Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, an emerging virus that utilizes host proteins ACE2 and TMPRSS2 as entry factors. Understanding the factors affecting the pattern and levels of expression of these genes is important for deeper understanding of SARS-CoV-2 tropism and pathogenesis. Here we explore the role of genetics and co-expression networks in regulating these genes in the airway, through the analysis of nasal airway transcriptome data from 695 children. We identify expression quantitative trait loci for both ACE2 and TMPRSS2, that vary in frequency across world populations. We find TMPRSS2 is part of a mucus secretory network, highly upregulated by type 2 (T2) inflammation through the action of interleukin-13, and that the interferon response to respiratory viruses highly upregulates ACE2 expression. IL-13 and virus infection mediated effects on ACE2 expression were also observed at the protein level in the airway epithelium. Finally, we define airway responses to common coronavirus infections in children, finding that these infections generate host responses similar to other viral species, including upregulation of IL6 and ACE2. Our results reveal possible mechanisms influencing SARS-CoV-2 infectivity and COVID-19 clinical outcomes.

32Coronavirus disease 2019 outcomes vary from asymptomatic infection to 33 death. This disparity may reflect different airway levels of the SARS-CoV-2 receptor, 34 ACE2, and the spike protein activator, TMPRSS2. Here we explore the role of genetics 35 and co-expression networks in regulating these genes in the airway, through the 36 analysis of nasal airway transcriptome data from 695 children. We identify expression 37 quantitative trait loci (eQTL) for both ACE2 and TMPRSS2, that vary in frequency 38 across world populations. Importantly, we find TMPRSS2 is part of a mucus secretory 39 network, highly upregulated by T2 inflammation through the action of interleukin-13, and 40 that interferon response to respiratory viruses highly upregulates ACE2 expression. 41Finally, we define airway responses to coronavirus infections in children, finding that 42 these infections upregulate IL6 while also stimulating a more pronounced cytotoxic 43 immune response relative to other respiratory viruses. Our results reveal mechanisms 44 likely influencing SARS-CoV-2 infectivity and COVID-19 clinical outcomes. 45 46 47 48 IL-13), which is common in both children and adults and has been associated with the 87 development of both asthma and COPD in a subgroup of patients [11][12][13] . T2 cytokines are 88 known to greatly modify gene expression in the airway epithelium, both through 89 transcriptional changes within cells and epithelial remodeling in the form of mucus 90 metaplasia 11, 14, 15 . Microbial infection is another strong regulator of airway epithelial 91 expression. In particular, respiratory viruses can modulate the expression of thousands 92 of genes within epithelial cells, while also recruiting and activating an assortment of 93 immune cells [16][17][18] . Even asymptomatic nasal carriage of respiratory viruses, which is 94 especially common in childhood, has been shown to be associated with both genome-95 wide transcriptional re-programming and infiltration of macrophages and neutrophils in 96 the airway epithelium 19 , demonstrating how viral infection can drive pathology even 97 without overt signs of illness. 98 99 . CC-BY-NC-ND 4.0 International license was not certified by peer review) is the author/funder. It is made available under a Genetic variation is another factor that may regulate gene expression in the airway 100 epithelium. Indeed, expression quantitative trait loci (eQTL) analyses carried out in 101 many tissues have suggested that as many as 70% of genes expressed by a tissue or 102organ are under genetic control 20 . Severity of human rhinovirus (HRV) respiratory illness 103 has specifically been associated with genetic variation in the epithelial genes CDHR3 21 104 and the ORMDL3 22 and, given differences in genetic variation across world populations, 105 it is possible that functional genetic variants in SARS-CoV-2-related genes could partly 106 explain population differences in COVID-19 clinical outcomes. 107 108 Finally, there are important questions regarding the host response to SARS-CoV-2...

Epstein-Barr virus (EBV) is a well-established B-cell-tropic virus associated with various lymphoproliferative diseases of both B-cell and non-B-cell origin.EBV is associated with a number of T-cell lymphomas; however, in vitro studies utilizing prototypical EBV type 1 (EBV-1) laboratory strains have generally failed to readily infect mature T cells in culture. The difficulties in performing in vitro T-cell experiments have left questions regarding the role of EBV in the pathogenesis of EBV-positive T-cell lymphoproliferative diseases largely unresolved. We report here that the EBV type 2 (EBV-2) strain displays a unique cell tropism for T cells. In remarkable contrast to EBV-1, EBV-2 readily infects primary T cells in vitro, demonstrating a propensity for CD8 ؉ T cells. EBV-2 infection of purified T cells results in expression of latency genes and ultimately leads to T-cell activation, substantial proliferation, and profound alteration of cytokine expression. The pattern of cytokine production is strikingly skewed toward chemokines with roles in lymphocyte migration, demonstrating that EBV-2 has the ability to modulate normal T-cell processes. Collectively, these novel findings identify a previously unknown cell population potentially utilized by EBV-2 to establish latency and lay the foundation for further studies to elucidate the role of EBV in the pathogenesis of T-cell lymphoproliferative diseases. IMPORTANCE The ability of EBV to infect T cells is made apparent by its association with a variety of T-cell lymphoproliferative disorders.However, studies to elucidate the pathogenic role of EBV in these diseases have been limited by the inability to conduct in vitro T-cell infection experiments. Here, we report that EBV-2 isolates, compromised in the capacity to immortalize B cells, infect CD3 ؉ T cells ex vivo and propose a working model of EBV-2 persistence where alteration of T-cell functions resulting from EBV-2 infection enhances the establishment of latency in B cells. If indeed EBV-2 utilizes T cells to establish a persistent infection, this could provide one mechanism for the association of EBV with T-cell lymphomas. The novel finding that EBV-2 infects T cells in culture will provide a model to understand the role EBV plays in the development of T-cell lymphomas. While Epstein-Barr virus (EBV) establishes lifelong latency in B cells and is associated with B-cell malignancies, it is also associated with malignancies and diseases that originate from T cells, including NK/T-cell lymphomas (1), hemophagocytic lymphohistiocytosis (2), hydroa vacciniforme (HV) (3), and chronic active EBV (CAEBV) (4, 5). In these diseases, EBV can be detected in CD4 ϩ T cells, CD8 ϩ T cells, or ␥␦ T cells (6, 7), with the virus predominantly existing as a latent infection (8, 9). The etiology of these T-cell diseases, and in particular whether EBV infection of T cells is an aberrancy in a virus known for its B-cell tropism in vitro and in vivo, remains unknown.Based on genetic differences in the Epstein-Barr nuclear ...

In response to the unmet need for timely accurate diagnosis and prognosis of acute infections and sepsis, host-immune-response-based tests are being developed to help clinicians make more informed decisions including prescribing antimicrobials, ordering additional diagnostics, and assigning level of care. One such test (InSep™, Inflammatix, Inc.) uses a 29-mRNA panel to determine the likelihood of bacterial infection, the separate likelihood of viral infection, and the risk of physiologic decompensation (severity of illness). The test, being implemented in a rapid point-of-care platform with a turnaround time of 30 min, enables accurate and rapid diagnostic use at the point of impact. In this report, we provide details on how the 29-biomarker signature was chosen and optimized, together with its molecular, immunological, and medical significance to better understand the pathophysiological relevance of altered gene expression in disease. We synthesize key results obtained from gene-level functional annotations, geneset-level enrichment analysis, pathway-level analysis, and gene-network-level upstream regulator analysis. Emerging findings are summarized as hallmarks on immune cell interaction, inflammatory mediators, cellular metabolism and homeostasis, immune receptors, intracellular signaling and antiviral response; and converging themes on neutrophil degranulation and activation involved in immune response, interferon, and other signaling pathways.

Background: Asthma is a heterogeneous disease. Clinical blood parameters differ by race/ethnicity and are used to distinguish asthma subtypes and inform therapies. Differences in subtypes may explain population-specific trends in asthma outcomes. However, these differences in racial/ethnic minority pediatric populations are unclear. Objective: We investigated the association of blood parameters and asthma subtypes with asthma outcomes and examined population-specific eligibility for biologic therapies in minority pediatric populations. Methods: Using data from 2 asthma case-control studies of pediatric minority populations, we performed case-control (N 5 3738) and case-only (N 5 2743) logistic regressions to quantify the association of blood parameters and asthma subtypes with asthma outcomes. Heterogeneity of these associations was tested using an interaction term between race/ethnicity and each exposure. Differences in therapeutic eligibility were investigated using chi-square tests. Results: Race/ethnicity modified the association between total IgE and asthma exacerbations. Elevated IgE level was associated with worse asthma outcomes in Puerto Ricans. Allergic asthma was associated with worse outcomes in Mexican Americans, whereas eosinophilic asthma was associated with worse outcomes in Puerto Ricans. A lower proportion of Puerto Ricans met dosing criteria for allergic asthma-directed biologic therapy than other groups. A higher proportion of Puerto Ricans qualified for eosinophilic asthma-directed biologic therapy than African Americans. Conclusions: We found population-specific associations between blood parameters and asthma subtypes with asthma outcomes. Our findings suggest that eligibility for asthma biologic therapies differs across pediatric racial/ethnic populations. These findings call for more studies in diverse populations for equitable treatment of minority patients with asthma. (J Allergy Clin Immunol 2021;nnn:nnn-nnn.)