COVID-19 and the human innate immune system

Abstract

The introduction of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the human population represents a tremendous medical and economic crisis. Innate immunity-as the first line of defense of our immune system-plays a central role in combating this novel virus. Here, we provide a conceptual framework for the interaction of the human innate immune system with SARS-CoV-2 to link the clinical observations with experimental findings that have been made during the first year of the pandemic. We review evidence that variability in innate immune system components among humans is a main contributor to the heterogeneous disease courses observed for coronavirus disease 2019 (COVID-19), the disease spectrum induced by SARS-CoV-2. A better understanding of the pathophysiological mechanisms observed for cells and soluble mediators involved in innate immunity is a prerequisite for the development of diagnostic markers and therapeutic strategies targeting COVID-19. However, this will also require additional studies addressing causality of events, which so far are lagging behind.

Keywords: COVID-19; SARS-CoV-2; genetics; granulocytes; immunosuppressive cells; innate immunity; interferon; monocytes; pandemic; trained immunity; viral sepsis.

Figure 1

Conceptualizing the interaction between the host immune response and the virus Proposed fields of research along the disease trajectory in five phases that influence pathophysiology with an emphasis on innate immunity. Methodologies suggested to be applied for addressing certain areas are represented as color-coded circles. These reflect frequently used methods in previously published studies on COVID-19. This is only a selection and we make no claim to completeness. The overall concept could be extended to the adaptive immune system and other organ systems. CyTOF, cytometry by time of flight, mass cytometry; ELISA; OLINK, plasma proteome by proximity extension assay; scRNA-seq, single-cell RNA sequencing; seq, sequencing; WGS, whole genome sequencing.

Figure 2

SARS-CoV-2 tropism, infection, and alarming the innate immune system (A) Major entry sites of SARS-CoV-2 via cells within the nasal cavity and the upper and lower respiratory tract. (B) Molecular determinants during SARS-CoV-2 infection of a cell. (C) SARS-CoV-2 is most likely recognized by PRRs recognizing foreign RNA including endosomal TLR3 and TLR7 as well as by cytoplasmic RIG-I and MDA5. Predicted downstream signaling events based on findings from genetic studies, functional and clinical observations, interaction mapping, or CRISPR screens. Interactions between SARS-CoV-2-derived proteins and cellular mechanisms or in case of interaction mapping derived information, detection of direct interaction between viral or host proteins. ORF3b was functionally determined to suppress type I IFN, but a direct target was not identified (Konno et al., 2020). ACE2, angiotensin-converting enzyme 2; IFNAR1, interferon-alpha/beta receptor alpha chain; IκB, inhibitor of κB; IKKα/ꞵ/γ/ε, IκB kinase α/ꞵ/γ/ε; IRAK1/4, interleukin-1 receptor-associated kinase 1/4; IRF3/7/9, interferon regulatory factor 3/7/9; ISG, interferon-stimulated genes; MDA5, melanoma differentiation-associated protein 5, RIG-I-like receptor dsRNA helicase enzyme; MyD88, myeloid differentiation primary response 88; NAP1, NF-κB-activating kinase-associated protein 1; NRP1, neuropilin 1; NSP, non-structural proteins of SARS-CoV-2; ORF, open reading frames of SARS-CoV-2; p50/65, the two subunits of NF-κB; RIG-1, retinoic acid-inducible gene I, a cytoplasmic pattern recognition receptor recognizing double-stranded RNA; RIP1, receptor interacting serine/threonine kinase 1; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; STAT1/2, signal transducer and activator of transcription 1/2; TAB1/2, TGF-beta activated kinase 1 binding protein 1/2; TAK1, TGF-beta activated kinase (encoded by MAP3K7); TBK1, TANK-binding kinase 1; TLR3, Toll-like receptor 3, CD283; TLR7/8, complex of Toll-like receptors 7 and 8, TLR7 also known as CD287 and CD288, respectively; TMPRSS2, transmembrane protease, serine 2; TRAF3/6, TNF receptor-associated factor 3/6; TRIF, TIR-domain-containing adaptor-inducing interferon-β; TYK2, tyrosine kinase 2; UNC93B1, Unc-93 homolog B1.

Figure 3

Soluble mediators during the disease course of COVID-19 Summarizing the principles established by many observational studies addressing the role of soluble mediators of the innate immune system. In red color severe (critical and fatal) disease courses, in yellow mild to moderate disease courses. (1) The term “days from symptom onset” is increasingly used to determine the kinetics of the disease. For this term, it needs to be considered that there exists variance in interpretation as well as in the time from infection to first symptoms, which is illustrated by the fading colors in the graph. (2 and 3) Temporal phases of COVID-19 have not been defined equally in all studies. However, in the majority of studies, “early” (2) describes the period up to 10 days after onset of symptoms, and “late” (3) the period from approximately days 11–25 after onset of symptoms. (4) Admission to hospital had been used initially, because it is a concrete data point. However, the time from viral infection to hospital admission can vary significantly, which complicates comparability of longitudinal studies using admission to hospital as the starting point. (5) Viral detection levels over time summarized following findings reported in Lucas et al. (2020). (6) The early local innate immune responses are very difficult to capture in a clinical setting since the time of viral infection is not known for most patients. Evidence from model systems indicate that type I and III IFN responses are most important; however, the magnitude and exact kinetic of this response in severe versus mild COVID-19 is still under debate. (7) Local innate immune responses (mainly in upper and lower respiratory tract). In addition to chemokines, some reports also mention proinflammatory mediators. Data for later time points are still rare. (8–10) Most often mentioned soluble markers in plasma or serum of patients with mild (8), moderate to severe (9) disease, or critically ill COVID-19 patients (including fatal outcomes) (10), mainly at the end of the first week and the beginning of the second week, at the end of the first week and the beginning of the second week, and at later time points, respectively. Asymptomatic SARS-CoV-2 infections have been shown to exhibit lower levels of cytokines (Long et al., 2020). Depending on study design and methodology, not all markers have been measured in all studies and at all time points.

Figure 4

Cellular changes during COVID-19 Depicted are the COVID-19-associated changes for the innate immune cells stratified by common disease characteristics (middle column) or such associated with either mild or severe disease courses, as well as stratified by location (local versus systemic) and time. ISG, interferon response gene; Mac, macrophage; mDC, myeloid dendritic cell; NKG2A, NK cell receptor (CD159a) encoded by killer cell lectin lectin-like receptor C1, KLRC1; pDC, plasmacytoid dendritic cell; SPP1, secreted phosphoprotein 1 (coding for osteopontin); TGF-B2, transforming growth factor beta 2; TIM3, T cell immunoglobulin and mucin domain-containing 3 (also known as hepatitis A virus cellular receptor 2, HAVCR2); TREM2, triggering receptor expressed on myeloid cells 2.

Figure 5

Genetic factors for COVID-19 susceptibility support the central role of the innate immune system The studies highlighted have already identified several loss-of-function mutations in molecules involved in the recognition of SARS-CoV-2 as well as important downstream signaling molecules important for a well-orchestrated and robust type I IFN response. Genes, for which loss-of-function mutations were identified, are depicted in bold pink with a pink circle. The autoimmune phenocopy of inborn type I IFN immunodeficiency is also depicted. For abbreviations, see Figure 2 legend.

Figure 6

Summary of current knowledge, outlook, and open questions Established disease courses describing cell and organ involvement during different phases of COVID-19 including the possibility of not only returning to homeostasis (convalescence) but also the potential chronification of the disease (“Long COVID-19”). Possible COVID-19 disease courses are depicted as differently colored curves of disease severity over time. Major open questions and future tasks concerning the innate immune response to SARS-CoV-2 are outlined along the five phases at the bottom of the figure.