ABSTRACT
PurposeMolecular mechanisms underlying COVID-19 susceptibility and severity are still poorly understood. The presence of genetic risk factors associated with ethnic background has been suggested, highlighting non-European ancestry as a risk factor for hospitalization in the United States. However, the representation of non-European populations in genomic case-control and cohort studies remains insufficient, and Latin American populations have been significantly understudied. Addressing this gap, we established The Chilean COVID-19 Biorepository, a multicentric endeavor comprising high-quality biological samples and associated data collected throughout Chile under stringent biobanking standards that ensure high quality, reproducibility, and interoperability. ParticipantsThe Chilean COVID-19 Biorepository was established by a network of nine nodes distributed in five macro-zones nationwide. The study enrolled adult participants living in Chile who had tested positive for SARS-CoV-2 infection and provided broad written informed consent. Blood samples were collected with EDTA and processed to store blood, plasma, buffy-coat, and DNA. Quality control measures, such as Standard Preanalytical Code (SPREC), incident reporting, DNA concentration, and absorbance ratio (260/280), were implemented to ensure the reliability and quality of the collected samples. Sociodemographic data, habits, clinical information, use of medications, and preexisting pathologies were registered. A weekly iterative workflow was implemented to ensure the quality and integrity of specimens and data. Findings to dateBetween October 2020 and February 2021, 2262 participants were recruited, pseudonymized, and categorized by disease severity into six categories, from asymptomatic to lethal. Notably, the Biorepository exhibited high compliance rates (>90%) across all quality control assessed items, reflecting high adherence to biobanking standards. A noteworthy feature of this cohort is the self-identification of 279 participants (12.3%) into thirteen different ethnic groups. Amerindian ancestry from genome-wide genetic data was 44.0%[SD15.5%] and increased to 61.2%[SD19.5%] when considering participants who identified as Native South Americans. As a data-contributor partner of the COVID-19 Host Genetics Initiative, the Chilean COVID-19 Biorepository has contributed to the publication of a second updated genome-wide association study, further enhancing our knowledge of the role of host genetics in susceptibility and severity to SARS-CoV-2. Future plansThe Chilean COVID-19 Biorepository, under the leadership of Latin American researchers from a Latin American country, substantially adds to the integration of Latin American populations in the global collections landscape. Just as ocurred with the COVID-19 Host Genetics Initiative, we expect that this repository will attract global network collaborations for comparative studies on the effects of COVID-19 across diverse populations, including exploring potential genetic advantages or disadvantages in the context of SARS-CoV-2 infection. Researchers involved in establishing this biorepository are currently associated within a collaborative initiative known as COVID-19 Genomics Network (C19-GenoNet), aimed to accelerate the identification of genetic factors in both hosts and pathogens that influence the short and long-term outcomes of SARS-CoV-2 infection. The broad informed consent utilized enables longitudinal cohort follow-up, thereby allowing for investigating the long-term consequences of SARS-CoV-2 infection, particularly concerning long-COVID. Thus, participants of this cohort were re-contacted to assess the development of long-COVID through a survey-based approach. The re-contact and recruitment procedures yielded a high response rate (82.11%), demonstrating strong participant engagement. In this case as well, this cohort has been leveraged by collaboration with the COVID-19 Host Genetics Initiative for the forthcoming publication of a genome-wide association study on long-COVID. The concerted endeavors invested in this Chilean initiative have led to the establishment and consolidation of C19-GenoNet as both a research network and a biobanking network. A comprehensive catalog of the C19-GenoNet biobank network has been created and is accessible online at https://redcovid.uchile.cl/. STRENGHT AND LIMITATIONS OF THIS STUDYO_LIThis study is one of the largest cohorts of COVID-19 patients with associated Biobank reported so far in Latin America. C_LIO_LIThe studys design and rigorous weekly monitoring ensured effective collection of high-quality simples and maximized the quality and completeness of data, with the ability to re-contact participants in case of problematic information. C_LIO_LIThere were no control or reliable information about the time between the infection and the sampling, which may hamper the comparison of some parameters among cases due to transcriptional dynamics after SARS-CoV-2 infection. C_LIO_LIThe study is based on a self-reported survey, which may represent a bias when analyzing specific clinical phenotypes. C_LI
Subject(s)
COVID-19 , Addison DiseaseABSTRACT
Background. Robust biomarkers that predict disease outcomes amongst COVID19 patients are necessary for both patient triage and resource prioritisation. Numerous candidate biomarkers have been proposed for COVID19. However, at present, there is no consensus on the best diagnostic approach to predict outcomes in infected patients. Moreover, it is not clear whether such tools would apply to other potentially pandemic pathogens and therefore of use as stockpile for future pandemic preparedness. Methods. We conducted a multi cohort observational study to investigate the biology and the prognostic role of interferon alpha inducible protein 27 (IFI27) in COVID19 patients. Findings. We show that IFI27 is expressed in the respiratory tract of COVID19 patients and elevated IFI27 expression is associated with the presence of a high viral load. We further demonstrate that systemic host response, as measured by blood IFI27 expression, is associated with COVID19 severity. For clinical outcome prediction (e.g. respiratory failure), IFI27 expression displays a high positive (0.83) and negative (0.95) predictive value, outperforming all other known predictors of COVID19 severity. Furthermore, IFI27 is upregulated in the blood of infected patients in response to other respiratory viruses. For example, in the pandemic H1N1/09 swine influenza virus infection, IFI27 like genes were highly upregulated in the blood samples of severely infected patients. Interpretation. These data suggest that prognostic biomarkers targeting the family of IFI27 genes could potentially supplement conventional diagnostic tools in future virus pandemics, independent of whether such pandemics are caused by a coronavirus, an influenza virus or another as yet to be discovered respiratory virus.
Subject(s)
Infections , Hematologic Diseases , Tumor Virus Infections , COVID-19 , Respiratory InsufficiencyABSTRACT
Pro-inflammatory immune responses are necessary for effective pathogen clearance, but cause severe tissue damage if not shut down in a timely manner1,2. Excessive complement and IFN-{gamma}-associated responses are known drivers of immunopathogenesis3 and are among the most highly induced immune programs in hyper-inflammatory SARS-CoV2 lung infection4. The molecular mechanisms that govern orderly shutdown and retraction of these responses remain poorly understood. Here, we show that complement triggers contraction of IFN-{gamma} producing CD4+ T helper (Th) 1 cell responses by inducing expression of the vitamin D (VitD) receptor (VDR) and CYP27B1, the enzyme that activates VitD, permitting T cells to both activate and respond to VitD. VitD then initiates the transition from pro-inflammatory IFN-{gamma}+ Th1 cells to suppressive IL-10+ Th1 cells. This process is primed by dynamic changes in the epigenetic landscape of CD4+ T cells, generating superenhancers and recruiting c-JUN and BACH2, a key immunoregulatory transcription factor5-7. Accordingly, cells in psoriatic skin treated with VitD increased BACH2 expression, and BACH2 haplo-insufficient CD4+ T cells were defective in IL-10 production. As proof-of-concept, we show that CD4+ T cells in the bronchoalveolar lavage fluid (BALF) of patients with COVID-19 are Th1-skewed and that VDR is among the top regulators of genes induced by SARS-CoV2. Importantly, genes normally down-regulated by VitD were de-repressed in CD4+ BALF T cells of COVID-19, indicating that the VitD-driven shutdown program is impaired in this setting. The active metabolite of VitD, alfacalcidol, and cortico-steroids were among the top predicted pharmaceuticals that could normalize SARS-CoV2 induced genes. These data indicate that adjunct therapy with VitD in the context of other immunomodulatory drugs may be a beneficial strategy to dampen hyperinflammation in severe COVID-19.