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Studies have demonstrated that at least 20% of individuals infected with SARS-CoV-2 remain asymptomatic1-4. Although most global efforts have focused on severe illness in COVID-19, examining asymptomatic infection provides a unique opportunity to consider early immunological features that promote rapid viral clearance. Here, postulating that variation in the human leukocyte antigen (HLA) loci may underly processes mediating asymptomatic infection, we enrolled 29,947 individuals, for whom high-resolution HLA genotyping data were available, in a smartphone-based study designed to track COVID-19 symptoms and outcomes. Our discovery cohort (n = 1,428) comprised unvaccinated individuals who reported a positive test result for SARS-CoV-2. We tested for association of five HLA loci with disease course and identified a strong association between HLA-B*15:01 and asymptomatic infection, observed in two independent cohorts. Suggesting that this genetic association is due to pre-existing T cell immunity, we show that T cells from pre-pandemic samples from individuals carrying HLA-B*15:01 were reactive to the immunodominant SARS-CoV-2 S-derived peptide NQKLIANQF. The majority of the reactive T cells displayed a memory phenotype, were highly polyfunctional and were cross-reactive to a peptide derived from seasonal coronaviruses. The crystal structure of HLA-B*15:01-peptide complexes demonstrates that the peptides NQKLIANQF and NQKLIANAF (from OC43-CoV and HKU1-CoV) share a similar ability to be stabilized and presented by HLA-B*15:01. Finally, we show that the structural similarity of the peptides underpins T cell cross-reactivity of high-affinity public T cell receptors, providing the molecular basis for HLA-B*15:01-mediated pre-existing immunity.

Preexisting anti–interferon-α (anti–IFN-α) autoantibodies in blood are associated with susceptibility to life-threatening COVID-19. However, it is unclear whether anti–IFN-α autoantibodies in the airways, the initial site of infection, can also determine disease outcomes. In this study, we developed a multiparameter technology, FlowBEAT, to quantify and profile the isotypes of anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and anti–IFN-α antibodies in longitudinal samples collected over 20 months from the airways and blood of 129 donors spanning mild to severe COVID-19. We found that nasal IgA1 anti–IFN-α autoantibodies were induced after infection onset in more than 70% of mild and moderate COVID-19 cases and were associated with robust anti–SARS-CoV-2 immunity, fewer symptoms, and efficient recovery. Nasal anti–IFN-α autoantibodies followed the peak of host IFN-α production and waned with disease recovery, revealing a regulated balance between IFN-α and anti–IFN-α response. In contrast, systemic IgG1 anti–IFN-α autoantibodies appeared later and were detected only in a subset of patients with elevated systemic inflammation and worsening symptoms. These data reveal a protective role for nasal anti–IFN-α in the immunopathology of COVID-19 and suggest that anti–IFN-α autoantibodies may serve a homeostatic function to regulate host IFN-α after viral infection in the respiratory mucosa. Editor's summary: Autoantibodies targeting interferon-α (IFN-α) have been found in the circulation of those with severe COVID-19 and are considered a bad sign for disease progression. However, less is known about IFN-α–specific autoantibodies in other tissues, such as the mucosa. Here, Babcock et al. used a multiparameter flow cytometry technique called FlowBEAT to show that IgA1 autoantibodies targeting IFN-α could be found in the nasal mucosa and were associated with improved responses to SARS-CoV-2. The induction of these anti–IFN-α autoantibodies was temporally linked to a decline in IFN-α itself, suggesting that elicitation of these autoantibodies may be a mechanism to temper inflammation in the respiratory mucosa. These data suggest that there is a complex, location-dependent, role for antibodies against IFN-α and that these antibodies may tip the balance between protection and pathology. —Courtney Malo [ABSTRACT FROM AUTHOR]

Meckel's diverticulum (MD) is known to cause surgical emergencies including intussusception, obstruction, and bleeding, but rarely results in perforation with pneumoperitoneum. Symptomatic MD is rare but most commonly presents in early childhood. We report a case of a 17-year-old male who presented with peritonitis and radiographic imaging demonstrating pneumoperitoneum and inflammation near the appendix and terminal ileum. Intraoperative findings revealed a perforated MD. A perforated MD may mimic a diagnosis of complicated appendicitis in the adolescent and adult population and should be considered in the differential diagnosis of patients presenting with pneumoperitoneum and an acute surgical abdomen., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Beltran et al.)