An early, transient Interferon-associated innate immune response associates with protection from SARS-CoV-2 infection

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A proportion of individuals exposed to respiratory viruses avoid contracting detectable infection. We tested the hypothesis that early innate immune responses associate with resistance to detectable infection in close contacts of COVID-19 cases. 48 recently-exposed household contacts of symptomatic COVID-19 cases were recruited in London, UK between May 2020 and March 2021 through a prospective, longitudinal observational study. Blood and nose and throat swabs were collected during the acute period of index case viral shedding and longitudinally thereafter. Magnitude of SARS-CoV-2 exposure was quantified, and serial PCR and serological assays used to determine infection status of contacts. Whole-blood RNA-seq was performed and analysed to identify transcriptomic signatures of early infection and resistance to infection. 24 highly-exposed household contacts became PCR-positive and seropositive whilst 24 remained persistently PCR-negative and seronegative. A 96-gene transcriptomic signature of early SARS-CoV-2 infection was identified using RNA-seq of longitudinal blood samples from PCR-positive contacts. This signature was dominated by interferon-associated genes and expression correlated positively with viral load. Elevated expression of this 96-gene signature was also observed during exposure in 25% (6/24) of persistently PCR-negative, seronegative contacts. PCR-negative contacts with elevated signature expression had higher-magnitude SARS-CoV-2 exposure compared to those with low signature expression. We validated this signature in SARS-CoV-2-infected individuals in two independent cohorts. In naturally-exposed healthcare workers (HCWs) we found that 7/58 (12%) PCR-negative HCWs exhibited elevated signature expression. Comparing gene-signature expression in SARS-CoV-2 Controlled Human Infection Model (CHIM) volunteers pre- and post-inoculation, we observed that 14 signature genes were transiently upregulated as soon as 6hr post-inoculation in PCR-negative volunteers, while in PCR-positive volunteers gene-signature upregulation did not occur until 3 days later. Our interferon-associated signature of early SARS-CoV-2 infection characterises a subgroup of exposed, uninfected contacts in three independent cohorts who may have successfully aborted infection prior to induction of adaptive immunity. The earlier transient upregulation of signature genes in PCR-negative compared to PCR-positive CHIM volunteers suggests that ultra-early interferon-associated innate immune responses correlate with, and may contribute to, protection against SARS-CoV-2 infection. This work was supported by the NIHR Health Protection Research Unit in Respiratory Infections, United Kingdom, NIHR Imperial College London, United Kingdom (Grant number: NIHR200927; AL) in partnership with the UK Health Security Agency and the NIHR Medical Research Council (MRC), United Kingdom (Grant number: MR/X004058/1). Support for sequencing was provided by the Imperial BRC Genomics Facility which is funded by the NIHR, United Kingdom. The development of the hybrid DABA assay used for quantification of SARS-CoV-2 anti-Spike RBD antibodies was supported by the MRC (MC_PC_19078).