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Host Cells Respond to Influenza Infection in Largely Similar Way, Single-Cell RNA-Seq Study Finds

NEW YORK (GenomeWeb) – Cells from influenza-infected tissues have the same generic transcriptional response to infection, but a new single-cell RNA sequencing study also found differences between infected and bystander cells.

A Tel Aviv University-led team of researchers profiled both host and viral transcriptomes from single cells they isolated from the lungs of infected and uninfected mice. As they reported today in Cell Systems, Tel Aviv's Irit Gat-Viks
and her colleagues found that a range of cell types become infected with the virus, often at low levels, while epithelial cells tended to harbor higher viral loads.

They further uncovered two transcriptional responses to infection, though noted that one differs between infected and bystander epithelial cells. This, the researchers noted, could be used to pinpoint infected cells and could lead to new treatment approaches.

"Our results open the way to interventions targeted specifically on infected cells [and] suggest principles of viral-host interactions that are applicable in influenza and possibly also in other pathogens," Gat-Viks
and her colleagues wrote in their paper.

The researchers isolated both immune and non-immune cells from mouse lungs two days after they had been infected with influenza. Using the single-cell RNA-seq approach MARS-seq, which profiles all polyadenylated mRNA, they analyzed more than 4,000 cells isolated from infected and uninfected mice.

Clustering the cells based on their transcriptomes placed them largely into nine groups: four clusters of non-immune cell types, such as epithelial cells or fibroblasts, and five specialized immune cell types, such as B cells or T cells.

As influenza viral mRNA is also polyadenylated, the researchers captured it from within the cells, as well. Using the amount of viral mRNA as a guide, the researchers divvied the cells into three groups: infected cells with high viral load, bystander cells with no viral load but which were derived from infected mice, and unexposed cells from uninfected mice.

A sizable amount of each of the nine cell types were infected, the researchers noted,  but epithelial cells bore the brunt of the infection as they had the highest percentage — 62 percent — of infected cells.

For each of the nine cell types, the researchers examined whether the expression of any genes differed between the treated and control cell and found that 450 genes were differentially expressed in at least one cell type. When they clustered these genes, the researchers uncovered a module of 101 genes that were consistently up-regulated during infection in both immune and non-immune cell types. Most of the genes in this module, they reported, are known IFN-stimulated genes, which the researchers said indicates this module is part of cell type-independent, general type I IFN response.

At the same time, the researchers noted seven mitochondrially encoded genes that were repressed in nearly all cell types. The researchers suggested that these modules together are two arms of the host cell response that's independent of cell type.

They further found, though, that infected and bystander epithelial cells differ in their expression of mitochondrial genes. Rather than the suppression observed in other cell types, bystander epithelial cells induce a number of mitochondrially encoded genes. This, the researchers said, could help the cells cope with the energetic demands of infection.

In addition, the researchers said their findings indicate that infected and bystander cells could be distinguished and allow tailored therapies to target only infected ones. "These findings open new avenues for targeted therapy aimed exclusively at infected cells," Gat-Viks and her colleagues wrote.