How environmental and genetic factors affect SARS-CoV-2 immune responses across populations

Individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibit a wide range of clinical alterations, from asymptomatic infection to fatal disease. In a recent study published in Bio Rxiv* A preprint server and international team of researchers investigate the genetic, immunological, and evolutionary factors that determine the enormous variability observed in the clinical presentation of coronavirus disease 2019 (COVID-19) Did.

study: Environmental and genetic factors for population differences in SARS-CoV-2 immune responses. Image credit: Billion Photos / Shutterstock.com

Background

Numerous epidemiological and genetic studies have elucidated the impact of genetic factors and variations in innate immunity, including congenital errors and neutralizing autoantibodies against type I interferons (IFNs), leading to various SARS-CoV-2 Contributes to associated clinical manifestations. The importance of ancestry-related differences in transcriptional responses to immune challenges has also been described.

Combined with evidence suggesting that viruses and other infectious agents have had an overwhelming impact on human evolution, the magnitude of variability in immune responses to SARS-CoV-2 and the extent of its drivers in populations around the world have been studied. A detailed investigation is urgently needed.

For example, in East Asians, strong genetic adaptations that began approximately 25,000 years ago have been reported for multiple human coronavirus-interacting proteins. In addition, many examples of human adaptation to ribonucleic acid (RNA) viruses as sources of population genetic differentiation have also been published.

There is also increasing evidence of COVID-19 severity modulation in modern Eurasians due to Neanderthal haplotypes. This is a key determinant of their gene transfer and immunity. Together, the data piques the scientific community’s curiosity about how these past natural selection events and archaic mixtures influence her immune response to SARS-CoV-2 in modern humans. Did.

About research

In the present study, researchers used single-cell RNA sequencing (scRNA-seq) in a population genetics approach to isolate peripheral blood mononuclei of 222 healthy donors of various ancestry stimulated by SARS-CoV- We characterized cell-type-specific transcriptional responses in cells (PBMCs). 2 or influenza A virus. Her PBMCs treated for 6 hours displayed a strong immune response and high cell viability, helping the team to obtain over one million high-quality single-cell transcriptomes.

The study population consisted of 80, 80 and 115 individuals of Central African, Western European and East Asian descent, respectively, exposed to different environmental conditions and thus representing different genetic ancestry. The impact of human genetic variants on transcriptional variation was assessed by mapping expression quantitative trait loci (eQTLs) focused on cis-regulatory variants.

Researchers have also investigated the contribution of natural selection to population differentiation of immune responses. To this end, they searched for overlap between eQTLs or reQTLs and genome-wide signals of local adaptation as measured by population branching statistics (PBS).

In addition, the contribution of cell ratio differences to the observed inter-individual variability in SARS-CoV-2 response was determined by focusing on individuals of central African and western European ancestry, all of whom during the same sampling campaign. We were recruited.

Finally, the functional impact of Neanderthal gene transfer on modern immune responses to viral challenge was studied. Using a set of 100,345 introgressed ‘archaic’ alleles or archaic single nucleotide polymorphisms (aSNPs), eQTL was over- or We decided if it was underrepresented.Taken together, this information has allowed researchers to understand the contribution of genetic variants that alter responses to SARS-CoV-2 in vitro Responding to COVID-19 Risk live.

Population-scale single-cell responses to SARS-CoV-2 and IAV. a, Study design. b and c, Uniform manifold approximation and projection (UMAP) of 1,047,824 peripheral blood mononuclear cells: resting (unstimulated; NS), stimulated with SARS-CoV-2 (COV) or influenza A virus (IAV) for 6 h . b, Colors indicate 22 different cell types deduced. c, Distribution of cells in NS, COV and IAV conditions on UMAP coordinates. Contour plots show the overall density of cells, with colored areas representing areas of high cell density in each condition (grey: NS, red: COV, blue: IAV). d, Comparison of transcriptional responses to SARS-CoV-2 and IAV across major immune systems. Characteristic inflammatory and interferon-stimulated genes are highlighted in orange and blue, respectively. e, Relative expression of transcripts encoding IFN-α by each immune cell type in response to SARS-CoV-2 and IAV. Bar length indicates the average number of IFN-α transcripts that each cell type contributes to the overall pool (cell type frequency × average number of IFN-α transcripts per cell). The dot area is proportional to the average level of IFN-α transcripts for each cell type (numbers per million). f, Correlation of her ISG activity scores between individuals after exposure to SARS-CoV-2 and IAV. Each dot corresponds to one individual in her (n = 222) and its color indicates the self-reported ancestry of the individual involved (AFB: Central Africa; EUB: Western Europe; ASH: East Asia).

Survey results

The proportion of cells altered by environmental exposure was a major factor in population differences in SARS-CoV-2 immune responses. The high proportion of memory cells detected in the lymphoid lineage of Africans and their association with persistent infection with cytomegalovirus (CMV) suggest that population-level differences in cellular activation status are primarily responsible for lifelong susceptibility to pathogens. It was suggested that it may be caused by exposure.

Socio-environmental factors have also been found to covariate with an individual’s genetic ancestry, which may lead to an overestimation of their impact on immune responses to SARS-CoV-2, a phenotypic variation.

Common genetic alleles also contribute to the observed variability of immune responses to viral challenge. However, their effects tend to be restricted to subsets of genes exhibiting strong population differentiation.

For example, the rs1142888-G variant is found more frequently in Europeans than in Africans due to selection events that occurred between 21,900 and 35,600 years ago. This variant causes a 2.8-fold greater expression of guanylate-binding protein 7 (GBP7) that promotes IAV replication by suppressing innate immunity.

GBP7 also regulates IFN-γ-induced oxidative host defense that confers resistance to intracellular bacteria such as Listeria and Mycobacterium tuberculosis, thereby providing a viable mechanism for positive selection at this locus. Offers.

Virus evolution has changed the genetic basis of infectious diseases over time. Thus, we observed limited overlap between selected alleles during this time in East Asia and reported genetic variants underlying COVID-19 risk.

However, the researchers found a SARS-CoV-2-specific reQTL in an East Asian ancestry consistent with the proposed timing of an ancient epidemic ~25,000 years ago that influenced the evolution of coronavirus host-interacting proteins. Found traces of selection events targeting the .

Delineating the genetic architecture of immune response variation across several cell types has provided mechanistic insight into the impact of COVID-19-associated alleles. For example, the efficiency of IFN signaling has been identified as essential for successful clinical outcome of SARS-CoV-2 infection.

An eQTL introgressed into Neanderthals at the mucin20 (MUC20) locus was found to increase expression in SARS-CoV-2-stimulated CD4+ T cells and reduce COVID-19 susceptibility. Presumably, the Neanderthal haplotype conferred greater resistance to viral infection through an effect similar to that of mucin in forming a barrier against infection in the nasal epithelium.

Conclusion

Overall, the study results highlight the importance of capturing the diversity of human immune responses to RNA viruses, especially SARS-CoV-2, using sc-RNA-seq approaches. These observations provide new insights into the environmental, genetic, and evolutionary drivers of immune response variation across populations with genetic variation.

*Important Notices

Bio Rxiv We publish a non-peer-reviewed, preliminary scientific report and should not be taken as conclusive, to guide clinical practice/health-related actions, or to be treated as established information.