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

Abstract

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.

Methods and Insights from Single-Cell Expression Quantitative Trait Loci

“…Interestingly, the previously mentioned OAS1 gene is a response eGene (81,121) where the ancestral version of its eQTL (rs10774671-G) is derived from an introgression event from Neanderthal into Europeans. These findings motivate future efforts to unveil the ancestral origins of specific physiological and disease responses and their biological contexts at the single-cell level using similar approaches to those recently introduced by Aquino et al (5).…”

Infectious diseases may have arrested the southward advance of microblades in Upper Palaeolithic East Asia

“…Various parasitic and infectious diseases, e.g. body lice [67][68][69], tapeworms [70,71], tuberculosis [72][73][74], malaria [75][76][77][78][79][80], papillomaviruses [81][82][83] and coronaviruses [84][85][86][87] are believed to have been associated with hominins since the Palaeolithic. Some of these diseases may have infected southern East Asian foragers, resulting in some populationlevel immunity and/or behavioural accommodation, whereas northern East Asian foragers would have been minimally exposed.…”

“…An interesting recent finding is that modern humans in East Asia may have been infected with coronavirus at least approximately 20 kya [ 84 , 87 ]. The evidence comprises signatures of selection on genes that code for coronavirus-interacting human proteins (CoV-VIPs).…”