Project description:Zoonotic viruses are an omnipresent threat to global health. Influenza A virus (IAV) transmits between birds, livestock, and humans. Proviral host factors involved in the cross-species interface are well known, less is known about antiviral mechanisms that suppress IAV zoonoses. We observed CpG dinucleotide depletion in human IAV relative to avian IAV. Notably, human ZAP selectively depletes CpG-enriched viral RNAs with its cofactor KHNYN. ZAP is conserved in tetrapods but we uncovered that avian species lack KHNYN. We found that chicken ZAP does not affect IAV (PR8) or CpG enriched IAV. Human ZAP or KHNYN independently restricted CpG enriched IAV by overexpression in chicken cells or knockout in human cells. Additionally, mammalian ZAP-L and KHNYN also independently restricted an avian retrovirus (ROSV). Curiously, platypus KHNYN, the most divergent from eutherian mammals, was also capable of direct restriction of multiple diverse viruses. We suggest that mammalian KHNYN may be a bona fide restriction factor with cell-autonomous activity. Furthermore, we speculate that through repeated contact between avian viruses and mammalian hosts, protein changes may accompany CpG-biased mutations or reassortment to evade mammalian ZAP and KHNYN.
Project description:Background. Leptospirosis is among the most widespread zoonoses worldwide. Severe pulmonary hemorrhagic syndrome (SPHS) represents a serious complication of leptospirosis, with poor understanding of its underlying mechanisms and an urgent need for identification of effective biomarkers. Methods. A nested case-control analysis of the blood specimens obtained from two previous multi-center cohorts was conducted. Candidate microRNAs were initially discovered through a global profiling of 800 serum microRNAs, then validated using real-time polymerase-chain reactions. We further conducted a multi-omics analysis incorporating transcriptomic and proteomic data to identify enriched pathways through which the newly identified microRNAs could regulate. Findings. A total of 28 SPHS and 140 non-SPHS patients were evaluated by serum microRNA profiling, revealing distinct expression patterns between the two phenotypes. From the top 81 significantly expressed microRNAs, seven were selected for validation. Among these, miR-5010-3p and miR-147b-3p had area under the curve (AUC) values of 0.72 (95% CI: 0·62–0·81) and 0·66 (95% CI: 0·55–0·76) for discriminating SPHS. Notably, the two microRNAs could detect SPHS in patients who were yet to manifest chest radiograph shadows at the time of sample collection, and in a subgroup of patients who were recruited on day 2 of illness or earlier, with consistent AUC values. Integrated gene-protein pathway enrichment analysis revealed numerous pathways involving host immune responses. Among these, the tumor necrosis factor signaling pathway was the most significant with many of its member genes being targeted by miR-5010-3p or miR-147b-3p.
Project description:Novel coronavirus causing Covid-19 identified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused pandemic in 2020. Although the virus and disease in humans has been thoroughly researched, so far there has not been animal model comparable to humans – genetically diverse species able to get infected and sick from Covid-19. The white-footed deermouse Peromyscus leucopus is a long-lived rodent and a key reservoir in North America for agents of several zoonoses including Lyme disease, babesiosis, anaplasmosis, and viral encephalitis. While persistently infected, this deermouse avoids apparent disability or diminished fitness. Its tolerance to infection with sometimes more than one pathogen makes P. leucopus comparable to bats. This study uses P. leucopus, LL colony stock, as a genetically diverse animal model for viral infection with SARS-CoV-2. We infected P. leucopus with SARS-CoV-2, collected plasma, lungs, and brain 3 and 6 days post-infection, and compared to control animals. P. leucopus mount an immune response against viral pathogens through production of neutralizing antibodies and genome-wide transcription of type I interferon stimulated genes in lungs compared to naïve animals. Viral RNA detection correlates with gene expression of type I interferon stimulated genes in response to viral infection in the brain. We report that diversity of outbred animals, their sex and age is reflected in the range of responses. These results show that P. leucopus is a viable animal model for SARS-CoV-2, particularly in research of viral infection of the brain.
Project description:Brucellosis is one of the most widespread bacterial zoonoses worldwide. Here, our aim was to identify the effector mechanisms controlling the early stages of intranasal infection with Brucella in C57BL/6 mice. During the first 48 hours of infection, alveolar macrophages (AMs) are the main cells infected in the lungs. Using RNA sequencing, we identified the aconitate decarboxylase 1 gene (Acod1; also known as Immune responsive gene 1), as one of the genes most upregulated in murine AMs in response to B. melitensis infection at 24 hours post-infection. Upregulation of Acod1 was confirmed by RT-qPCR in lungs infected with B. melitensis and B. abortus. We observed that Acod1-/- C57BL/6 mice display a higher bacterial load in their lungs than wild-type (wt) mice following B. melitensis or B. abortus infection, demonstrating that Acod1 participates in the control of pulmonary Brucella infection. The ACOD1 enzyme is mostly produced in mitochondria of macrophages, and converts cis-aconitate, a metabolite in the Krebs cycle, into itaconate. Dimethyl itaconate (DMI), a chemically-modified membrane permeable form of itaconate, has a dose-dependent inhibitory effect on Brucella growth in vitro. Interestingly, modelling studies suggest the binding of itaconate into the binding site of isocitrate lyase. DMI does not inhibit multiplication of the isocitrate lyase deletion mutant ∆aceA B. abortus in vitro. Finally, we observed that, unlike the wt strain, the ∆aceA B. abortus strain multiplies similarly in wt and Acod1-/- C57BL/6 mice. These data suggest that bacterial isocitrate lyase might be a target of itaconate in AMs.
Project description:Novel coronavirus causing Covid-19 identified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused pandemic in 2020. Although the virus and disease in humans has been thoroughly researched, so far there has not been animal model comparable to humans – genetically diverse species able to get infected and sick from Covid-19. The white-footed deermouse Peromyscus leucopus is a long-lived rodent and a key reservoir in North America for agents of several zoonoses including Lyme disease, babesiosis, anaplasmosis, and viral encephalitis. While persistently infected, this deermouse avoids apparent disability or diminished fitness. Its tolerance to infection with sometimes more than one pathogen makes P. leucopus comparable to bats. This study uses P. leucopus, LL colony stock, as a genetically diverse animal model for viral infection with SARS-CoV-2. We infected P. leucopus with SARS-CoV-2, collected plasma, lungs, and brain 3 and 6 days post-infection, and compared to control animals. P. leucopus mount an immune response against viral pathogens through production of neutralizing antibodies and genome-wide transcription of type I interferon stimulated genes in lungs compared to naïve animals. Viral RNA detection correlates with gene expression of type I interferon stimulated genes in response to viral infection in the brain. We report that diversity of outbred animals, their sex and age is reflected in the range of responses. These results show that P. leucopus is a viable animal model for SARS-CoV-2, particularly in research of viral infection of the brain.
Project description:Novel coronavirus causing Covid-19 identified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused pandemic in 2020. Although the virus and disease in humans has been thoroughly researched, so far there has not been animal model comparable to humans – genetically diverse species able to get infected and sick from Covid-19. The white-footed deermouse Peromyscus leucopus is a long-lived rodent and a key reservoir in North America for agents of several zoonoses including Lyme disease, babesiosis, anaplasmosis, and viral encephalitis. While persistently infected, this deermouse avoids apparent disability or diminished fitness. Its tolerance to infection with sometimes more than one pathogen makes P. leucopus comparable to bats. This study uses P. leucopus, LL colony stock, as a genetically diverse animal model for viral infection with SARS-CoV-2. We infected P. leucopus with SARS-CoV-2, collected plasma, lungs, and brain 3 and 6 days post-infection, and compared to control animals. P. leucopus mount an immune response against viral pathogens through production of neutralizing antibodies and genome-wide transcription of type I interferon stimulated genes in lungs compared to naïve animals. Viral RNA detection correlates with gene expression of type I interferon stimulated genes in response to viral infection in the brain. We report that diversity of outbred animals, their sex and age is reflected in the range of responses. These results show that P. leucopus is a viable animal model for SARS-CoV-2, particularly in research of viral infection of the brain.