CLIA-certified laboratories were enrolled through the IMPACT biorepository study 15. In the IMPACT study, biospecimens including blood, nasopharyngeal swabs, saliva, urine and stool samples were collected at study enrolment (baseline denotes the first time point) and longitudinally on average every 3 to 7 days (serial time points). The detailed demographics and clinical characteristics of these 98 participants are shown in Extended Data Table 1. Plasma and peripheral blood mononuclear cells (PBMCs) were isolated from whole blood, and plasma was used for titre measurements of SARS-CoV-2 spike S1 protein-specific IgG and IgM antibodies (anti-S1-IgG and-IgM) and cytokine or chemokine measurements. Freshly isolated PBMCs were stained and analysed by flow cytometry 15. We obtained longitudinal serial time-point samples from a subset of these 98 study participants (n = 48; information in Extended Data Table 1). To compare the immune phenotypes between sexes, two sets of data analyses were performed in parallel-baseline and longitudinal, as described below. As a control group, healthcare workers (HCWs) from Yale-New Haven Hospital were enrolled who were uninfected with COVID-19. Demographics and background information for the HCW group and the demographics of HCWs for cytokine assays and flow cytometry assays for the primary analyses are in Extended Data Table 1. Demographic data, time-point information of the samples defined by the days from the symptom onset (DFSO) in each patient, treatment information, and raw data used to generate figures and tables is in Supplementary Table 1. Baseline analysis The baseline analysis was performed on samples from the first time point of patients who met the following criteria: not in intensive care unit (ICU), had not received tocilizumab, and had not received high doses of corticosteroids (prednisone equivalent of more than 40 mg) before the first sample collection date. This patient group, cohort A, consisted of 39 patients (17 male and 22 female) (Extended Data Tables 1, 2). Intersex and transgender individuals were not represented in this study. Figures 1-4 represent analyses of baseline raw values obtained from patients in cohort A. In cohort A patients, male and female patients were matched in terms of age, body mass index (BMI), and DFSO at the first time point sample collection (Extended Data Fig. 1a). However, there were significant differences in age and BMI between HCW controls and patients (patients had higher age and BMI values) (Extended Data Table 1), and therefore an age-and BMI-adjusted difference-indifferences analysis was also performed in parallel (Extended Data Table 3). Longitudinal analysis As parallel secondary analyses, we performed longitudinal analysis on a total patient cohort (cohort B) to evaluate the difference in immune response over the course of the disease between male and female patients. Cohort B included all patient samples from cohort A (including several time-point samples from the cohort A patients) as well as an additional 59 patients who d...

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus on the consequences of CNS infections. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in infected and neighboring neurons. However, no evidence for type I interferon responses was detected. We demonstrate that neuronal infection can be prevented by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate SARS-CoV-2 neuroinvasion in vivo. Finally, in autopsies from patients who died of COVID-19, we detect SARS-CoV-2 in cortical neurons and note pathological features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV-2 and an unexpected consequence of direct infection of neurons by SARS-CoV-2.

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COVID-19 manifests with a wide spectrum of clinical phenotypes that are characterized by exaggerated and misdirected host immune responses1–8. While pathological innate immune activation is well documented in severe disease1, the impact of autoantibodies on disease progression is less defined. Here, we used a high-throughput autoantibody discovery technique called Rapid Extracellular Antigen Profiling (REAP) to screen a cohort of 194 SARS-CoV-2 infected COVID-19 patients and healthcare workers for autoantibodies against 2,770 extracellular and secreted proteins (the “exoproteome”). We found that COVID-19 patients exhibit dramatic increases in autoantibody reactivities compared to uninfected controls, with a high prevalence of autoantibodies against immunomodulatory proteins including cytokines, chemokines, complement components, and cell surface proteins. We established that these autoantibodies perturb immune function and impair virological control by inhibiting immunoreceptor signaling and by altering peripheral immune cell composition, and found that murine surrogates of these autoantibodies exacerbate disease severity in a mouse model of SARS-CoV-2 infection. Analysis of autoantibodies against tissue-associated antigens revealed associations with specific clinical characteristics and disease severity. In summary, these findings implicate a pathological role for exoproteome-directed autoantibodies in COVID-19 with diverse impacts on immune functionality and associations with clinical outcomes.

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Reports indicate that 30-60% of patients with COVID-19 suffer from CNS symptoms. Yet, there is no consensus whether the virus can infect the brain, or what the consequences of infection are. Following SARS-CoV-2 infection of human brain organoids, clear evidence of infection was observed, with accompanying metabolic changes in the infected and neighboring neurons. Further, no evidence for the type I interferon responses was detected. We demonstrate that neuronal infection can be prevented either by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Finally, using mice overexpressing human ACE2, we demonstrate in vivo that SARS-CoV-2 neuroinvasion, but not respiratory infection, is associated with mortality. These results provide evidence for the neuroinvasive capacity of SARS-CoV2, and an unexpected consequence of direct infection of neurons by SARS-CoV2.