We previously reported widespread differential expression of long non-
protein-coding RNAs (ncRNAs) in response to
virus infection. Here, we expanded the study through small
RNA transcriptome sequencing analysis of the host response to both severe acute respiratory syndrome coronavirus (SARS-CoV) and influenza virus
infections across four founder mouse strains of the Collaborative Cross, a recombinant inbred mouse resource for mapping complex traits. We observed differential expression of over 200 small RNAs of diverse classes during
infection. A majority of identified
microRNAs (
miRNAs) showed divergent changes in expression across mouse strains with respect to SARS-CoV and influenza virus
infections and responded differently to a highly pathogenic reconstructed 1918 virus compared to a minimally pathogenic seasonal influenza virus isolate. Novel insights into
miRNA expression changes, including the association with pathogenic outcomes and large differences between in vivo and in vitro experimental systems, were further elucidated by a survey of selected
miRNAs across diverse
virus infections. The small RNAs identified also included many non-
miRNA small RNAs, such as small nucleolar RNAs (snoRNAs), in addition to nonannotated small RNAs. An integrative sequencing analysis of both small RNAs and long transcripts from the same samples showed that the results revealing differential expression of
miRNAs during
infection were largely due to transcriptional regulation and that the predicted
miRNA-
mRNA network could modulate global host responses to
virus infection in a combinatorial fashion. These findings represent the first integrated sequencing analysis of the response of host small RNAs to
virus infection and show that small RNAs are an integrated component of complex networks involved in regulating the host response to
infection.
IMPORTANCE: Most studies examining the host transcriptional response to
infection focus only on
protein-coding genes. However, mammalian genomes transcribe many short and long non-
protein-coding RNAs (ncRNAs). With the advent of deep-sequencing technologies, systematic transcriptome analysis of the host response, including analysis of ncRNAs of different sizes, is now possible. Using this approach, we recently discovered widespread differential expression of host long (>200
nucleotide [nt]) ncRNAs in response to
virus infection. Here, the samples described in the previous report were again used, but we sequenced another fraction of the transcriptome to study very short (about 20 to 30 nt) ncRNAs. We demonstrated that
virus infection also altered expression of many short ncRNAs of diverse classes. Putting the results of the two studies together, we show that small RNAs may also play an important role in regulating the host response to
virus infection.