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Host–pathogen interactions
Cell and tissue biology of human MPXV infections
MPXV is a complex double-stranded DNA virus with more than 200 genes. Unusually, it replicates within the cell cytoplasm.
MPXV hijacks several cellular pathways to facilitate its replication and trafficking to the cell surface and to other cells.
It also deploys multiple mechanisms of immune evasion to thwart host protective responses.
Thematic leads
Thematic lead 1
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Thematic lead 2
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Host-pathogen interactions knowledge gaps
Primary knowledge gaps identified in the Mpox R&D Roadmap 2026:
Host factors and immunity
What genetic influences and immune mechanisms determine protection against MPXV infection and disease severity?
Viral evolution, clades and pathogenesis
What are the evolutionary mechanisms driving MPXV adaptation and genetic determinants of clade-specific pathogenesis?
Cell and tissue biology of infection
What are the mechanisms governing MPXV cell entry, cellular tropism, and dissemination?
Experimental model systems
How can experimental systems be improved to better model MPXV infection and enhance translatability?
More detailed research questions can be found in the Mpox R&D Roadmap 2026.
Host-pathogen interactions workplan
A CORC workplan for the host-pathogen interactions theme is in development.
Host-pathogen interactions background
New mpox medical countermeasures are required, based on a thorough understanding of host–MPXV interactions. However, fundamental gaps remain in understanding the host–virus interactions that determine immune protection, viral evolution, disease severity and transmission.
Poxviruses are complex double-stranded DNA viruses that, unusually, replicate exclusively in the cell cytoplasm. During the virus cycle, three types of virus particles are generated, but only two – mature virus (MV) and extracellular virus (EV) – are infectious. EV particles have an extra outer envelope containing a distinct set of envelope proteins.
MPXV attaches to human cells by recognising glycosaminoglycans (GAGs), present on multiple types of cell. Cell entry involves membrane fusion and is dependent on a multicomponent viral entry-fusion complex (EFC) containing 15 viral proteins[1]. Following infection, poxviruses synthesise most of the proteins necessary for their replicative cycle, in a cascade fashion, with each stage dependent on the completion of the previous stage[2].
Once inside the cell, the inner structure (the core, containing viral DNA within a nucleocapsid structure) contains all the components required for synthesis of mRNAs necessary for the early (pre-replicative) stage of gene expression. Transcripts are then extruded from virus cores into the cell cytoplasm, where they are directed to cellular ribosomes for the synthesis of early proteins, including proteins involved in host immune modulation, viral DNA replication and transcription factors important for late stages of gene expression.
Replication of viral DNA then follows, using viral enzymes. Once new copies of virus genomes start being synthesised, the post-replicative stage of gene expression is launched. Virus morphogenesis begins, following the synthesis of proteins necessary for the construction of immature virus particles. Proteolytic processing by viral proteases generates the MV forms, which are the most abundant type of virus particles but remain inside infected cells.
A proportion of MV are directed to the trans-Golgi, where they acquire two additional membranes, mediated by several viral proteins. The resulting wrapped viruses (WV) are directed to the cytoplasmic membrane, where the most external membrane fuses with the cytoplasmic membrane, externalising a double-envelope virus, the EV. EVs can remain associated with the cellular membrane (CEVs) or detach from the cellular surface (EEVs). CEVs are propelled to neighbouring cells through actin tails polymerised following a virus-orchestrated hijacking of cellular proteins involved in actin polymerisation. EVs are responsible for long-distance cell infection.
[1] Lin CS, Li CA, Wang CH et al. Cryo-EM structure of the vaccinia virus entry fusion complex reveals a multicomponent fusion machinery. Sci Adv. 2026;12(3):eaec0254. doi: 10.1126/sciadv.aec0254.
[2] Moss B. Understanding the biology of monkeypox virus to prevent future outbreaks. Nat Microbiol. 2024;9(6):1408-1416. doi: 10.1038/s41564-024-01690-1.
[3] Li H, Huang QZ, Zhang H et al. The landscape of immune response to monkeypox virus. EBioMedicine. 2023;87:104424. doi: 10.1016/j.ebiom.2022.104424.
Host responses
MPXV infection triggers a variety of innate immune responses, which are the target of multiple mpox immune evasion mechanisms, for example targeting IFN responses, blocking of viral DNA recognition, inhibiting natural killer cell activity, and triggering the death of dendritic cells.
MPXV also triggers both cellular and humoral immune responses. Infection triggers a Th1-type response, which is also suppressed by MPXV, promoting viral persistence. MPXV infection also induces binding and neutralising antibody responses (IgA, IgG and IgM), of variable strength and duration. A variety of immunodominant viral antigens have been identified, including A35R and B6R (EV antigens) and H3L and E8L (MV antigens). Natural protection likely depends on a combination of T-cell and antibody-based responses.
Host responses may also have pathogenic effects[3]. Excessively high levels of a variety of inflammatory mediators could contribute to tissue damage and the severity of disease.
[1] Lin CS, Li CA, Wang CH et al. Cryo-EM structure of the vaccinia virus entry fusion complex reveals a multicomponent fusion machinery. Sci Adv. 2026;12(3):eaec0254. doi: 10.1126/sciadv.aec0254.
[2] Moss B. Understanding the biology of monkeypox virus to prevent future outbreaks. Nat Microbiol. 2024;9(6):1408-1416. doi: 10.1038/s41564-024-01690-1.
[3] Li H, Huang QZ, Zhang H et al. The landscape of immune response to monkeypox virus. EBioMedicine. 2023;87:104424. doi: 10.1016/j.ebiom.2022.104424.
