Lyme disease (LD), the most prevalent tick-borne disease of humans in the Northern Hemisphere, is caused by the spirochetal bacterium of Borreliella burgdorferi (Bb) sensu lato complex. In nature, Bb spirochetes are continuously transmitted between Ixodes ticks and mammalian or avian reservoir hosts. Peromyscus leucopus mice are considered the primary mammalian reservoir of Bb in the United States. Earlier studies demonstrated that experimentally infected P. leucopus mice do not develop disease. In contrast, C3H mice, a widely used laboratory strain of Mus musculus in the LD field, develop severe Lyme arthritis. To date, the exact tolerance mechanism of P. leucopus mice to Bb-induced infection remains unknown. To address this knowledge gap, the present study has compared spleen transcriptomes of P. leucopus and C3H/HeJ mice infected with Bb strain 297 with those of their respective uninfected controls. Overall, the data showed that the spleen transcriptome of Bb-infected P. leucopus mice was much more quiescent compared to that of the infected C3H mice. To date, the current investigation is one of the few that have examined the transcriptome response of natural reservoir hosts to Borreliella infection. Although the experimental design of this study significantly differed from those of two previous investigations, the collective results of the current and published studies have consistently demonstrated very limited transcriptomic responses of different reservoir hosts to the persistent infection of LD pathogens.ImportanceThe bacterium Borreliella burgdorferi (Bb) causes Lyme disease, which is one of the emerging and highly debilitating human diseases in countries of the Northern Hemisphere. In nature, Bb spirochetes are maintained between hard ticks of Ixodes spp. and mammals or birds. In the United States, the white-footed mouse, Peromyscus leucopus, is one of the main Bb reservoirs. In contrast to humans and laboratory mice (e.g., C3H mice), white-footed mice rarely develop clinical signs (disease) despite being (persistently) infected with Bb. How the white-footed mouse tolerates Bb infection is the question that the present study has attempted to address. Comparisons of genetic responses between Bb-infected and uninfected mice demonstrated that, during a long-term Bb infection, C3H mice reacted much stronger, whereas P. leucopus mice were relatively unresponsive.

Background SARS‐CoV‐2, a ssRNA virus in the same coronavirus family as SARS‐CoV‐1, is responsible for causing COVID‐19, a respiratory disorder with symptoms ranging from mild flu‐like symptoms to severe respiratory distress and organ failure. There is evidence of increased expression of inflammatory cytokines and other interferon stimulated genes (ISGs) due to innate immune activation. These have been linked with severity of symptoms and clinical outcomes of infected patients. However, there is still little known about the expression of one particular ISG, adenosine deaminase acting on RNA (ADAR), more specifically ADAR1p150 isoform that in addition to its role in transcriptome diversity is also responsible for fighting off viral infections by editing viral RNA. Genomes of both SARS‐CoV‐1 and SARS‐CoV‐2 have been shown to experience RNA editing that in turn influences viral evolution. However, the effects of altered ADAR editing patterns in the host transcriptome in coronavirus infections have not been explored. We hypothesize that changes to ADAR editing patterns, driven by differential expression of ADAR during viral infection, negatively affect protein structure and function. Changes in ADAR editing profiles can help explain underlying molecular mechanisms of the broad spectrum of symptoms seen in patients with COVID‐19. Methods Here we use a publicly available RNA sequencing dataset with intestinal (Caco2), lung epithelial (Calu3) and lymph node (H1299) cell lines infected with SARS‐CoV‐1 and SARS‐CoV‐2 to map differential ADAR editing patterns during infection. We used our previously developed RNA‐seq pipeline AIDD (Automated Isoform Diversity Detector) to explore immune gene expression profiles and map ADAR editing landscapes using machine learning, including Guttman scaling and random forest analysis. Results There is significantly higher expression of ADAR1p150 isoform in lung epithelial cell line, but not in the intestinal cell line or the lymph node cell line in SARS‐CoV‐2 infection. Additionally, expression of ADAR1p150 is highly correlated with identification of ADAR editing sites with high and moderate impact on protein structure and function in SARS‐CoV‐1 in lung epithelium, but is negatively correlated in intestinal cells. SARS‐CoV‐2‐infected cells show similar patterns; however, the strength of the correlation is moderate. These results indicate differential ADAR editing in protein coding regions seen in SARS‐CoV‐1 and ‐2 infections may play a role in molecular mechanisms underlying clinical symptoms seen during infection. Conclusions Dynamic changes to protein structure and function like those caused by ADAR editing can help shed light on the pathogenesis of COVID‐19 and may provide novel investigative avenues for therapeutic options.