Pathogenic signatures and therapeutic evaluation of emergent MPXV Clade Ib in low-susceptibility and immunocompromised mouse models

BMC Microbiology https://doi.org/10.1186/s12866-026-05273-4 Article in Press Pathogenic signatures and therapeutic evaluation of emergent MPXV Clade Ib in lowsusceptibility and immunocompromised mouse models Hongyu Han, Xiaowei Wang, Yongchang Wu, Xiaorong Yang, Peng Qian, Xiaoqing Xie, Dongmei Jiang, Shan Wu, Xiaoping Tang, Quanhai Pang & Haisheng Yu Received: 9 March 2026 Accepted: 3 June 2026 Cite this article as: Han H., Wang X., Wu Y. et al. Pathogenic signatures and therapeutic evaluation of emergent MPXV Clade Ib in low-susceptibility and immunocompromised mouse models. BMC Microbiol (2026). https://doi. org/10.1186/s12866-026-05273-4 A E R P S S We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply. 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To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. ACCEPTED ARTICLEMANUSCRIPT IN PRESS Pathogenic Signatures and Therapeutic Evaluation of Emergent MPXV Clade Ib in Low-Susceptibility and Immunocompromised Mouse Models Hongyu Hana,b#, Xiaowei Wanga,b#, Yongchang Wub,c, Xiaorong Yangb,c, Peng Qianb,c, Xiaoqing Xieb,c, Dongmei Jiangb,c, Shan Wub,c, Xiaoping Tangb,c*, Quanhai Panga*, Haisheng Yub,c* aCollege of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, 030800, China. bInstitute of Infectious Diseases, Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, 510440, China. cGuangzhou Key Laboratory of Clinical Pathogen Research for Infectious Diseases, Guangzhou, 510440, China. #These S S E R P authors contributed equally: Hongyu Han and Xiaowei Wang. *Corresponding author: Haisheng Yu (; +86 134 IN 2671 6511), Quanhai Pang (; +86 134 5323 0899) and E L C I T R A Xiaoping Tang (; +86 135 0152 5993) Abstract: Background: Monkeypox (Mpox) is a zoonotic disease that threatens global public health. Different clades of monkeypox virus (MPXV) vary in transmissibility and pathogenicity. In 2023, a clade Ib MPXV variant emerged in the Democratic Republic of the Congo, continued to spread in parts of Africa, and subsequently spilled over to other regions, posing new challenges for outbreak prevention and control. Results: We established stable mouse models of MPXV Clade Ib infection by intranasally infecting C57BL/6/STAT1-/-, AGB6 (C57BL/6- Ifngr1-/-Ifnar1-/-), C57BL/6, and BALB/c mice. Susceptible strains showed marked body weight loss, high viral loads in tissues, and severe histopathological lesions. RNA-seq analysis of spleens at the early stage of infection showed that differentially expressed genes were mainly enriched in interferon-mediated antiviral pathways and inflammatory cytokine-related pathways, whereas genes associated with adaptive immune responses were downregulated. Comparative analysis showed that MPXV Clade Ib caused more severe disease phenotypes than clade IIb under the ACCEPTED ARTICLEMANUSCRIPT IN PRESS same experimental conditions, which is consistent with reported differences in clinical severity. Conclusion: We established reproducible mouse models for MPXV Clade Ib infection and demonstrated that Clade Ib showed greater replication capacity and pathogenicity than Clade IIb in these models. This study also provides a foundation for subsequent research on the pathogenesis of MPXV and the evaluation of antiviral efficacy. Keywords: Mpox; Monkeypox virus; MPXV Clade Ib; Mouse model; Pathogenicity Introduction Monkeypox (Mpox) is a zoonotic disease caused by the Monkeypox virus (MPXV). Phylogenetically, MPXV diverges into two primary lineages: Clade I (subclades Ia and Ib) and Clade II (subclades IIa and IIb)[1, 2]. Historically, Mpox has been primarily endemic to Central and West Africa[3]. In 2022, a global outbreak driven by Clade IIb S S E R P rapidly spread to non-endemic countries, prompting the World Health Organization (WHO) to declare it a Public Health Emergency of International Concern (PHEIC) in July IN of that year[4]. In September 2023, the Democratic Republic of the Congo (DRC) reported E L C I T R A the emergence of a novel Clade Ib variant, which has subsequently spread to regions outside Africa[5]. In view of the potential risk of global spread, the WHO re-declared Mpox a PHEIC in August 2024, underscoring the persistent and severe challenges facing global public health security[6]. Transmission patterns and clinical outcomes vary across different MPXV clades[7]. The Clade IIb variant responsible for the 2022 outbreak was primarily transmitted through sexual contact among men who have sex with men (MSM) and has generally been associated with a low case fatality rate[8]. In contrast, Clade Ib has been associated with more severe clinical outcomes and sustained human-to-human transmission. It frequently infects children through close household contact, while heterosexual transmission and sexual networks involving female sex workers also represent major routes of spread[9-11]. Clinically, although both clades present with typical symptoms such as fever, rash, and lymphadenopathy, Clade Ib is more often associated with severe ACCEPTED ARTICLEMANUSCRIPT IN PRESS generalized rashes and persistent genital lesions. These manifestations substantially increase the disease burden and pose a particularly severe threat to children, pregnant women, and immunocompromised individuals[12, 13]. However, while mucocutaneous lesions are the typical symptoms, the occurrence of respiratory involvement and its complications also warrants attention. A review of epidemiological and clinical data from past mpox outbreaks indicates that, in addition to direct contact with patients' skin lesions or bodily fluids, respiratory exposure may contribute (...truncated)