Brucella induces heme oxygenase‐1 expression to promote its infection

Transboundary and Emerging DiseasesVolume 69, Issue 5 p. 2697-2711 ORIGINAL ARTICLE Brucella induces heme oxygenase-1 expression to promote its infection Hai Hu, Hai Hu Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, P. R. ChinaSearch for more papers by this authorMingxing Tian, Mingxing Tian orcid.org/0000-0002-6794-2639 Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, P. R. ChinaSearch for more papers by this authorYi Yin, Yi Yin Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, P. R. ChinaSearch for more papers by this authorDong Zuo, Dong Zuo Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, P. R. ChinaSearch for more papers by this authorXiang Guan, Xiang Guan Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, P. R. ChinaSearch for more papers by this authorChan Ding, Corresponding Author Chan Ding [email protected] Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, P. R. China Jiangsu Coinnovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, P. R. China Correspondence Shengqing Yu and Chan Ding, Shanghai Veterinary Research Institute, CAAS, Shanghai, 200241, P. R. China. Email: [email protected]; [email protected]Search for more papers by this authorShengqing Yu, Corresponding Author Shengqing Yu [email protected] orcid.org/0000-0003-1586-4277 Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, P. R. China Jiangsu Coinnovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, P. R. China Correspondence Shengqing Yu and Chan Ding, Shanghai Veterinary Research Institute, CAAS, Shanghai, 200241, P. R. China. Email: [email protected]; [email protected]Search for more papers by this author Hai Hu, Hai Hu Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, P. R. ChinaSearch for more papers by this authorMingxing Tian, Mingxing Tian orcid.org/0000-0002-6794-2639 Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, P. R. ChinaSearch for more papers by this authorYi Yin, Yi Yin Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, P. R. ChinaSearch for more papers by this authorDong Zuo, Dong Zuo Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, P. R. ChinaSearch for more papers by this authorXiang Guan, Xiang Guan Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, P. R. ChinaSearch for more papers by this authorChan Ding, Corresponding Author Chan Ding [email protected] Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, P. R. China Jiangsu Coinnovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, P. R. China Correspondence Shengqing Yu and Chan Ding, Shanghai Veterinary Research Institute, CAAS, Shanghai, 200241, P. R. China. Email: [email protected]; [email protected]Search for more papers by this authorShengqing Yu, Corresponding Author Shengqing Yu [email protected] orcid.org/0000-0003-1586-4277 Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, P. R. China Jiangsu Coinnovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, P. R. China Correspondence Shengqing Yu and Chan Ding, Shanghai Veterinary Research Institute, CAAS, Shanghai, 200241, P. R. China. Email: [email protected]; [email protected]Search for more papers by this author First published: 17 December 2021 https://doi.org/10.1111/tbed.14422Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abstract Brucellosis is a zoonotic and contagious infectious disease caused by Brucella spp, which causes substantial economic losses to animal husbandry and leads to severe public health problems. Brucella have evolved multiple strategies to escape host immunity and survive within host cells. Elucidating the immune evasion strategies during Brucella infection will facilitate the control of brucellosis. The host enzyme, heme oxygenase-1 (HO-1), is a multifunctional protein that functions during inflammatory diseases and microbial infections. However, how HO-1 functions during Brucella infection is rarely studied. In this study, we evaluated the role of HO-1 during Brucella infection. We found that Brucella infection induced HO-1 expression in macrophages. We further showed that HO-1 was regulated by PI3K, AMPK kinase, and nuclear erythroid-related factor 2 (Nrf2) in macrophages. Interestingly, knocking out HO-1 or inhibiting the activity of HO-1 significantly decreased Brucella intracellular growth. Inducing the expression of HO-1 by treatment with CoPP promoted Brucella intracellular growth. Mechanistic analyses indicated that the effect of HO-1 was not meditated by HO-1 metabolites, but by decreasing the production of reactive oxygen species (ROS), TNF-α, and IL-1β. Moreover, Brucella induced HO-1 expression in bone marrow-derived macrophages (BMDMs) and mice. When the expression of HO-1 was knocked down in BMDMs, the intracellular survival of Brucella was reduced. Furthermore, the induction of HO-1 by CoPP significantly increased bacterial loads in vivo. Thus, we demonstrated that Brucella induced HO-1 expression to promote its survival and growth in vitro and in vivo. This study also identified HO-1 as a novel innate immune evasion factor during Brucella infection. CONFLICT OF INTEREST The authors declare no conflict of interest. Open Research DATA AVAILABILITY STATEMENT The data that support the findings of this study are available from the corresponding author upon reasonable request. Supporting Information Filename Description tbed14422-sup-0001-FigureS1.pdf131.9 KB Figure S1. (a) (b) The toxic effects of SnPP and CoPP on RAW264.7 cells were determined by a non-radioactive cytotoxicity assay. (c) The toxic effects of SnPP and CoPP on bacteria were determined by CFU assays. (d) The toxic effects of NAC on RAW264.7 cells were determined by a non-radioactive cytotoxicity assay. (d) The toxic effects of NAC on bacteria were determined by CFU assays. Data were analyzed using the two-way ANOVA method. no significance, *P < 0.05, **P < 0.01. tbed14422-sup-0002-FigureS2.pdf126.2 KB Figure S2. (a) The mRNA levels of HO-1 in spleens were determined by qPCR after Brucella infection. (b) The protein levels of HO-1 in spleens were determined by immunoblot analysis after Brucella infection. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume69, Issue5September 2022Pages 2697-2711 RelatedInformation