Mouse-adapted SARS-CoV-2 replicates efficiently in the upper and lower respiratory tract of BALB/c and C57BL/6J mice.
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ABSTRACT:
SUBMITTER: Wang J
PROVIDER: S-EPMC7401472 | biostudies-literature | 2020 Oct
REPOSITORIES: biostudies-literature
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Mouse-adapted SARS-CoV-2 replicates efficiently in the upper and lower respiratory tract of BALB/c and C57BL/6J mice.
Wang Jinliang J Shuai Lei L Wang Chong C Liu Renqiang R He Xijun X Zhang Xianfeng X Sun Ziruo Z Shan Dan D Ge Jinying J Wang Xijun X Hua Ronghong R Zhong Gongxun G Wen Zhiyuan Z Bu Zhigao Z
Protein & cell 20201001 10
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Project description:UNLABELLED:In March 2013, three fatal human cases of infection with influenza A virus (H7N9) were reported in China. Since then, human cases have been accumulating. Given the public health importance of this virus, we performed a pathogenicity study of the H7N9 virus in the cynomolgus macaque model, focusing on clinical aspects of disease, radiographic, histological, and gene expression profile changes in the upper and lower respiratory tracts, and changes in systemic cytokine and chemokine profiles during infection. Cynomolgus macaques developed transient, mild to severe disease with radiographic evidence of pulmonary infiltration. Virus replicated in the upper as well as lower respiratory tract, with sustained replication in the upper respiratory tract until the end of the experiment at 6 days after inoculation. Virus shedding occurred mainly via the throat. Histopathological changes in the lungs were similar to those observed in humans, albeit less severe, with diffuse alveolar damage, infiltration of polymorphonuclear cells, formation of hyaline membranes, pneumocyte hyperplasia, and fibroproliferative changes. Analysis of gene expression profiles in lung lesions identified pathways involved in tissue damage during H7N9 infection as well as leads for development of therapeutics targeting host responses rather than virus replication. Overall, H7N9 infection was not as severe in cynomolgus macaques as in humans, supporting the possible role of underlying medical complications in disease severity as discussed for human H7N9 infection (H. N. Gao et al., N. Engl. J. Med. 368:2277-2285, 2013, doi:10.1056/NEJMoa1305584). IMPORTANCE:Influenza A virus H7N9 emerged early in 2013, and human cases have continued to emerge since then. Although H7N9 virus-induced disease in humans is often very severe and even lethal, the majority of reported H7N9 cases occurred in older people and people with underlying medical conditions. To better understand the pathogenicity of this virus, healthy cynomolgus macaques were inoculated with influenza A virus H7N9. Cynomolgus macaques were used as a model because the receptor distribution for H7N9 virus in macaques was recently shown to be more similar to that in humans than that of other frequently used animal models. From comparison with previous studies, we conclude that the emerging H7N9 influenza virus was more pathogenic in cynomolgus macaques than seasonal influenza A viruses and most isolates of the pandemic H1N1 virus but less pathogenic than the 1918 Spanish influenza virus or highly pathogenic avian influenza (HPAI) H5N1 virus.
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Project description:BALB/c is an inbred stress-sensitive mouse strain exhibiting low brain serotonin (5-HT) content and a 5-HT biosynthetic enzyme tryptophan hydroxylase (Tph2) variant reported to have lower catalytic activity compared with other inbred base strains. To evaluate other mechanisms that may explain low 5-HT, we compared BALB/cJ mice and a control inbred strain C57Bl/6J mice, for expression of Tph2 mRNA, TPH2 protein and regional levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid. Tph2 mRNA and TPH2 protein in brainstem dorsal raphe nuclei was assayed by in situ hybridization and immunocytochemistry respectively. 5-HT and 5-hydroxyindoleacetic acid were determined by HPLC. BALB/cJ mice had 20% less Tph2 mRNA and 28% fewer TPH2 immunolabeled neurons than C57Bl/6J mice (t = -2.59, p = 0.02). The largest difference in Tph2 transcript expression was in rostral dorsal raphe nuclei (t = 2.731, p = 0.008). 5-HT was 15% lower in the midbrain and 18% lower in the cerebral cortex of BALB/cJ compared with C57Bl/6J mice (p < 0.05). The behavioral differences in BALB/cJ mice relative to the C57Bl/6J strain may be due in part, to fewer 5-HT neurons and lower Tph2 gene expression resulting in less 5-HT neurotransmission. Future studies quantifying expression per neuron are needed to determine whether less expression is explained by fewer neurons or also less expression per neuron, or both.
| S-EPMC4222035 | biostudies-literature
Project description:BackgroundUnderstanding the complex structures and interactions of the bacterial communities inhabiting the upper (URT) and lower (LRT) respiratory tract of pigs is at an early stage. The objective of this study was to characterize the bacterial topography of three URT (nostrils, choana, and tonsils) and LRT (proximal trachea, left caudal lobe and secondary bronchi) sites in pigs. Thirty-six post-mortem samples from six pigs were analysed by 16S rRNA gene quantification and sequencing, and the microbiota in nostrils and trachea was additionally profiled by shotgun sequencing.ResultsThe bacterial composition obtained by the two methods was congruent, although metagenomics recovered only a fraction of the diversity (32 metagenome-assembled genomes) due to the high proportion (85-98%) of host DNA. The highest abundance of 16S rRNA copies was observed in nostrils, followed by tonsils, trachea, bronchi, choana and lung. Bacterial richness and diversity were lower in the LRT compared to the URT. Overall, Firmicutes and Proteobacteria were identified as predominant taxa in all sample types. Glasserella (15.7%), Streptococcus (14.6%) and Clostridium (10.1%) were the most abundant genera but differences in microbiota composition were observed between the two tracts as well as between sampling sites within the same tract. Clear-cut differences were observed between nasal and tonsillar microbiomes (R-values 0.85-0.93), whereas bacterial communities inhabiting trachea and lung were similar (R-values 0.10-0.17). Moraxella and Streptococcus were more common in bronchial mucosal scraping than in lavage, probably because of mucosal adherence. The bacterial microbiota of the choana was less diverse than that of the nostrils and similar to the tracheal microbiota (R-value 0.24), suggesting that the posterior nasal cavity serves as the primary source of bacteria for the LRT.ConclusionWe provide new knowledge on microbiota composition and species abundance in distinct ecological niches of the pig respiratory tract. Our results shed light on the distribution of opportunistic bacterial pathogens across the respiratory tract and support the hypothesis that bacteria present in the lungs originate from the posterior nasal cavity. Due to the high abundance of host DNA, high-resolution profiling of the pig respiratory microbiota by shotgun sequencing requires methods for host DNA depletion.
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Project description:Routine screening of lung transplant recipients and hospital patients for respiratory virus infections allowed to identify human rhinovirus (HRV) in the upper and lower respiratory tracts, including immunocompromised hosts chronically infected with the same strain over weeks or months. Phylogenetic analysis of 144 HRV-positive samples showed no apparent correlation between a given viral genotype or species and their ability to invade the lower respiratory tract or lead to protracted infection. By contrast, protracted infections were found almost exclusively in immunocompromised patients, thus suggesting that host factors rather than the virus genotype modulate disease outcome, in particular the immune response. Complete genome sequencing of five chronic cases to study rhinovirus genome adaptation showed that the calculated mutation frequency was in the range observed during acute human infections. Analysis of mutation hot spot regions between specimens collected at different times or in different body sites revealed that non-synonymous changes were mostly concentrated in the viral capsid genes VP1, VP2 and VP3, independent of the HRV type. In an immunosuppressed lung transplant recipient infected with the same HRV strain for more than two years, both classical and ultra-deep sequencing of samples collected at different time points in the upper and lower respiratory tracts showed that these virus populations were phylogenetically indistinguishable over the course of infection, except for the last month. Specific signatures were found in the last two lower respiratory tract populations, including changes in the 5'UTR polypyrimidine tract and the VP2 immunogenic site 2. These results highlight for the first time the ability of a given rhinovirus to evolve in the course of a natural infection in immunocompromised patients and complement data obtained from previous experimental inoculation studies in immunocompetent volunteers.
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Project description:Uncertainty persists whether anaerobic bacteria represent important pathogens in aspiration pneumonia. In a nested case-control study of mechanically ventilated patients classified as macro-aspiration pneumonia (MAsP, n = 56), non-macro-aspiration pneumonia (NonMAsP, n = 91), and uninfected controls (n = 11), we profiled upper (URT) and lower respiratory tract (LRT) microbiota with bacterial 16S rRNA gene sequencing, measured plasma host-response biomarkers, analyzed bacterial communities by diversity and oxygen requirements, and performed unsupervised clustering with Dirichlet Multinomial Models (DMM). MAsP and NonMAsP patients had indistinguishable microbiota profiles by alpha diversity and oxygen requirements with similar host-response profiles and 60-day survival. Unsupervised DMM clusters revealed distinct bacterial clusters in the URT and LRT, with low-diversity clusters enriched for facultative anaerobes and typical pathogens, associated with higher plasma levels of SPD and sCD14 and worse 60-day survival. The predictive inter-patient variability in these bacterial profiles highlights the importance of microbiome study in patient sub-phenotyping and precision medicine approaches for severe pneumonia.
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Project description:We reported earlier that the endocochlear potential (EP) differs between C57BL/6J (B6) and BALB/cJ (BALB) mice, being lower in BALBs by about 10 mV (Ohlemiller et al. Hear Res 220: 10-26, 2006). This difference corresponds to strain differences with respect to the density of marginal cells in cochlear stria vascularis. After about 1 year of age, BALB mice also tend toward EP reduction that correlates with further marginal cell loss. We therefore suggested that early sub-clinical features of the BALB stria vascularis may predispose these mice to a condition modeling Schuknecht's strial presbycusis. We further reported (Ohlemiller et al. J Assoc Res Otolaryngol 12: 45-58, 2011) that the acute effects of a 2-h 110 dB SPL noise exposure differ between B6 and BALB mice, such that the EP remains unchanged in B6 mice, but is reduced by 40-50 mV in BALBs. In about 25 % of BALBs, the EP does not completely recover, so that permanent EP reduction may contribute to noise-induced permanent threshold shifts in BALBs. To identify genes and alleles that may promote natural EP variation as well as noise-related EP reduction in BALB mice, we have mapped related quantitative trait loci (QTLs) using 12 recombinant inbred (RI) strains formed from B6 and BALB (CxB1-CxB12). EP and strial marginal cell density were measured in B6 mice, BALB mice, their F1 hybrids, and RI mice without noise exposure, and 1-3 h after broadband noise (4-45 kHz, 110 dB SPL, 2 h). For unexposed mice, the strain distribution patterns for EP and marginal cell density were used to generate preliminary QTL maps for both EP and marginal cell density. Six QTL regions were at least statistically suggestive, including a significant QTL for marginal cell density on chromosome 12 that overlapped a weak QTL for EP variation. This region, termed Maced (Marginal cell density QTL) supports the notion of marginal cell density as a genetically influenced contributor to natural EP variation. Candidate genes for Maced notably include Foxg1, Foxa1, Akap6, Nkx2-1, and Pax9. Noise exposure produced significant EP reductions in two RI strains as well as significant EP increases in two RI strains. QTL mapping of the EP in noise-exposed RI mice yielded four suggestive regions. Two of these overlapped with QTL regions we previously identified for noise-related EP reduction in CBA/J mice (Ohlemiller et al. Hear Res 260: 47-53, 2010) on chromosomes 5 and 18 (Nirep). The present map may narrow the Nirep interval to a ~10-Mb region of proximal Chr. 18 that includes Zeb1, Arhgap12, Mpp7, and Gjd4. This study marks the first exploration of natural gene variants that modulate the EP. Their orthologs may underlie some human hearing loss that originates in the lateral wall.
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Project description:BackgroundThe microbiota of the bovine upper respiratory tract has been recently characterized, but no data for the lower respiratory tract are available. A major health problem in bovine medicine is infectious bronchopneumonia, the most common respiratory syndrome affecting cattle. With this study, we used 16S rRNA gene sequencing to characterize and compare the microbial community composition of the upper and lower respiratory tracts in calves.ResultsThe microbiota of the upper (nasal swab [NS]) and the lower (trans-tracheal aspiration [TTA]) respiratory tracts of 19 post-weaned Piedmontese calves with (8/19) and without (11/19) clinical signs of respiratory disease, coming from six different farms, was characterized by 16S rRNA gene metabarcoding. A total of 29 phyla (29 in NS, 21 in TTA) and 305 genera (289 in NS, 182 in TTA) were identified. Mycoplasma (60.8%) was the most abundant genus identified in both the NS (27.3%) and TTA (76.7%) samples, followed by Moraxella (16.6%) in the NS and Pasteurella (7.3%) in the TTA samples. Pasteurella multocida (7.3% of total operational taxonomic units [OTUs]) was the most abundant species in the TTA and Psychrobacter sanguinis (1.1% of total OTUs) in the NS samples. Statistically significant differences between the NS and the TTA samples were found for both alpha (Shannon index, observed species, Chao1 index, and Simpson index; P = 0.001) and beta (Adonis; P = 0.001) diversity. Comparison of the NS and TTA samples by farm origin and clinical signs revealed no statistical difference (P > 0.05), except for farm origin for the NS samples when compared by the unweighted UniFrac metric (P = 0.05).ConclusionsUsing 16S rRNA gene sequencing, we characterized the microbiota of the upper and lower respiratory tracts of calves, both healthy individuals and those with clinical signs of respiratory disease. Our results suggest that environmental factors may influence the composition of the upper airway microbiota in cattle. While the two microbial communities (upper and lower airways) differed in microbial composition, they shared several OTUs, suggesting that the lung microbiota may be a self-sustaining, more homogeneous ecosystem, influenced by the upper respiratory tract microbiota.
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Project description:Analyses of human lung metagenome by nanopore sequencing
| PRJNA720304 | ENA
Project description:Granuloma formation is an inflammatory response of the host against invading pathogens or indigestible substances. We generated mesenteric oil granulomas by injecting pristane into the peritoneal cavity (PC) of mice, and compared oil granuloma formation in the C57BL/6J and BALB/cByJ strains of mice. The formation and kinetics of oil granulomas were distinct between the two strains. In C57BL/6J mice, injected pristane induced oil granuloma formation at both the mesenteric centers (MG) and margins (SG). MG was resolving by 11 weeks, and SG persisted. In BALB/cByJ mice, MG developed slower but persisted longer than in C57BL/6J mice, and SG resolved sooner than in C57BL/6J mice. Injection of India ink revealed that phagocytes were localised mainly to the SG in C57BL/6J mice, but were located diffusely in both MG and SG of BALB/cByJ mice. SG cells expressed more monocyte chemotactic protein-1 (MCP-1) mRNA than MG cells in C57BL/6J mice, but there was no difference in MCP-1 expression between the MG and SG in BALB/cByJ mice. These observations suggest that the recruitment of inflammatory leucocytes under the direction of chemokines differentiates the patterns of granuloma responses to pristane in C57BL/6J and BALB/cByJ mice.
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Project description:BackgroundLower respiratory infections caused by ssRNA viruses are a major health burden globally. Translational mouse models are a valuable tool for medical research, including research on respiratory viral infections. In in vivo mouse models, synthetic dsRNA can be used as a surrogate for ssRNA virus replication. However, studies investigating how genetic background of mice impacts the murine lung inflammatory response to dsRNA is lacking. Hence, we have compared lung immunological responses of BALB/c, C57Bl/6N and C57Bl/6J mice to synthetic dsRNA.MethodsdsRNA was administered intranasally to BALB/c, C57Bl/6N and C57Bl/6J mice once/day for three consecutive days. Lactate dehydrogenase (LDH) activity, inflammatory cells, and total protein concentration were analyzed in bronchoalveolar lavage fluid (BALF). Pattern recognition receptors levels (TLR3, MDA5 and RIG-I) were measured in lung homogenates using RT-qPCR and western blot. Gene expression of IFN-β, TNF-α, IL-1β and CXCL1 was assessed in lung homogenates by RT-qPCR. ELISA was used to analyze protein concentrations of CXCL1 and IL-1β in BALF and lung homogenates.ResultsBALB/c and C57Bl/6J mice showed infiltration of neutrophils to the lung, and an increase in total protein concentration and LDH activity in response to dsRNA administration. Only modest increases in these parameters were observed for C57Bl/6N mice. Similarly, dsRNA administration evoked an upregulation of MDA5 and RIG-I gene and protein expression in BALB/c and C57Bl/6J, but not C57Bl/6N, mice. Further, dsRNA provoked an increase in gene expression of TNF-α in BALB/c and C57Bl/6J mice, IL-1β only in C57Bl/6N mice and CXCL1 exclusively in BALB/c mice. BALF levels of CXCL1 and IL-1β were increased in BALB/c and C57Bl/6J mice in response to dsRNA, whereas the response of C57Bl/6N was blunt. Overall, inter-strain comparisons of the lung reactivity to dsRNA revealed that BALB/c, followed by C57Bl/6J, had the most pronounced respiratory inflammatory responses, while the responses of C57Bl/6N mice were attenuated.ConclusionsWe report clear differences of the lung innate inflammatory response to dsRNA between BALB/c, C57Bl/6J and C57Bl/6N mice. Of particular note, the highlighted differences in the inflammatory response of C57Bl/6J and C57Bl/6N substrains underscore the value of strain selection in mouse models of respiratory viral infections.
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