In the ever-evolving landscape of infectious diseases, the intersection of complex viral infections and immune-compromised hosts represents an urgent frontier in biomedical research. A groundbreaking study recently published in Nature Communications has provided unprecedented insights into how Mpox virus (formerly known as monkeypox virus) orchestrates multifaceted pathogenic mechanisms within immunodeficient hosts, specifically focusing on SIVmac239-infected rhesus macaques. Through high-resolution multi-organ proteomic profiling, this innovative research delineates the nuanced interplay between viral pathogenicity and host immune status, shedding light on the systemic consequences of Mpox virus infection in the context of simian immunodeficiency virus (SIV) co-infection.
The study confronts a critical gap in our understanding of how Mpox virus manifests in individuals with compromised immune systems, a demographic increasingly relevant in current public health scenarios amid overlapping viral epidemics. Employing a meticulous experimental model, rhesus macaques were first infected with SIVmac239, a pathogenic clone of SIV that mirrors human immunodeficiency virus (HIV) infection in its immunosuppressive profile. Subsequent Mpox virus inoculation enabled researchers to simulate viral co-infection dynamics analogous to those potentially encountered in immunocompromised human hosts.
Central to this investigation is the utilization of cutting-edge proteomic technologies to obtain multi-organ profiles that map the proteome-wide alterations induced by Mpox virus during co-infection. These advanced methodologies allowed for the identification of specific protein expression changes across diverse anatomical compartments, revealing that the virus does not merely cause localized pathology but triggers systemic deregulation of key biological pathways. Proteomic shifts were particularly pronounced in lymphoid tissues, lungs, liver, and gastrointestinal tract, aligning with clinical manifestations often observed in severe poxviral infections.
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The proteomic data uncovered a cascade of immune response modulations, including aberrant activation of inflammatory mediators and dysregulation of antiviral signaling pathways. Notably, the co-infected rhesus macaques exhibited a disrupted balance in cytokine production, with heightened levels of pro-inflammatory cytokines such as IL-6, TNF-α, and IFN-γ, which collectively contribute to pathogenic inflammation. This protracted inflammatory milieu likely exacerbates tissue damage and facilitates viral dissemination beyond primary sites of infection.
Equally revealing was the observation that Mpox virus infection in the context of SIV co-infection led to marked alterations in metabolic pathways, implicating impaired cellular energetics and redox states as contributing factors to disease progression. Proteomic signatures indicated suppression of mitochondrial function and an increased presence of oxidative stress markers, implicating these cellular dysfunctions as key drivers of the observed multi-organ pathology. These findings provide a molecular foundation for understanding the systemic deterioration observed in severe Mpox virus infections exacerbated by immunosuppression.
Moreover, the study highlights the virus’s ability to subvert host antiviral defenses by downregulating critical components of the interferon-stimulated gene (ISG) network. This evasion strategy undermines early innate immune responses, potentially allowing unchecked viral replication during the initial stages of infection. Coupled with impaired adaptive immunity due to SIV-mediated CD4+ T-cell depletion, the virus exploits an immunocompromised environment to amplify its pathogenic potential.
Interestingly, the histopathological analyses conducted alongside proteomic assessments revealed extensive tissue damage characterized by necrosis, infiltration of inflammatory cells, and evidence of viral antigen presence across multiple organs. Such pathological hallmarks mirror clinical observations in human cases of Mpox, particularly in immunosuppressed individuals, reinforcing the translational relevance of the macaque model for studying disease mechanisms and therapeutic interventions.
Investigating the temporal dynamics of the infection, the researchers documented a progressive escalation of proteomic abnormalities over the course of infection, with early alterations in immune cell signaling pathways preceding widespread tissue pathology. This temporal resolution underscores the importance of early detection and intervention to curb the systemic spread and severe outcomes associated with Mpox virus infection in vulnerable populations.
The implications of these findings reach beyond the immediate viral pathogenesis, touching upon broader themes of host-pathogen interactions, immune senescence, and viral evolution in immunocompromised milieus. By illuminating the proteomic landscape that underpins Mpox virus infection during SIV-induced immunodeficiency, the study paves the way for targeted therapeutic approaches aimed at modulating host immune responses, ameliorating inflammation, and restoring metabolic homeostasis.
Importantly, this research also raises critical questions about viral transmission dynamics and the potential for increased viral shedding in immunocompromised hosts. The heightened systemic viral load and multifocal tissue involvement observed suggest that co-infected individuals could serve as enhanced reservoirs for viral persistence and dissemination, emphasizing the need for tailored public health strategies in outbreaks where immunosuppressive conditions prevail.
On a methodological level, the integration of proteomic technologies with classical virology and immunopathology exemplifies the power of interdisciplinary approaches to unravel complex biological phenomena. The comprehensive multi-organ analysis employed here offers a robust blueprint for future investigations into other viral co-infections and their systemic consequences, highlighting the necessity of systems-level understanding in infectious diseases research.
From a clinical perspective, these insights advocate for vigilant monitoring of Mpox virus infection in patients with underlying immunodeficiencies, including those living with HIV/AIDS or undergoing immunosuppressive therapies. The molecular signatures identified could inform biomarker development for disease severity and progression, facilitating personalized management strategies that address both viral and host factors.
Furthermore, the study contributes to the broader discourse on emerging zoonoses and the challenges posed by viral spillover events into immunologically vulnerable populations. As Mpox virus continues to garner global attention due to its epidemic potential, elucidating the factors that drive severe disease manifestations is paramount to informing vaccine strategies, antiviral development, and public health preparedness.
In conclusion, this landmark investigation provides a detailed proteomic atlas of Mpox virus infection in an immunocompromised primate model, unveiling the multifactorial mechanisms of viral pathogenesis across organ systems. The synergy between viral immune evasion, inflammatory dysregulation, and metabolic disruption delineated here not only advances fundamental understanding but also holds transformative potential for the development of targeted interventions in vulnerable patient populations. As infectious disease threats intensify in complexity, such integrative studies underscore the imperative of holistic biological inquiry to safeguard global health.
Subject of Research: The pathogenicity and multi-organ proteomic profiling of Mpox virus infection in rhesus macaques co-infected with simian immunodeficiency virus (SIVmac239).
Article Title: The pathogenicity and multi-organ proteomic profiles of Mpox virus infection in SIVmac239-infected rhesus macaques.
Article References:
Zhang, D., Liu, J., Zhu, L. et al. The pathogenicity and multi-organ proteomic profiles of Mpox virus infection in SIVmac239-infected rhesus macaques.
Nat Commun 16, 7653 (2025). https://doi.org/10.1038/s41467-025-62919-z
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Tags: biomedical research on viral infectionsemerging infectious diseases researchHIV-related research advancementsimmune system response to virusesimmunocompromised hostsmonkeypox virus pathogenicityMpox virus infectionproteomic profiling technologiespublic health implications of mpoxSIVmac239 rhesus macaquessystemic effects of Mpox virusviral co-infection dynamics
