The immune response as a double-edged sword: The lesson learnt during the COVID-19 pandemic

Abstract

The COVID-19 pandemic has represented an unprecedented challenge for the humanity, and scientists around the world provided a huge effort to elucidate critical aspects in the fight against the pathogen, useful in designing public health strategies, vaccines and therapeutic approaches. One of the first pieces of evidence characterizing the SARS-CoV-2 infection has been its breadth of clinical presentation, ranging from asymptomatic to severe/deadly disease, and the indication of the key role played by the immune response in influencing disease severity. This review is aimed at summarizing what the SARS-CoV-2 infection taught us about the immune response, highlighting its features of a double-edged sword mediating both protective and pathogenic processes. We will discuss the protective role of soluble and cellular innate immunity and the detrimental power of a hyper-inflammation-shaped immune response, resulting in tissue injury and immunothrombotic events. We will review the importance of B- and T-cell immunity in reducing the clinical severity and their ability to cross-recognize viral variants.

Keywords: COVID-19; cross-immunity; cytokine storm; immunopathogenesis; protective immunity.

FIGURE 1

Protective and pathogenic pathways of the innate immune response during SARS‐CoV‐2 infection. Protective innate response: surrounded by a green hatched line, includes both soluble (a and b) and cellular components (d). (a) Mannose‐binding lectin (MBL) binds to trimeric Spike, thus inhibiting viral infection; (b) Early activation of type‐I IFN response exerts antiviral effect and prevents severe clinical manifestations; (d) Early expansion of cytotoxic NK cells contributes to viral clearance and associates with mild clinical presentation. Pathogenic innate response: surrounded by a red hatched line, includes both soluble (c, e and f) and cellular components (g–i). (c) Antibody anti‐type‐I IFN block the IFN antiviral activity and associates with a severe clinical outcome; (e) Lung resident myeloid and MAIT cells produce huge amounts of inflammatory cytokines and chemokines that, in turn, massively recruit macrophages and neutrophils from the peripheral blood, thus exacerbating the cytokine storm; (f) The huge amount of inflammatory mediators reaches the bloodstream, inducing a cascade of events contributing to the host injury; (g) The inflammatory storm induces a massive expansion of myeloid derived suppressor cells (MDSC) that can reduce the inflammation but strongly impair the antigen‐specific T‐cell response; (h) Expanded MDSC participate to platelet activation by reducing the plasmatic arginine. (i) The inflammatory storm triggers several detrimental pathways as complement activation, hypercoagulation, endothelial damage, arterial and venous embolism with NET formation

FIGURE 2

Protective and pathogenic pathways of the T‐cell response during SARS‐CoV‐2 infection. Protective T‐cell response: surrounded by a green hatched line. (a) A low inflammatory environment allows a well‐balanced differentiation of antigen‐specific T cells, contributing to viral clearance and to antibody production; (b) Antigen‐specific T cells induced by natural infection or vaccination have a broad range of viral strain recognition, including different VOCs. Pathogenic T‐cell response: surrounded by a red hatched line, includes cellular components (d–g). (c) A huge inflammatory environment induces hyperactivation of both specific and unspecific T cells; (d) The strong production of inflammatory cytokines leads to overexpression of apoptotic processes inducing lymphocyte death; (e) Lymphocyte death is associated with lymphopenia, one the main markers of severe/fatal COVID‐19; (f) Bystander‐activated unspecific T cells contribute to tissue damage.

FIGURE 3

Protective and pathogenic pathways of the adaptive B‐cell response during SARS‐CoV‐2 infection. Protective B‐cell response: surrounded by a green hatched line. (a) In mild COVID‐19 (bottom), the germinal centre reaction generates memory B cells with different affinities for the virus, short‐lived plasmablasts (PB), and long‐lived plasma cells that home to the bone marrow. A fraction of the memory B cells migrate to the site of viral invasion and become resident memory B cells secreting IgA antibodies for local protection. A similar mechanism of protection is generated by vaccination. In breakthrough infections, vaccine‐induced memory B cells rapidly migrate to mucosal sites for local defence. Pathogenic B‐cell response: surrounded by a red hatched line. (b) The increase of inflammatory cytokines disrupts the architecture of the germinal centres by dislocating follicular T cells. The B‐cell response occurs at extrafollicular sites, where B cell remodelling and antigen‐based selection is impaired. At mucosal sites, natural/cross‐reactive antibodies try to limit viral invasion.