Emerging Microbes & Infections最新文献

{"title":"Rapid surge of reassortant A(H1N1) influenza viruses in Danish swine and their zoonotic potential.","authors":"Pia Ryt-Hansen, Sophie George, Charlotte Kristiane Hjulsager, Ramona Trebbien, Jesper Schak Krog, Marta Maria Ciucani, Sine Nygaard Langerhuus, Jennifer DeBeauchamp, Jeri Carol Crumpton, Taylor Hibler, Richard J Webby, Lars Erik Larsen","doi":"10.1080/22221751.2025.2466686","DOIUrl":"10.1080/22221751.2025.2466686","url":null,"abstract":"<p><p>In 2018, a single detection of a novel reassortant swine influenza A virus (swIAV) was made in Denmark. The hemagglutinin (HA) of the virus was from the H1N1 pandemic 2009 (H1N1pdm09) lineage and the neuraminidase (NA) from the H1N1 Eurasian avian-like swine lineage (H1N1av). By 2022, the novel reassortant virus (H1pdm09N1av) constituted 27% of swIAVs identified through the Danish passive swIAV surveillance program. Sequencing detected two H1pdm09N1av genotypes; Genotype 1 contained an entire internal gene cassette of H1N1pdm09 origin, Genotype 2 differed by carrying an NS gene segment of H1N1av origin. The internal gene cassette of Genotype 2 became increasingly dominant, not only in the H1pdm09N1av population, but also in other Danish enzootic swIAV subtypes. Phylogenetic analysis of the HA genes from H1pdm09N1av viruses revealed a monophyletic source, a higher substitution rate compared to other H1N1pdm09 viruses and genetic differences with human seasonal and other swine adapted H1N1pdm09 viruses. Correspondingly, H1pdm09N1av viruses were antigenically distinct from human H1N1pdm09 vaccine viruses. Both H1pdm09N1av genotypes transmitted between ferrets by direct contact, but only Genotype 1 was capable of efficient aerosol transmission. The rapid spread of H1pdm09N1av viruses in Danish swine herds is concerning for swine and human health. Their zoonotic threat is highlighted by the limited pre-existing immunity observed in the human population, aerosol transmission in ferrets and the finding that the internal gene cassette of Genotype 2 was present in the first two zoonotic influenza infections ever detected in Denmark.</p>","PeriodicalId":11602,"journal":{"name":"Emerging Microbes & Infections","volume":" ","pages":"2466686"},"PeriodicalIF":8.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11849018/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143406513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An immunocompetent mouse model revealed that congenital Zika virus infection disrupted hippocampal function by activating autophagy.","authors":"Wei Yang, Zhan-Zhan Bian, Zhe Li, Yi-Teng Zhang, Li-Bo Liu, Jia-Tong Chang, Dan Li, Pei-Gang Wang, Jing An, Wei Wang","doi":"10.1080/22221751.2025.2465327","DOIUrl":"10.1080/22221751.2025.2465327","url":null,"abstract":"<p><p>Congenital Zika virus (ZIKV) infection significantly affects neurological development in infants and subsequently induces neurodevelopmental abnormality symptoms; however, the potential mechanism is still unknown. Therefore, in order to effectively intervene in neurodevelopmental abnormalities in infected infants, it is necessary to identify the main brain regions affected by congenital infection. In this study, we constructed a congenital ZIKV-infected murine model using immunocompetent human STAT2 knock-in mice, which presented long-term neurodevelopmental abnormalities with abnormal neurodevelopmental symptoms. We found that the hippocampus, which regulates cognitive behaviour and processes spatial information and navigation, was the main brain region affected by congenital infection and that hippocampal cells were more prone to autophagy during the growth period of these mice at the transcriptional and pathological levels. These findings highlighted that congenital ZIKV infection could interrupt hippocampal function by activating autophagy, thus providing a theoretical basis for the clinical treatment of congenital ZIKV-infected infants.</p>","PeriodicalId":11602,"journal":{"name":"Emerging Microbes & Infections","volume":" ","pages":"2465327"},"PeriodicalIF":8.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11873970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143406511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reverse genetics-derived cattle H5N1 virus from Clade 2.3.4.4b shows enhanced systemic infectivity and pathogenicity than an older Clade 1 H5N1 virus in BALB/c mice.","authors":"Na Xiao, Xiang Yong Oong, Yanxia Chen, Can Li, Howard Chun-Ho Chung, Pui Wang, Zhanhong Ye, Alvin Hiu-Chung Lam, Jianpiao Cai, Wenchen Song, Andrew Chak-Yiu Lee, Hin Chu, Kin-Hang Kok, Jasper Fuk-Woo Chan, Shuofeng Yuan, Honglin Chen, Kwok-Yung Yuen, Anna Jin-Xia Zhang","doi":"10.1080/22221751.2025.2475836","DOIUrl":"10.1080/22221751.2025.2475836","url":null,"abstract":"<p><p>The newly emerged avian influenza A H5N1 Clade 2.3.4.4b can infect dairy cows and shed live virus in their milk. Sporadic cattle-to-human infections have been reported, highlighting the urgent need to understand its pathogenesis in mammals. Using both non-lactating and lactating BALB/c mice, we examined the viral tissue tropism, histopathological damages, and host immune responses upon intranasal inoculation with a reverse-genetic virus constructed based on A/dairy cattle/Texas/24-008749-003/2024 (Cattle-H5N1) and comparing with an older reference Clade 1 virus, A/Vietnam/1194/2004 virus (VNM1194-H5N1). Cattle-H5N1 was highly lethal in mice (mLD₅₀ = 1.48PFU) with broad tissue tropism and produced higher titer in respiratory tissue and multiple extrapulmonary organs than VNM1194-H5N1. In the lungs, Cattle-H5N1 infection of airway epithelium, type II pneumocytes and CD45⁺ immune cells were at a higher frequency than those of VNM1194-H5N1-infected mice, resulting in severe epithelial destruction and diffuse alveolar damage accompanied by elevated lung and serum pro-inflammatory cytokine/chemokines. Although both H5N1 viruses showed lactating mammary gland tropism, the gland tissue was more severely damaged after Cattle-H5N1 infection with abundant viral antigens expression in glandular cells, associated fat and lymphoid tissues. Furthermore, more suckling mice co-housed with Cattle-H5N1 infected lactating mice were virus-positive (7/30 pups) than VNM1194-H5N1. Brains were heavily infected by Cattle-H5N1, and neurological signs such as body-rolling/spinning, trembling and/or limb paralysis were seen only in Cattle-H5N1 infected mice. The spleen was more severely damaged by Cattle-H5N1 infection, which showed massive viral antigen expression accompanied by severe apoptosis and splenic atrophy, concluding that Cattle-H5N1 is more virulent in mice than VNM1194-H5N1.</p>","PeriodicalId":11602,"journal":{"name":"Emerging Microbes & Infections","volume":" ","pages":"2475836"},"PeriodicalIF":8.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Marked neurotropism and potential adaptation of H5N1 clade 2.3.4.4.b virus in naturally infected domestic cats.","authors":"Shubhada K Chothe, Surabhi Srinivas, Sougat Misra, Noel Chandan Nallipogu, Elizabeth Gilbride, Lindsey LaBella, Swastidipa Mukherjee, Christian H Gauthier, Heidi L Pecoraro, Brett T Webb, James M Pipas, Santhamani Ramasamy, Suresh V Kuchipudi","doi":"10.1080/22221751.2024.2440498","DOIUrl":"10.1080/22221751.2024.2440498","url":null,"abstract":"<p><p>In April 2024, ten cats died in a rural South Dakota (SD) residence, showing respiratory and neurological symptoms. Necropsy and laboratory testing of two cats confirmed H5N1 clade 2.3.4.4b infection. The viral genome sequences are closely related to recent SD cattle H5N1 sequences. Cat H5N1 genomes had unique mutations, including T143A in haemagglutinin, known to affect infectivity and immune evasion, and two novel mutations in PA protein (F314L, L342Q) that may affect polymerase activity and virulence, suggesting potential virus adaptation. Dead cats showed systemic infection with lesions and viral antigens in multiple organs. Higher viral RNA and antigen in the brain indicated pronounced neurotropism. Lectin-histochemistry revealed widespread co-expression of sialic acid α-2,6 and α-2,3 receptors, suggesting cats could serve as mixing vessels for reassortment of avian and mammalian influenza viruses. No differences in clade 2.2 or 2.3.4.4b H5 pseudoviruses binding to cat lung/brain tissues indicated the neurotropism is unlikely mediated by receptor binding affinity.</p>","PeriodicalId":11602,"journal":{"name":"Emerging Microbes & Infections","volume":" ","pages":"2440498"},"PeriodicalIF":8.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11654043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mosquito populations originating from nonendemic areas have the potential to transmit recently emerging Japanese encephalitis virus genotype IV.","authors":"Astri Nur Faizah, Daisuke Kobayashi, Faustus Akankperiwen Azerigyik, Ryo Matsumura, Izumi Kai, Yoshihide Maekawa, Yukiko Higa, Kentaro Itokawa, Toshinori Sasaki, Kris Cahyo Mulyatno, Sri Subekti, Maria Inge Lusida, Etik Ainun Rohmah, Yasuko Mori, Yusuf Ozbel, Chizu Sanjoba, Tran Vu Phong, Tran Cong Tu, Shinji Kasai, Kyoko Sawabe, Haruhiko Isawa","doi":"10.1080/22221751.2024.2438661","DOIUrl":"10.1080/22221751.2024.2438661","url":null,"abstract":"<p><p>Japanese encephalitis virus (JEV) genotype IV (GIV) is one of the least common and most neglected genotypes worldwide, having been identified only on a few Indonesian islands until it was recently found to be the cause of outbreaks that occurred in several Australian states in early 2022. Given the limited availability of information, the vector range for JEV GIV remains unknown; thus, understanding this range could prove invaluable for future prevention efforts in new areas. Herein, we experimentally exposed four mosquito colonies originated from various countries with no previous reports of GIV to JEV GIV strain 19CxBa-83-Cv, which was isolated from <i>Culex vishnui</i> Theobald collected in Bali in 2019. At 7 and 14 days post-JEV GIV exposure through a membrane feeding method, mosquito bodies, head-wings-legs, and saliva were harvested for infection, dissemination, and transmission efficiency analyses. The results showed robust transmission efficiencies of the virus by <i>Culex tritaeniorhynchu</i>s Giles (∼74%) and <i>Aedes albopictus</i> Skuse (∼52%) from Japan, followed by <i>Culex quinquefasciatus</i> Say from Vietnam (∼35%) and <i>Culex pipiens</i> form <i>molestus</i> from Turkey (∼18%). Although significant differences were observed, we found that the four mosquito species could transmit JEV GIV. The efficiency of biological transmission of this restricted genotype by mosquitoes from various origins suggests that these mosquito species could support localized transmission if the genotype were introduced to their respective areas. This study emphasizes the importance of remaining vigilant and continuing arbovirus surveillance in all locations.</p>","PeriodicalId":11602,"journal":{"name":"Emerging Microbes & Infections","volume":" ","pages":"2438661"},"PeriodicalIF":8.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Utilizing wastewater surveillance to model behavioural responses and prevent healthcare overload during \"Disease X\" outbreaks.","authors":"Wenxiu Chen, Wei An, Chen Wang, Qun Gao, Chunzhen Wang, Lan Zhang, Xiao Zhang, Song Tang, Jianxin Zhang, Lixin Yu, Peng Wang, Dan Gao, Zhe Wang, Wenhui Gao, Zhe Tian, Yu Zhang, Wai-Yin Ng, Tong Zhang, Ho-Kwong Chui, Jianying Hu, Min Yang","doi":"10.1080/22221751.2024.2437240","DOIUrl":"10.1080/22221751.2024.2437240","url":null,"abstract":"<p><p>During the COVID-19 pandemic, healthcare systems worldwide faced severe strain. This study, utilizing wastewater virus surveillance, identified that periodic spontaneous avoidance behaviours significantly impacted infectious disease transmission during rapid and intense outbreaks. To incorporate these behaviours into disease transmission analysis, we introduced the Su-SEIQR model and validated it using COVID-19 wastewater data from Beijing and Hong Kong. The results demonstrated that the Su-SEIQR model accurately reflected trends in susceptible populations and confirmed cases during the COVID-19 pandemic, highlighting the role of spontaneous collective avoidance behaviours in generating periodic fluctuations. These fluctuations helped reduce infection peaks, thereby alleviating pressure on healthcare systems. However, the effect of these spontaneous behaviours on mitigating healthcare overload was limited. Consequently, we incorporated healthcare capacity constraints into the model, adjusting parameters to further guide population behaviours during the pandemic, aiming to keep the outbreak within manageable limits and reduce strain on healthcare resources. This study provides robust support for the development of environmental and public health policies during pandemics by constructing an innovative transmission model, which effectively prevents healthcare overload. Additionally, this approach can be applied to managing future outbreaks of unknown viruses or \"Disease X\".</p>","PeriodicalId":11602,"journal":{"name":"Emerging Microbes & Infections","volume":" ","pages":"2437240"},"PeriodicalIF":8.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SARS-CoV-2 and HCoV-OC43 regulate host m6A modification via activation of the mTORC1 signalling pathway to facilitate viral replication.","authors":"Shixiong Zhou, Xianfeng Hui, Weiwei Wang, Chunbei Zhao, Meilin Jin, Yali Qin, Mingzhou Chen","doi":"10.1080/22221751.2024.2447620","DOIUrl":"10.1080/22221751.2024.2447620","url":null,"abstract":"<p><p>N6-methyladenosine (m6A) is the most prevalent post-transcriptional modification in eukaryotic RNA and is also present in various viral RNAs, where it plays a crucial role in regulating the viral life cycle. However, the molecular mechanisms through which viruses regulate host RNA m6A methylation are not fully understood. In this study, we reveal that SARS-CoV-2 and HCoV-OC43 infection enhance host m6A modification by activating the mTORC1 signalling pathway. Specifically, the viral non-structural protein nsp14 upregulates the expression of S-adenosylmethionine synthase MAT2A in an mTORC1-dependent manner. This mTORC1-MAT2A axis subsequently stimulates the synthesis of S-adenosylmethionine (SAM). The increase of SAM then enhances the m6A methylation of host RNA and facilitates viral replication. Our findings uncover a molecular mechanism by which viruses regulate host m6A methylation and provide insights into how SARS-CoV-2 hijacks host cellular epitranscriptomic modifications to promote its replication.</p>","PeriodicalId":11602,"journal":{"name":"Emerging Microbes & Infections","volume":" ","pages":"2447620"},"PeriodicalIF":8.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11852242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Highly pathogenic avian influenza virus (H5N5) detected in an Atlantic walrus (<i>Odobenus rosmarus rosmarus</i>) in the Svalbard Archipelago, Norway, 2023.","authors":"Alexander Postel, Nele Gremmel, Christian Lydersen, Kit M Kovacs, Luca A Schick, Ursula Siebert, Ingebjørg H Nymo, Paul Becher","doi":"10.1080/22221751.2025.2456146","DOIUrl":"10.1080/22221751.2025.2456146","url":null,"abstract":"<p><p>We present the first documented case of highly pathogenic avian influenza virus (HPAIV) subtype H5N5 in an Atlantic walrus (<i>Odobenus rosmarus rosmarus</i>). The animal was found dead in Svalbard, Norway, in 2023. Sequence analysis revealed the highest genetic similarity with virus isolates from different avian hosts.</p>","PeriodicalId":11602,"journal":{"name":"Emerging Microbes & Infections","volume":" ","pages":"2456146"},"PeriodicalIF":8.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11795765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effectiveness of nirmatrelvir/ritonavir and molnupiravir on post-COVID-19 outcomes among outpatients: a target trial emulation investigation.","authors":"Yuchen Wei, Christopher Boyer, Katherine Min Jia, Guozhang Lin, Huwen Wang, Conglu Li, Chi Tim Hung, Xiaoting Jiang, Carrie Ho Kwan Yam, Tsz Yu Chow, Yawen Wang, Shi Zhao, Zihao Guo, Kehang Li, Aimin Yang, Chris Ka Pun Mok, David S C Hui, Ka Chun Chong, Eng Kiong Yeoh","doi":"10.1080/22221751.2025.2469648","DOIUrl":"10.1080/22221751.2025.2469648","url":null,"abstract":"<p><p>Limited studies compared the effectiveness of nirmatrelvir/ritonavir and molnupiravir against a control group on post-COVID-19 conditions. Our study examined the association of nirmatrelvir/ritonavir and molnupiravir with post-acute mortality and hospitalizations among outpatients using real-world outpatient records of COVID-19 designated clinics in Hong Kong. This is an observational study using a target trial emulation framework, involving nirmatrelvir-ritonavir versus no antiviral treatment (Trial 1) and molnupiravir versus no antiviral treatment (Trial 2). Outcomes included post-acute mortality, all-cause hospitalization, and hospitalization due to 13 selected sequelae. Relative effectiveness was assessed by comparing the cumulative incidence between two groups, reported as relative risk (RR), along with risk differences (RD) during day 0-30, 31-180, and 181-360. After screening, 140,477 and 96,030 patients were included in Trial 1 and 2, respectively. Compared with no treatment, nirmatrelvir/ritonavir-treated patients exhibited a significantly lower risk of post-acute mortality (31-180 days: RR, 0.71; 95% CI, 0.54-0.96; RD, 0.20%; 181-360 days: RR, 0.64; 95% CI, 0.50-0.82; RD, 0.32%) and all-cause hospitalization (31-180 days: RR, 0.82; 95% CI, 0.76-0.88; RD, 1.11%; 181-360 days: RR, 0.83; 95% CI, 0.78-0.89; RD, 1.18%). Patients receiving molnupiravir had a lower risk of 30-day mortality, but no significant beneficial effect was observed for the post-acute outcomes. In conclusion, this study demonstrated the effectiveness of nirmatrelvir/ritonavir in reducing post-COVID-19 outcomes among outpatients. While we observed the short-term effectiveness of molnupiravir in reducing mortality, no protective effect on long-term post-COVID-19 outcomes was observed.</p>","PeriodicalId":11602,"journal":{"name":"Emerging Microbes & Infections","volume":" ","pages":"2469648"},"PeriodicalIF":8.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881657/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular turn in <i>Yersinia pestis</i> pathogenesis: implications of the <i>gppA</i> frameshift for bacterial survival in human macrophage.","authors":"Hongyan Chen, Shiyang Cao, Yazhou Zhou, Tong Wang, Yang Jiao, Yafang Tan, Yarong Wu, Yifan Ren, Yajun Song, Jing-Ren Zhang, Zongmin Du, Ruifu Yang","doi":"10.1080/22221751.2025.2467778","DOIUrl":"10.1080/22221751.2025.2467778","url":null,"abstract":"<p><p><i>Yersinia pestis</i>, the etiological agent of the devastating plague, has caused three pandemics in human history. While known for its fatality, it has long been intriguing that biovar microtus strains are highly attenuated to humans. The survival and replication within macrophages are critical in the early stages of the <i>Y. pestis</i> lifestyle within warm-blooded hosts. Here, we demonstrate that a frameshift truncation of <i>gppA</i>, a gene encoding the phosphohydrolase GppA that responsible for the conversion of stringent response alarmone pppGpp to ppGpp, significantly promotes <i>Y. pestis</i> to survive inside human macrophages. This frameshift mutation of <i>gppA</i> is present in all the evolutionary branches formed by the modern <i>Y. pestis</i> strains responsible for the plague pandemics, while the relative ancient microtus strains express a functional GppA showing high activity in catalyzing pppGpp to ppGpp conversion. This adaptive evolution potentially explains why microtus <i>Y. pestis</i> strains exhibit attenuated virulence in humans in contrast to the lethal pathogenicity of non-microtus strains. Transcriptome analysis suggests that the disturbed balance of the ratio of ppGpp to pppGpp caused by GppA inactivation results in an upregulation of genes involved in the synthesis of branched-chain amino acids, which are essential for bacterial growth. This enhanced survival ability within macrophages could be a key factor for the virulence of <i>Y. pestis</i> towards humans. Our work sheds light on the molecular mechanisms behind <i>Y. pestis</i> host-specific pathogenicity, offering significant implications for enhancing our ability to predict and counteract the emergence of new infectious diseases.</p>","PeriodicalId":11602,"journal":{"name":"Emerging Microbes & Infections","volume":" ","pages":"2467778"},"PeriodicalIF":8.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11878169/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143406482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}