Antiviral innate immunity is diminished in the upper respiratory tract of severe COVID-19 patients

Abstract

Understanding early innate immune responses to coronavirus disease 2019 (COVID‐19) is crucial to developing targeted therapies to mitigate disease severity. Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infection elicits interferon expression leading to transcription of IFN-stimulated genes (ISGs) to control viral replication and spread. SARS-CoV-2 infection also elicits NF-κB signaling which regulates inflammatory cytokine expression contributing to viral control and likely disease severity. Few studies have simultaneously characterized these two components of innate immunity to COVID-19. We designed a study to characterize the expression of interferon alpha-2 (IFNA2) and interferon beta-1 (IFNB1), both type-1 interferons (IFN-1), interferon-gamma (IFNG), a type-2 interferon (IFN-2), ISGs, and NF-κB response genes in the upper respiratory tract (URT) of patients with mild (outpatient) versus severe (hospitalized) COVID-19. Further, we characterized the weekly dynamics of these responses in the upper and lower respiratory tracts (LRTs) and blood of severe patients to evaluate for compartmental differences. We observed significantly increased ISG and NF-κB responses in the URT of mild compared with severe patients early during illness. This pattern was associated with increased IFNA2 and IFNG expression in the URT of mild patients, a trend toward increased IFNB1-expression and significantly increased STING/IRF3/cGAS expression in the URT of severe patients. Our by-week across-compartment analysis in severe patients revealed significantly higher ISG responses in the blood compared with the URT and LRT of these patients during the first week of illness, despite significantly lower expression of IFNA2, IFNB1, and IFNG in blood. NF-κB responses, however, were significantly elevated in the LRT compared with the URT and blood of severe patients during peak illness (week 2). Our data support that severe COVID-19 is associated with impaired interferon signaling in the URT during early illness and robust pro-inflammatory responses in the LRT during peak illness.

Interferon signaling in the nasal epithelium distinguishes among lethal and common cold respiratory viruses and is critical for viral clearance

“…Viruses such as HRV-16, HCoV-229E, and HCoV-NL63 are typically associated with upper respiratory tract replication and symptoms, as well as early resolution of infection. Reports of IFN-mediated restriction of HRVs, as well as recent nasopharyngeal sequencing studies of COVID-19 patients that correlate early nasal IFN induction with reduced disease severity suggest that IFN responses in the nasal epithelium may be critical determinants of disease course 16–18,66,67 . Relatively few studies have utilized nasal cell models to compare common cold-associated viruses with more lethal respiratory viruses.…”

“…Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID- 19), causes a spectrum of respiratory disease ranging from asymptomatic infections to lethal pneumonia. Sequencing studies of nasopharyngeal swabs acquired from COVID-19 patients have correlated early IFN response signatures in patients' noses with reduced disease severity, whereas patients with muted ISG profiles tended to have worse outcomes [16][17][18] . Consistent with antiviral IFN responses in the nose as determinants of disease outcome, nasally delivered IFN has shown promise as an antiviral strategy in various animal models of SARS-CoV-2 19,20 .…”

“…Thus, the omicron BA.1 variant has a unique phenotype, whereby it induces stronger IFN responses in nasal cell cultures than SARS-CoV-2 WA-1 but exhibits reduced IFN sensitivity and therefore does not illustrate temperature sensitivity nor does it undergo IFN-mediated clearance.Efficient induction of antiviral IFN signaling in the nasal epithelium has the potential to restrict the spread of respiratory viruses to the lower airway, thus preventing the development of more severe lung disease. Viruses such as HRV-16, HCoV-229E, and HCoV-NL63 are typically associated with upper respiratory tract replication and symptoms, as well as early resolution of infection.Reports of IFN-mediated restriction of HRVs, as well as recent nasopharyngeal sequencing studies of COVID-19 patients that correlate early nasal IFN induction with reduced disease severity suggest that IFN responses in the nasal epithelium may be critical determinants of disease course[16][17][18]66,67 . Relatively few studies have utilized nasal cell models to compare common cold-associated viruses with more lethal respiratory viruses.…”

Innate and Adaptive Immunity during SARS-CoV-2 Infection: Biomolecular Cellular Markers and Mechanisms

“…It is of note that type II IFN and type III IFN can be secreted by NK and T cells, and few studies document whether type III IFN affects antibody class-switching. Therefore, as a key mediator of anti-viral responses within the respiratory tract, it is now being seen that IFNA2 and IFNG gene expression in the respiratory tract is accompanied by increases in IFNB1, and also with reduced early IFNA2, but that this IFN response seems to occur in sera rather than tissues [ 83 , 84 , 85 ].…”