regulate pathogenic T cells, and boost productive B cell antibody responses. NAbs, neutralizing antibodies.