Profile Url: nico-marr
Researcher at HBKU
Four endemic human coronaviruses (HCoVs) are commonly associated with acute respiratory infection in humans. B cell responses to these “common cold” viruses remain incompletely understood. Here we report a comprehensive analysis of CoV-specific antibody repertoires in 231 children and 1168 adults using phage-immunoprecipitation sequencing. Seroprevalence of antibodies to endemic HCoVs ranged between ~4 and 27% depending on the species and cohort. We identified at least 136 novel linear B cell epitopes. Antibody repertoires against endemic HCoVs were qualitatively different between children and adults in that anti-HCoV IgG specificities more frequently found among children targeted functionally important and structurally conserved regions of the spike, nucleocapsid and matrix proteins. Moreover, antibody specificities targeting the highly conserved fusion peptide region and S2’ cleavage site of the spike protein were broadly cross-reactive with peptides of epidemic human and non-human coronaviruses. In contrast, an acidic tandem repeat in the N-terminal region of the Nsp3 subdomain of the HCoV-HKU1 polyprotein was the predominant target of antibody responses in adult donors. Our findings shed light on the dominant species-specific and pan-CoV target sites of human antibody responses to coronavirus infection, thereby providing important insights for the development of prophylactic or therapeutic monoclonal antibodies and vaccine design. ### Competing Interest Statement The authors have declared no competing interest.
The heterogeneity of COVID-19 lies within its diverse symptoms and severity, ranging from mild to lethal. Acute respiratory distress syndrome (ARDS) has been shown to be the leading cause of mortality in COVID-19 patients, characterized by a hyper cytokine storm. Autoimmunity is proposed to occur as a result of COVID-19, given the high similarity of the immune responses observed in COVID-19 and autoimmune diseases. Here, we investigate the level of autoimmune antibodies in COVID-19 patients with different severities. Initial screening for antinuclear antibodies (ANA) IgG revealed that 1.6% (2/126) and 4% (5/126) of ICU COVID-19 cases developed strong and moderate ANA levels, respectively. However, all the non-ICU cases (n=273) were ANA negative. The high ANA level was confirmed by immunofluorescence (IFA) and large-scale autoantibody screening by phage immunoprecipitation-sequencing (PhIP-Seq). Indeed, the majority of the samples showed "speckled" ANA pattern by microscopy, and we demonstrate that samples of ICU patients with strong and moderate ANA levels contain autoantibody specificities that predominantly targeted proteins involved in intracellular signal transduction, metabolism, apoptotic processes, and cell death; further denoting reactivity to nuclear and cytoplasmic antigens. In conclusion, our results further support the notion of routine screening for autoimmune responses in COVID-19 patients, which might help improve disease prognosis and patient management. Further, results provide compelling evidence that ANA-positive individuals should be excluded from being donors for convalescent plasma therapy in the context of Covid-19.
Inborn errors of human IFN-γ immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to an inherited deficiency of the transcription factor T-bet. This deficiency abolishes the expression of T-bet target genes, including IFNG , by altering chromatin accessibility and DNA methylation in CD4+ T cells. The patient has profoundly diminished counts of mycobacterial-reactive circulating NK, invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+ γδ T lymphocytes, and of non-mycobacterial-reactive classic TH1 lymphocytes, the remainders of which also produce abnormally low amounts of IFN-γ. Other IFN-γ-producing lymphocyte subsets however develop normally, but with low levels of IFN-γ production, with exception of Vδ2− γδ T lymphocytes, which produce normal amounts of IFN-γ in response to non-mycobacterial stimulation, and non-classic TH1 (TH1*) lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of, and IFN-γ production by, innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2+ γδ T cells), with mycobacterial-specific, IFN-γ-producing, purely adaptive αβ TH1* cells unable to compensate for this deficit. ### Competing Interest Statement Dr. Glimcher serves on the Board of Directors of GlaxoSmithKline Pharmaceutical Company and the Analog Device Corporation and formerly served on the Boards of Bristol Myers Squibb Pharmaceutical Company and the Waters Corporation. She is also on the Scientific Advisory Boards of Abpro, Kaleido, and Repare biotechnology companies. Dr. Casanova serves on the Scientific Advisory Boards of ADMA Biologics Inc., Celgene and Kymera Therapeutics, Inc.. He also consults for Elixiron Immunotherapeutics. Other authors declare no competing interests.
The relationship between viral infection and obesity has been known for several decades but epidemiological data related to obesity is limited to only a few viral pathogens. To identify associations between viral infections and obesity, a high-throughput virome-wide serological profiling tool, VirScan, was used to measure antibody responses to a wide range of viruses. Serum specimens from 457 Qatari adults (lean=184;obese=273) and 231 Qatari children (lean=111;obese=120) were assessed by VirScan. Pediatric specimens were simultaneously tested by conventional serology for several herpesviruses to validate VirScan results. Viral association with obesity was determined by calculation of odds ratio (OR) and p -values from Fisher test, and by multivariate regression analysis to adjust for age and gender, with Bonferroni correction for multiple testing. Comprehensive serological profiling of Qatari adult population with VirScan revealed positive and negative associations ( p <0.05) of antibody responses to members of Herpesviridae and Picornaviridae families, respectively, with obesity. After adjusting p -values for multiple comparisons, only herpes simplex virus 1 (HSV-1) and Rhinovirus A were positively (OR=3.3; 95%CI 2.15-4.99; p =2.787E-08) and negatively (OR=0.4; 95%CI 0.26-0.65; p =1.175E-03) associated with obesity. At the peptide level, higher prevalence of antibodies against several peptide epitopes of HSV-1/2 was positively (OR=2.35-3.82; p ≤3.981E-05) associated with obesity. No such associations were seen at the species or peptide levels in the pediatric population. By multivariate regression analysis, HSV-1 was independently associated with obesity irrespective of age and gender. These findings are in agreement with limited data on the adipogenic properties of HSV-1 observed in vitro. Importance The state of Qatar has one of the highest rates of obesity and associated morbidities in the world. Although obesity is predominantly caused by the intake of high calorie diet and reduced physical activities, other factors including infections with certain viruses have been reported. Among these viruses, human adenoviruses were widely studied but epidemiological data for other viruses in relation to human obesity are limited. Here, we studied the association of obesity in Qatari adults and children with a wide range of viral pathogens using VirScan, a virome-wide serological profiling tool. Our results indicate significant association HSV-1 with obesity in the adult population only. Furthermore, we have identified a set of HSV peptides as candidate obesogenic factors for future studies.