COVID-19: Immunology and treatment options

Abstract

The novel coronavirus SARS-CoV2 causes COVID-19, a pandemic threatening millions. As protective immunity does not exist in humans and the virus is capable of escaping innate immune responses, it can proliferate, unhindered, in primarily infected tissues. Subsequent cell death results in the release of virus particles and intracellular components to the extracellular space, which result in immune cell recruitment, the generation of immune complexes and associated damage. Infection of monocytes/macrophages and/or recruitment of uninfected immune cells can result in massive inflammatory responses later in the disease. Uncontrolled production of pro-inflammatory mediators contributes to ARDS and cytokine storm syndrome. Antiviral agents and immune modulating treatments are currently being trialled. Understanding immune evasion strategies of SARS-CoV2 and the resulting delayed massive immune response will result in the identification of biomarkers that predict outcomes as well as phenotype and disease stage specific treatments that will likely include both antiviral and immune modulating agents.

Fig. 1

Structure of SARS-CoV2. The spike protein (S) facilitates binding to the trans-membrane ACE2 host receptor; the envelope (E) protein together with the membrane (M) protein form the viral envelope and determine its shape; the hemagglutinin esterase (HE) protein may resemble another cell entry mechanism of novel CoVs; the nucleocapsid (N) protein in bound to the RNA genome of the virus to form the nucleocapsid.

Fig. 2

Immune evasion strategies of SARS-CoV2. A) SARS-CoV2 infects airway epithelial cells through interactions with the trans-membrane enzyme ACE2 (a). While RNA viruses usually activate TLR3 and/or 7 in endosomes (b) and cytosolic RNA sensors RIG-I and MDA-5 (c), SARS-COV2 effectively suppresses the activation of TNF receptor-associated factors (TRAF) 3 and 6, thereby limiting activation of the transcription factors NFκB and IRF3 and 7, thereby suppressing early pro-inflammatory responses through type I interferons (IFN) and pro-inflammatory effector cytokines IL-1, IL-6 and TNF-α (red symbols). Furthermore, novel CoVs inhibit the activation of STAT transcription factors (d) in response to type I IFN receptor activation, which further limits antiviral response mechanisms. Altogether, this prohibits virus containment through activation of anti-viral programs and the recruitment of immune cells. B) Tissue monocytes/macrophages express ACE2 to a significantly lower extent, making infection through this route less likely (a). However, immune complexes consisting of ineffective antibodies against e.g. seasonal CoVs and virus particles may be taken up by macrophages through Fcγ receptors resulting in their infection (b). In a process referred to as antibody directed enhancement (ADE), virions inhibit type I IFN signaling in infected macrophages while allowing pro-inflammatory IL-1, IL-6 and TNF-α expression, which may contribute to hyperinflammation and cytokine storm syndrome (c,d). Inhibited type 1 IFN signaling suppresses anti-viral programs, while increased IL-1, IL-6 and TNF-α expression auto-amplifies itself through positive feedback loops (f).

Fig. 3

Inflammatory response through monocytes macrophages. Uninfected monocytes/macrophages from the blood stream invade the lungs where they detect virus particles and/or cytoplasmic and nuclear components. Within immune complexes, these particles are taken up into the cell (a) where they are presented to TLRs, activating NFκB and/or IRF dependent pro-inflammatory pathways (b,c). As a result, uninfected monocytes/macrophages produce significant amounts of pro-inflammatory cytokines (d,e) which recruit additional innate and adaptive immune cells and cause additional tissue damage.

Fig. 4

Inflammatory mechanisms in immune complex vasculitis.

Fig. 5

Potential therapeutic targets in COVID-19. While no approved and evidence-based treatments are available for COVID-19, a number of treatments promise potential. Virus particles may be caught and inactivated using antibodies from convalescent patients. Recombinant soluble ACE2 protein may bind SARS-CoV2 and/or mediate anti-inflammatory effects to prevent pulmonary damage and hyper-inflammation. (Hydroxy-)chloroquine, potentially in combination with azithromycin), can change the pH of endosomes and reduce virus entry and replication. Furthermore, both medications have immune-modulating effects that may control pro-inflammatory cytokine expression. Anti-viral treatment with protease inhibitors (lopinavir, ritonavir, etc.) and/or nucleoside analogues (remdesivir, etc.) can limit virus replication. As SARS-CoV2 suppresses antiviral cytokine production, virus clearance may also be supported by the substitution of type 1 interferons, which activate their cytokine receptor (IFNAR) and induce anti-viral cellular programs. Hyperinflammation and resulting tissue damage may be prevented through immune modulation. Blocking IL-1 signaling (e.g. through recombinant IL-1 receptor antagonist anakinra) or IL-6 signaling (e.g. through IL-6 receptor antibody tocilizumab) may limit further immune activation, tissue damage and cytokine storms. Additional, less specific effects may be mediated through corticosteroids, immunoglobulins, hydroxychloroquine and/or azithromycin.