{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T16:54:18Z","timestamp":1772643258295,"version":"3.50.1"},"reference-count":32,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T00:00:00Z","timestamp":1751241600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key Research and Development Program of China","award":["2024YFC2309300"],"award-info":[{"award-number":["2024YFC2309300"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Nocardia, an easily missed but potentially fatal opportunistic pathogen, can lead to serious infections like lung and brain abscesses. Intranasal inoculation (IN) is the traditional approach for constructing a Nocardia-induced pneumonia mice model, while it usually only results in limited local bacterial infection in the lungs. To comprehensively assess infection dynamics across distinct pulmonary inoculation routes in mice models, this study compared the pathogenicity of three different Nocardia farcinica pneumonia models established via IN, intratracheal aerosolization (ITA), and intratracheal instillation (ITI). C57BL\/6J mice were infected with N. farcinica through IN, ITA and ITI with comparative analyses of bacterial distribution in lungs, survival rate, weight, bacterial load, inflammatory cytokines, histopathological characteristics and transcriptome differences. The findings suggest that ITA N. farcinica infections caused severer clinical symptoms, higher mortality, pulmonary bacterial load, levels of inflammatory cytokines in bronchoalveolar lavage fluid, and more significant histopathological damage to lungs than IN and ITI. Furthermore, ITA resulted in better lung bacterial distribution and delivery efficiency than ITI and IN. Transcriptome analysis of lungs from N. farcinica infected mice via IN, ITA and ITI revealed significant differential gene expression, whereas ITA route resulted in a larger fold change. ITA provides a more consistent and severe model of N. farcinica pneumonia in mice than IN and ITI, which can make the bacteria more evenly distributed in the lungs, leading to more severe pathological damage and higher mortality rates. In conclusion, ITA is an optimal route for developing animal models of N. farcinica pneumonia infections.<\/jats:p>","DOI":"10.3390\/biom15070950","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T07:55:43Z","timestamp":1751442943000},"page":"950","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Intratracheal Aerosolization of Nocardia farcinica in Mice Optimizes Bacterial Distribution and Enhances Pathogenicity Compared to Intranasal Inoculation and Intratracheal Instillation"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-4862-0705","authenticated-orcid":false,"given":"Bingqian","family":"Du","sequence":"first","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102200, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziyu","family":"Song","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102200, China"},{"name":"Wenzhou Key Laboratory of Sanitary Microbiology, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jirao","family":"Shen","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102200, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiang","family":"Yao","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102200, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuai","family":"Xu","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102200, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaotong","family":"Qiu","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102200, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2723-2173","authenticated-orcid":false,"given":"Min","family":"Yuan","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102200, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0947-8839","authenticated-orcid":false,"given":"Zhenjun","family":"Li","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102200, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Traxler, R.M., Bell, M.E., Lasker, B., Headd, B., Shieh, W.J., and McQuiston, J.R. (2022). Updated Review on Nocardia Species: 2006\u20132021. Clin. Microbiol. Rev., 35.","DOI":"10.1128\/cmr.00027-21"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1128\/CMR.7.3.357","article-title":"The medically important aerobic actinomycetes: Epidemiology and microbiology","volume":"7","author":"McNeil","year":"1994","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Thipmontree, W., and Suputtamonkol, Y. (2024). Comparison of clinical outcomes of pulmonary nocardiosis between AIDS and non-AIDS patients. BMC Infect. Dis., 28.","DOI":"10.1186\/s12879-024-09519-2"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Ji, X., Han, L., Zhang, W., Sun, L., Xu, S., Qiu, X., Fan, S., and Li, Z. (2022). Molecular, cellular and neurological consequences of infection by the neglected human pathogen Nocardia. BMC Biol., 20.","DOI":"10.1186\/s12915-022-01452-7"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"107147","DOI":"10.1016\/j.micpath.2024.107147","article-title":"Multicenter systematic review of clinical characteristics, diagnostic optimization, and personalized treatment for brain Nocardia infections","volume":"198","author":"Shen","year":"2025","journal-title":"Microb. Pathog."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e12436","DOI":"10.1097\/MD.0000000000012436","article-title":"Manifestations and outcomes of nocardia infections: Comparison of immunocompromised and nonimmunocompromised adult patients","volume":"97","author":"Steinbrink","year":"2018","journal-title":"Medicine"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1093\/infdis\/134.3.286","article-title":"Nocardial infections in the United States, 1972\u22121974","volume":"134","author":"Beaman","year":"1976","journal-title":"J. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.micpath.2017.11.012","article-title":"Nocardiosis from 1888 to 2017","volume":"114","year":"2018","journal-title":"Microb. Pathog."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1097\/00005792-199807000-00004","article-title":"Nocardia bacteremia. Report of 4 cases and review of the literature","volume":"77","author":"Kontoyiannis","year":"1998","journal-title":"Medicine"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1128\/CMR.7.2.213","article-title":"Nocardia species: Host-parasite relationships","volume":"7","author":"Beaman","year":"1994","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_11","first-page":"1444","article-title":"Factors affecting survival in nocardiosis","volume":"108","author":"Presant","year":"1973","journal-title":"Am. Rev. Respir. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Hashemzadeh, M., Dezfuli, A.A.Z., Khosravi, A.D., Savari, M., and Jahangirimehr, F. (2021). Genotypic and phenotypic prevalence of Nocardia species in Iran: First systematic review and meta-analysis of data accumulated over years 1992\u20132021. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0254840"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.ijid.2016.10.031","article-title":"Nocardia elegans infection: A case report and literature review","volume":"54","author":"Nakamura","year":"2017","journal-title":"Int. J. Infect. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.diagmicrobio.2018.12.007","article-title":"Clinical features, identification, antimicrobial resistance patterns of Nocardia species in China: 2009\u20132017","volume":"94","author":"Huang","year":"2019","journal-title":"Diagn. Microbiol. Infect. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Shen, J., Han, L., Yao, J., Qiu, X., Xu, S., Liu, X., Li, F., and Li, Z. (2024). Infection route influence the consequences of Nocardia farcinica infection in BALB\/c mice. BMC Infect. Dis., 24.","DOI":"10.1186\/s12879-024-09877-x"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1128\/iai.22.3.867-877.1978","article-title":"Lung response to congenitally athymic (nude), heterozygous, and Swiss Webster mice to aerogenic and intranasal infection by Nocardia asteroides","volume":"22","author":"Beaman","year":"1978","journal-title":"Infect. Immun."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Bergamini, G., Perico, M.E., Di Palma, S., Sabatini, D., Andreetta, F., Defazio, R., Felici, A., Ferrari, L., and Subbian, S. (2021). Mouse pneumonia model by Acinetobacter baumannii multidrug resistant strains: Comparison between intranasal inoculation, intratracheal instillation and oropharyngeal aspiration techniques. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0260627"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1186\/s12985-024-02516-6","article-title":"Comparative pathogenicity of influenza virus-induced pneumonia mouse model following intranasal and aerosolized intratracheal inoculation","volume":"21","author":"Jin","year":"2024","journal-title":"Virol. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"102606","DOI":"10.1016\/j.tube.2025.102606","article-title":"Preclinical model of Mycobacteroides abscessus lung disease by nose-only exposure of mice to bacterial powder aerosol","volume":"151","author":"Verma","year":"2025","journal-title":"Tuberculosis"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"14925","DOI":"10.1073\/pnas.0406410101","article-title":"The complete genomic sequence of Nocardia farcinica IFM 10152","volume":"101","author":"Ishikawa","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7S","DOI":"10.1177\/0192623312438738","article-title":"International harmonization of toxicologic pathology nomenclature: An overview and review of basic principles","volume":"40","author":"Mann","year":"2012","journal-title":"Toxicol. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"i884","DOI":"10.1093\/bioinformatics\/bty560","article-title":"fastp: An ultra-fast all-in-one FASTQ preprocessor","volume":"34","author":"Chen","year":"2018","journal-title":"Bioinformatics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.3317","article-title":"HISAT: A fast spliced aligner with low memory requirements","volume":"12","author":"Kim","year":"2015","journal-title":"Nat. Methods"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Li, B., and Dewey, C.N. (2011). RSEM: Accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinform., 12.","DOI":"10.1186\/1471-2105-12-323"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Love, M.I., Huber, W., and Anders, S. (2014). Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol., 15.","DOI":"10.1186\/s13059-014-0550-8"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e12","DOI":"10.1002\/imt2.12","article-title":"Majorbio Cloud: A one-stop, comprehensive bioinformatic platform for multiomics analyses","volume":"1","author":"Ren","year":"2022","journal-title":"Imeta"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1080\/17460913.2024.2355738","article-title":"Mice fatal pneumonia model induced by less-virulent Streptococcus pneumoniae via intratracheal aerosolization","volume":"19","author":"Wang","year":"2024","journal-title":"Future Microbiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s40794-024-00229-w","article-title":"Secreted protein NFA47630 from Nocardia farcinica IFM10152 induces immunoprotective effects in mice","volume":"10","author":"Han","year":"2024","journal-title":"Trop. Dis. Travel Med. Vaccines"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e01620","DOI":"10.1016\/j.idcr.2022.e01620","article-title":"Disseminated nocardiosis in an immunocompetent host with occupational exposure","volume":"30","author":"Lam","year":"2022","journal-title":"IDCases."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e0089324","DOI":"10.1128\/msystems.00893-24","article-title":"Activation of NF-\u03baB\/MAPK signaling and induction of apoptosis by salicylate synthase NbtS in Nocardia farcinica promotes neuroinflammation development","volume":"9","author":"Shen","year":"2024","journal-title":"mSystems"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Wu, J., Ma, Y., Nie, Y., Wang, J., Feng, G., Hao, L., Huang, W., Li, Y., and Liu, Z. (2022). Functional Characterization of Largemouth Bass (Micropterus salmoides) Soluble Fc\u03b3R Homolog in Response to Bacterial Infection. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232213788"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1084\/jem.186.7.1027","article-title":"A critical role for Syk in signal transduction and phagocytosis mediated by Fcgamma receptors on macrophages","volume":"186","author":"Crowley","year":"1997","journal-title":"J. Exp. Med."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/7\/950\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:02:03Z","timestamp":1760032923000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/7\/950"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,30]]},"references-count":32,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["biom15070950"],"URL":"https:\/\/doi.org\/10.3390\/biom15070950","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,30]]}}}