Environmental and genetic drivers of population differences in SARS-CoV-2 immune responses (preprint)

Humans display vast clinical variability upon SARS-CoV-2 infection, partly due to genetic and immunological factors. However, the magnitude of population differences in immune responses to SARS-CoV-2 and the mechanisms underlying such variation remain unknown. Here we report single-cell RNA-sequencing data for peripheral blood mononuclear cells from 222 healthy donors of various ancestries stimulated with SARS-CoV-2 or influenza A virus. We show that SARS-CoV-2 induces a weaker, but more heterogeneous interferon-stimulated gene activity than influenza A virus, and a unique pro-inflammatory signature in myeloid cells. We observe marked population differences in transcriptional responses to viral exposure that reflect environmentally induced cellular heterogeneity, as illustrated by higher rates of cytomegalovirus infection, affecting lymphoid cells, in African-descent individuals. Expression quantitative trait loci and mediation analyses reveal a broad effect of cell proportions on population differences in immune responses, with genetic variants having a narrower but stronger effect on specific loci. Additionally, natural selection has increased immune response differentiation across populations, particularly for variants associated with SARS-CoV-2 responses in East Asians. We document the cellular and molecular mechanisms through which Neanderthal introgression has altered immune functions, such as its impact on the myeloid response in Europeans. Finally, colocalization analyses reveal an overlap between the genetic architecture of immune responses to SARS-CoV-2 and COVID-19 severity. Collectively, these findings suggest that adaptive evolution targeting immunity has also contributed to current disparities in COVID-19 risk.

Follow-up of hospitalized COVID-19 survivors: assessment of short- and long-term cardiovascular sequelae after SARS-CoV-2 infection

Aims Cardiovascular sequelae in COVID-19 survivors remain largely unclear and can potentially go unrecognized. Reports on follow-up focused on cardiovascular evaluation after hospital discharge are currently scarce. Aim of this prospective study was to assess cardiovascular sequelae in previously hospitalized COVID-19 survivors. Methods and results The study was conducted at ‘Sapienza’ University of Rome—Policlinico ‘Umberto I’. After 2 months from discharge, n = 230 COVID-19 survivors underwent a follow-up visit at a dedicated ‘post-COVID Outpatient Clinic’. A cardiovascular evaluation including electrocardiogram (ECG), Troponin and echocardiography was performed. Further tests were requested when clinically indicated. Medical history, symptoms, arterial-blood gas, blood tests, chest computed tomography, and treatment of both in-hospital and follow-up evaluation were recorded. A 1-year telephone follow-up was performed. A total of 36 (16%) COVID-19 survivors showed persistence or delayed onset of cardiovascular disease at 2-months follow-up visit. Persistent condition was recorded in 62% of survivors who experienced an in-hospital cardiovascular disease. Delayed cardiovascular involvement included: myocarditis, pericarditis, ventricular disfunction, new onset of systemic hypertension and arrhythmias. At 1-year telephone follow-up, 105 (45%) survivors reported persistent symptoms, with dyspnoea and fatigue being the most frequent. 60% of survivors showed persistent chest CT abnormalities and among those 28% complained of persistent cardiopulmonary symptoms at long term follow-up. Conclusions Our preliminary data showed persistent or delayed onset of cardiovascular involvement (16%) at short-term follow-up and persistent symptoms (45%) at long-term follow-up. These findings suggest the need for monitoring COVID-19 survivors.

Genetic control of the dynamic transcriptional response to immune stimuli and glucocorticoids at single cell resolution (preprint)

Synthetic glucocorticoids, such as dexamethasone, have been used as treatment for many immune conditions, such as asthma and more recently severe COVID-19. Single cell data can capture more fine-grained details on transcriptional variability and dynamics to gain a better understanding of the molecular underpinnings of inter-individual variation in drug response. Here, we used single cell RNA-seq to study the dynamics of the transcriptional response to glucocorticoids in activated Peripheral Blood Mononuclear Cells from 96 African American children. We employed novel statistical approaches to calculate a mean-independent measure of gene expression variability and a measure of transcriptional response pseudotime. Using these approaches, we demonstrated that glucocorticoids reverse the effects of immune stimulation on both gene expression mean and variability. Our novel measure of gene expression response dynamics, based on the diagonal linear discriminant analysis, separated individual cells by response status on the basis of their transcriptional profiles and allowed us to identify different dynamic patterns of gene expression along the response pseudotime. We identified genetic variants regulating gene expression mean and variability, including treatment-specific effects, and demonstrated widespread genetic regulation of the transcriptional dynamics of the gene expression response.

Does the human placenta express the canonical cell entry mediators for SARS-CoV-2? (preprint)

The pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected over 3.8 million people, including pregnant women. To date, no consistent evidence of vertical transmission for SARS-CoV-2 exists. This new coronavirus canonically utilizes the angiotensin-converting enzyme 2 (ACE2) receptor and the serine protease TMPRSS2 for cell entry. Herein, building upon our previous single cell study of the placenta (Pique-Regi, 2019), another study, and new single-cell/nuclei RNA-sequencing data, we investigated the expression of ACE2 and TMPRSS2 throughout pregnancy as well as in third-trimester chorioamniotic membranes. We report that co-transcription of ACE2 and TMPRSS2 is negligible, thus not a likely path of vertical transmission for SARS-CoV-2 at any stage of pregnancy. In contrast, receptors for Zika virus and cytomegalovirus which cause congenital infections are highly expressed by placental cell types. These data suggest that SARS-CoV-2 is unlikely to infect the human placenta through the canonical cell entry mediators; yet, other interacting proteins could still play a role in the viral infection.