Defective activation and regulation of type I interferon immunity is associated with increasing COVID-19 severity

Abstract

Host immunity to infection with SARS-CoV-2 is highly variable, dictating diverse clinical outcomes ranging from asymptomatic to severe disease and death. We previously reported reduced type I interferon in severe COVID-19 patients preceded clinical worsening. Further studies identified genetic mutations in loci of the TLR3- or TLR7-dependent interferon-I pathways, or neutralizing interferon-I autoantibodies as risk factors for development of COVID-19 pneumonia. Here we show in patient cohorts with different severities of COVID-19, that baseline plasma interferon α measures differ according to the immunoassay used, timing of sampling, the interferon α subtype measured, and the presence of autoantibodies. We also show a consistently reduced induction of interferon-I proteins in hospitalized COVID-19 patients upon immune stimulation, that is not associated with detectable neutralizing autoantibodies against interferon α or interferon ω. Intracellular proteomic analysis shows increased monocyte numbers in hospitalized COVID-19 patients but impaired interferon-I response after stimulation. We confirm this by ex vivo whole blood stimulation with interferon-I which induces transcriptomic responses associated with inflammation in hospitalized COVID-19 patients, that is not seen in controls or non-hospitalized moderate cases. These results may explain the dichotomy of the poor clinical response to interferon-I based treatments in late stage COVID-19, despite the importance of interferon-I in early acute infection and may guide alternative therapeutic strategies.

Characterisation of the pro-inflammatory cytokine signature in severe COVID-19

“…One of the most important centres around the temporal association between immune markers and how these relate to disease trajectories and outcomes. For instance, recent studies have demonstrating that the timing when cytokines are measured may be critical in understanding the immune response in acute COVID-19 (58) understanding which markers are elevated at each stage of the disease and how this relates to COVID-19 outcomes is an important area for research in identifying different inflammatory phenotypes for targeted therapy in acute COVID-19. Approaches such as point-of-care testing for inflammatory markers and detailed characterisation of the immune response in COVID-19 may allow targeted treatment for different immune sub-phenotypes in both severe COVID-19 other critical illness states (59).…”

“…One of the most important centres around the temporal association between immune markers and how these relate to disease trajectories and outcomes. For instance, recent studies have demonstrating that the timing when cytokines are measured may be critical in understanding the immune response in acute COVID-19 ( 58 ). Further understanding which markers are elevated at each stage of the disease and how this relates to COVID-19 outcomes is an important area for future research in identifying different inflammatory phenotypes for targeted therapy in acute COVID-19.…”

NULISA: a novel proteomic liquid biopsy platform with attomolar sensitivity and high multiplexing

“…In particular, we observed robust and sustained induction of all three types of interferons in patients with mild disease. Type I and type III interferons are the body's first-line defense against viral replication and spreading at the site of infection 38,39 , but their detection in the blood requires ultra-high sensitivity 40 . One previous study was unable to detect circulating IFNB and IFNG in COVID-19 patient sera using traditional ELISA 41 , and another study using the more sensitive SIMOA assay was able to detect IFNA in some patients but not in controls 27 .…”

“…To our knowledge, the current study is the first to report the detection of IFNW1 in circulation and the detection of all three interferon types in a single assay. In fact, the different detection sensitivities of different assays used in various studies might have contributed to discrepant findings regarding the relationship between interferons and disease severity 40 . Some studies found a less pronounced interferon alpha response in patients with severe disease than in those with mild disease 41,42 , another study reported persistently higher interferon alpha and lambda levels in patients with severe disease than in those with moderate disease 43 , and yet another study found no association between interferon alpha levels and disease severity 28 .…”

Comprehensive assessment and diagnostic value of the parameters of the immune system associated with susceptibility and resistance to COVID-19

“…Опубликованные исследования выявили генетические мутации в локусах TLR3-или TLR7-зависимых путей интерферона-I с синтезом нейтрализующие аутоантитела к интерферону альфа [18]. Исходно высокий уровень, вероятно, снижает чувствительность рецепторов к интерферону и в результате отсутствие противовирусного действия [19] при тяжёлом течении COVID-19 [21], поскольку образование ловушек может спровоцировать иммунотромбоз, обусловленный активацией тромбоцитов и нейтрофилов [22].…”