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The coronavirus disease 2019 (COVID-19) can evolve to clinical manifestations resembling systemic autoimmune diseases, with the presence of autoantibodies that are still poorly characterized. To address this issue, we performed a cross-sectional study of 246 individuals to determine whether autoantibodies targeting G protein-coupled receptors (GPCRs) and renin-angiotensin system (RAS)-related molecules were associated with COVID-19-related clinical outcomes. Moderate and severe patients exhibited the highest autoantibody levels, relative to both healthy controls and patients with mild COVID-19 symptoms. Random Forest, a machine learning model, ranked anti-GPCR autoantibodies targeting downstream molecules in the RAS signaling pathway such as the angiotensin II type 1 and Mas receptor, and the chemokine receptor CXCR3 as the three strongest predictors of severe disease. Moreover, while the autoantibody network signatures were relatively conserved in patients with mild COVID-19 compared to healthy controls, they were disrupted in moderate and most perturbed in severe patients. Our data indicate that the relationship between autoantibodies targeting GPCRs and RAS-related molecules associates with the clinical severity of COVID-19, suggesting novel molecular pathways for therapeutic interventions.

Since the 2015 to 2016 outbreak in America, Zika virus (ZIKV) infected almost 900,000 patients. This international public health emergency was mainly associated with a significant increase in the number of newborns with congenital microcephaly and abnormal neurologic development, known as congenital Zika syndrome (CZS). Furthermore, Guillain–Barré syndrome (GBS), a neuroimmune disorder of adults, has also been associated with ZIKV infection. Currently, the number of ZIKV-infected patients has decreased, and most of the cases recently reported present as a mild and self-limiting febrile illness. However, based on its natural history of a typical example of reemerging pathogen and the lack of specific therapeutic options against ZIKV infection, new outbreaks can occur worldwide, demanding the attention of researchers and government authorities. Here, we discuss the clinical spectrum and immunopathological mechanisms underlying ZIKV-induced neurological manifestations. Several studies have confirmed the tropism of ZIKV for neural progenitor stem cells by demonstrating the presence of ZIKV in the central nervous system (CNS) during fetal development, eliciting a deleterious inflammatory response that compromises neurogenesis and brain formation. Of note, while the neuropathology of CZS can be due to a direct viral neuropathic effect, adults may develop neuroimmune manifestations such as GBS due to poorly understood mechanisms. Antiganglioside autoantibodies have been detected in multiple patients with ZIKV infection–associated GBS, suggesting a molecular mimicry. However, further additional immunopathological mechanisms remain to be uncovered, paving the way for new therapeutic strategies.

Made available in DSpace on 2021-06-25T15:20:28Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-05-24 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Ontario Research Fund Natural Sciences Research Council Canada Foundation for Innovation IBM Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Santander Universidades (Banco Santander Brasil S/A) The fact that the COVID-19 fatality rate varies by sex and age is poorly understood. Notably, the outcome of SARS-CoV-2 infections mostly depends on the control of cytokine storm and the increasingly recognized pathological role of uncontrolled neutrophil activation. Here, we used an integrative approach with publicly available RNA-Seq data sets of nasopharyngeal swabs and peripheral blood leukocytes from patients with SARS-CoV-2, according to sex and age. Female and young patients infected by SARS-CoV-2 exhibited a larger number of differentially expressed genes (DEGs) compared with male and elderly patients, indicating a stronger immune modulation. Among them, we found an association between upregulated cytokine/chemokine- and downregulated neutrophil-related DEGs. This was correlated with a closer relationship between female and young subjects, while the relationship between male and elderly patients was closer still. The association between these cytokine/chemokines and neutrophil DEGs is marked by a strongly correlated interferome network. Here, female patients exhibited reduced transcriptional levels of key proinflammatory/neutrophil-related genes, such as CXCL8 receptors (CXCR1 and CXCR2), IL-1 beta, S100A9, ITGAM, and DBNL, compared with male patients. These genes are well known to be protective against inflammatory damage. Therefore, our work suggests specific immune-regulatory pathways associated with sex and age of patients infected with SARS-CoV-2 and provides a possible association between inverse modulation of cytokine/chemokine and neutrophil transcriptional signatures. Univ Sao Paulo, Dept Immunol, Inst Biomed Sci, Lineu Prestes Ave 1730, BR-05508 Sao Paulo, Brazil Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin & Toxicol Anal, Sao Paulo, SP, Brazil Univ Freiburg, Fac Med, Dept Hematol & Oncol, Freiburg, Germany Haraldsplass Deaconess Hosp, Dept Internal Med, Bergen, Norway Sao Paulo State Univ, Inst Biosci, Dept Struct & Funct Biol, Botucatu, SP, Brazil Univ Sao Paulo, Inst Biomed Sci, Dept Microbiol, Vaccine Dev Lab, Sao Paulo, Brazil Univ Toronto, Krembil Res Inst, Univ Hlth Network, Toronto, ON, Canada Univ Toronto, Dept Med Biophys, Toronto, ON, Canada Univ Toronto, Dept Comp Sci, Toronto, ON, Canada Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA Seattle Childrens Res Inst, Seattle, WA USA Universal Sci Educ & Res Network, Network Immun Infect Malignancy & Autoimmun, Sao Paulo, Brazil Sao Paulo State Univ, Inst Biosci, Dept Struct & Funct Biol, Botucatu, SP, Brazil FAPESP: 2017/05264-7 FAPESP: 2018/188869 FAPESP: 2020/01688-0 FAPESP: 2020/07069-0 FAPESP: 2020/07972-1 FAPESP: 2020/09146-1 FAPESP: 13/50343-1 CNPq: 311530/2019-2 Ontario Research Fund: 34876 Natural Sciences Research Council: 203475 Canada Foundation for Innovation: 29272 Canada Foundation for Innovation: 225404 Canada Foundation for Innovation: 33536 CAPES: 001

Clinical and hyperinflammatory overlap between COVID-19 and hemophagocytic lymphohistiocytosis (HLH) has been reported. However, the underlying mechanisms are unclear. Here we show that COVID-19 and HLH have an overlap of signaling pathways and gene signatures commonly dysregulated, which were defined by investigating the transcriptomes of 1253 subjects (controls, COVID-19, and HLH patients) using microarray, bulk RNA-sequencing (RNAseq), and single-cell RNAseq (scRNAseq). COVID-19 and HLH share pathways involved in cytokine and chemokine signaling as well as neutrophil-mediated immune responses that associate with COVID-19 severity. These genes are dysregulated at protein level across several COVID-19 studies and form an interconnected network with differentially expressed plasma proteins which converge to neutrophil hyperactivation in COVID-19 patients admitted to the intensive care unit. scRNAseq analysis indicated that these genes are specifically upregulated across different leukocyte populations, including lymphocyte subsets and immature neutrophils. Artificial intelligence modeling confirmed the strong association of these genes with COVID-19 severity. Thus, our work indicates putative therapeutic pathways for intervention. Funding: We acknowledge the Latin American Society of Immunodeficiencies (LASID) for providing the research funding of LFS (LASID Fellowship award 2020), and the Sao Paulo Research Foundation (FAPESP grants 2018/18886-9, 2020/01688-0, and 2020/07069-0 to OCM) for financial support. Computational analysis was supported by FAPESP and partially by the grants from Ontario Research Fund (#34876), Natural Sciences Research Council (NSERC #203475), Canada Foundation for Innovation (CFI #29272, #225404, #33536), and IBM granted to IJ, the National Institutes of Health (NHLBI) through award HL130704 granted to AJ, as well as the NIH P4 GM108538 granted to KAO and JJC. This study was financed in part by the coordination for the improvement of higher education personnel – Brazil (CAPES) – finance code 001. Declaration of Interests: The authors have declared that no conflict of interest exists.