Innate immune and inflammatory responses to SARS-CoV-2: Implications for COVID-19

Abstract

COVID-19 can result in severe disease characterized by significant immunopathology that is spurred by an exuberant, yet dysregulated, innate immune response with a poor adaptive response. A limited and delayed interferon I (IFN-I) and IFN-III response results in exacerbated proinflammatory cytokine production and in extensive cellular infiltrates in the respiratory tract, resulting in lung pathology. The development of effective therapeutics for patients with severe COVID-19 depends on our understanding of the pathological elements of this unbalanced innate immune response. Here, we review the mechanisms by which SARS-CoV-2 both activates and antagonizes the IFN and inflammatory response following infection, how a dysregulated cytokine and cellular response contributes to immune-mediated pathology in COVID-19, and therapeutic strategies that target elements of the innate response.

Keywords: SARS-CoV-2; coronavirus; cytokines; immune antagonism; immune evasion; inflammatory; innate immunity; interferon.

Figure 1

Schematic of the SARS-CoV-2 genome SARS-CoV-2 is a 30 kb, positive-strand RNA virus with a genome divided into non-structural genes (Nsps) on the 5′ end (pink and blue boxes representing contributions from ORF1a and ORF1b [together, polyprotein 1ab, pp1ab] with numbered Nsps) and structural and accessory genes interspersed on the 3′ end. Nsps 1–16 are critical for viral replication and have some immune evasion functions, while the major structural genes spike (S), membrane (M), envelope (E), and nucleocapsid (N) make up the virion. Accessory genes 3a, 3b, 6, 7a, 7b, 8, 9b, 9c, and 10 are not necessary for viral replication, but may play a structural or immune evasion role, as seen in other CoV accessory proteins. Dotted lines represent magnified genome portions.

Figure 2

Innate immune antagonism by SARS-CoV-2 proteins Coronavirus replication occurs in double-membraned vesicles (DMVs), which can shield viral RNA (ssRNA and dsRNA) from recognition by PRRs such as TLR3, TLR7, RIG-I, and MDA5. These PRRs activate adaptors TRIF and MyD88 downstream of TLRs, and MAVS and TBK1 downstream of RIG-I and MDA5 beginning at the interferon production pathway. Activation of IRF3, IRF7, or NFκB results in their nuclear translocation and in the transcriptional activation of immune genes including inflammatory cytokines and IFN. The dotted line represents the transition to IFN signaling beginning with IFN-I binding IFNAR to initiate JAK/STAT signaling and formation of the ISGF3 complex STAT1/STAT2/IRF9, which translocates into the nucleus to activate ISRE transcription. SARS-CoV-2-encoded proteins (red) inhibit multiple aspects of these pathways, resulting in decreased IFN and altered proinflammatory cytokine expression. Many of the SARS-CoV-2 IFN antagonists have been identified by overexpression assays in vitro, and thus await in vivo confirmation of their role in the virus’s replication and pathogenesis (black).

Figure 3

Kinetics of the innate immune response to COVID-19 (A) A mild disease course is generally characterized by an IFN response that is robust, coincides with the peak of viral replication, results in rapid viral clearance, and is the resolution of IFN and of other inflammatory responses. As disease severity increases, the IFN-I and -III response is milder and delayed relative to viral replication. This allows for prolonged viral replication and for the prolonged expression of IFN and inflammatory cytokines that contribute to immune-mediated pathogenesis. (B) Based on animal models and available clinical data, IFN-I treatment at early time points (relative to viral replication and symptom onset) is expected to enhance virus clearance and the rapid resolution of the inflammatory response and clinical symptoms. Late IFN-I treatment is expected not to enhance viral clearance, nor reduce inflammatory cytokine and chemokine responses, producing no change or possibly exacerbated clinical symptoms.

Figure 4

Animal models of COVID-19 Various laboratory animals, particularly mice, hamsters, ferrets, and non-human primates, have been used to model different aspects of COVID-19 to develop antiviral drugs and to improve our understanding of COVID-19 disease in humans. Because mice are not naturally susceptible to initial isolates of SARS-CoV-2, due to the incompatibility of the virus with mouse ACE2, adenovirus-5-transduced human ACE2-transgenic mice (Ad5-hACE2) and hACE2-transgenic mice have been used to confer susceptibility. Wild-type (WT) mice can also be infected with mouse-adapted (MA) SARS-CoV-2. Hamsters and ferrets are naturally susceptible to SARS-CoV-2 infection and can transmit virus to uninfected animals, enabling studies of viral transmission. Non-human primates are also naturally susceptible to SARS-CoV-2 and, as the laboratory animal most closely related to humans, represent an important model for preclinical trials of therapeutics and vaccines (Muñoz-Fontela et al., 2020).