Human genetic and immunological determinants of critical COVID-19 pneumonia

Abstract

SARS-CoV-2 infection is benign in most individuals but, in around 10% of cases, it triggers hypoxaemic COVID-19 pneumonia, which leads to critical illness in around 3% of cases. The ensuing risk of death (approximately 1% across age and gender) doubles every five years from childhood onwards and is around 1.5 times greater in men than in women. Here we review the molecular and cellular determinants of critical COVID-19 pneumonia. Inborn errors of type I interferons (IFNs), including autosomal TLR3 and X-chromosome-linked TLR7 deficiencies, are found in around 1-5% of patients with critical pneumonia under 60 years old, and a lower proportion in older patients. Pre-existing auto-antibodies neutralizing IFNα, IFNβ and/or IFNω, which are more common in men than in women, are found in approximately 15-20% of patients with critical pneumonia over 70 years old, and a lower proportion in younger patients. Thus, at least 15% of cases of critical COVID-19 pneumonia can be explained. The TLR3- and TLR7-dependent production of type I IFNs by respiratory epithelial cells and plasmacytoid dendritic cells, respectively, is essential for host defence against SARS-CoV-2. In ways that can depend on age and sex, insufficient type I IFN immunity in the respiratory tract during the first few days of infection may account for the spread of the virus, leading to pulmonary and systemic inflammation.

Figure 1.. Inborn errors of type I IFN immunity and autoantibodies neutralizing type I IFNs underlie life-threatening COVID-19 pneumonia by interfering with type I IFN immunity in tissue-resident respiratory epithelial cells and blood plasmacytoid dendritic cells.

There are 17 human type I IFNs, each encoded by a specific, intron-less gene: 13 subtypes of IFN-α, IFN-β, IFN-ε, IFN-κ, and IFN-ω, and three human type III IFNs (IFN-λ1-3). Autoantibodies to IFN-α, IFN-β, and/or IFN-ω have been identified in about 15% of patients with critical COVID-19 pneumonia. Monogenic inborn errors of TLR3- and/or TLR7-dependent type I IFN immunity have been identified in about 1-5% of patients with critical COVID-19 pneumonia (genes shown in red). SARS-CoV-2 infection can induce type I IFN production in a TLR3-dependent manner in tissue-resident respiratory epithelial cells (RECs, which express TLR3 but not TLR7) and in a TLR7-dependent manner in circulating plasmacytoid dendritic cells (pDCs, which express TLR7 but not TLR3)^[200]. IRF7 is constitutively expressed in pDCs, at higher levels than in other cell types, whereas it is mostly induced by viral infection in RECs^[200]. IRF7 activation is required to produce type I IFNs other than IFN-β^[33]. IFN: interferon; Auto-Ab: autoantibody, ISGs: interferon-stimulated genes.

Figure 2.. Inborn errors of type I IFN immunity and autoantibodies neutralizing type I IFNs underlie life-threatening COVID-19 pneumonia by facilitating the spread of the virus during the first few days of infection, triggering secondary leukocytic inflammation.

In a two-step model of pathogenesis of critical COVID-19^[12], inadequate type I IFN immunity during the first few hours and days of infection results in the spread of the virus to the lungs, blood, and beyond. This results, one to two weeks later, in pulmonary and systemic hyperinflammation, largely due to the recruitment and activation of leukocytes, which produce excessive amounts of cytokines in a last-ditch attempt to eradicate the virus that should have been eradicated by type I IFN but was not. The two-step model suggests that early administration of type I IFN at the onset of SARS-CoV-2 infection, in ambulatory patients, or even before infection in exposed individuals at risk of severe disease, may halt disease progression in patients without auto-Abs to the corresponding type I IFN and without IEIs downstream from type I IFN receptors. IFN: interferon; IEI: inborn errors of immunity; Auto-Ab: autoantibody, ISGs: interferon-stimulated genes.

Figure 3.. Inborn errors of type I IFN immunity and autoantibodies neutralizing type I IFNs underlie life-threatening COVID-19 pneumonia by aggravating the natural age-dependent decline of type I IFN immunity in the mucosae and blood.

Inborn errors of type I IFN immunity conferring predisposition to critical COVID-19 pneumonia are represented in slightly declining proportion across age groups in the general population, as they may underlie critical influenza and related life-threatening viral illnesses. In contrast the frequency of auto-Abs against type I IFN increases exponentially after the age of 65 years (y axis on the left), attesting to a breakdown of tolerance in the elderly population. Global type I IFN immunity in the respiratory tract mucosae (RECs) and in the blood (pDCs) is shown to decline with age, under the influence of aging and environmental triggers^{[190, 191]}. This decline in global type I IFN immunity over time may increase the risk of life-threatening COVID-19 (referred to as penetrance, for both IEI and autoantibodies) associated with genetic and immunological etiologies in elderly patients. All three risk factors — IEIs, auto-Abs, and tonic levels of type I IFNs — may contribute to critical COVID-19 pneumonia (right panel). IEIs and auto-Abs appear to affect different patients, while the gradual decrease in tonic levels of type I IFNs can aggravate the consequences of both IEIs and auto-Ab. Overall, the cohort of patients with life-threatening COVID-19 is enriched with IEI in young patients and with auto-Abs in elderly patients. IEI: inborn errors of immunity; IFR: infection-fatality ratio; auto-Ab: autoantibody.