This PhD opportunity is being offered as part of the LSTM and Lancaster University Doctoral Training Partnership. Find out more about the studentships and how to apply.
| Abstract | The world is witnessing the start and continuation of several MPOX epidemics, emerging from central and eastern Africa, imposing devastating consequences on affected regions and spreading outside of the African continent. The steep rise in MPXV infections triggered the declaration of MPOX as a public-health emergency of continental security (PHECS) on 2024, 13th August by African CDC and a public health emergency of international concern (PHEIC) by WHO on 2024, August 14th. MPXV, in contrast to smallpox virus, originates from animal reservoirs, and its eradication is virtually impossible. Gaining an understanding of the biology of this emerging virus, its interplay with the human immune system, modes of intra-host propagation and viral immune evasion mechanisms is crucial for the sustainable development of effective preventive and therapeutic antiviral strategies for those who are unable or unwilling to access vaccines. The two objectives of this PhD project are to: 1) characterise the cellular tropism and replication of MPXV in human circulating immune cells and individual immune cell types and the corresponding cell-intrinsic responses. Our preliminary data demonstrate susceptibility and permissiveness of human PBMCs to MPXV infection, with regulatory CD4+ T-cells, monocytes and cycling NK representing the key target cells. These findings clearly demonstrate the possibility that circulating blood cells contribute to viral production and systemic virus dissemination. The PhD student will define the cell type-specific contribution to virus progeny generation and define cellular expression profiles in productively versus incompletely or abortively infected cell types in the context of ex vivo and in vivo infection with clade II and I viruses. Furthermore, we will characterise to which extent MPXV-infected cells are susceptible to antibody-mediated cellular cytotoxic elimination. Understanding how MPXV interacts with human leukocytes is key to develop strategies against prolonged and systemic dissemination which is more likely to occur in immunocompromised individuals. 2) investigate the consequence of de novo MPXV infection on pre-established HIV-1 infection. Given the overlapping target cell profile among PBMCs for HIV-1 and MPXV clade IIb in monocytes and regulatory CD4+ T-cells, and the stark reprogramming of the intracellular milieu by MPXV infection, we hypothesise that HIV-1 reactivation will be facilitated during MPOX, resulting in viral gene expression even under ART which is associated with immunosenescence and aberrant inflammation. We will test this idea in cell lines and primary PBMCs from people living with HIV ex vivo exposed to MPXV. Results could have important implications for the monitoring of viral load in people living with HIV-1 undergoing MPXV infection. |
| Where does this project lie in the translational pathway? | T1 - Basic Research,T2 - Human /Clinical Research |
| Expected Outputs | Publications as well as proof-of-concept data to support grant applications for further research towards MPOX therapy. Generate fist candidates for MPOX therapy (focussing on intra-patient spread) to be developed further. |
| Training Opportunities | Hands-on training in all above mentioned methods by experienced members of the group. Furthermore, the student will be encouraged to learn additional methods beneficial to the project in the context of collaborations, and will have full access to soft skills trainings (self-organization, communication, presentation etc.) |
| Skills Required | Background in virology and/or immunology. Interest in conducting basic research in order to contribute to close a clinical knowledge gap. |
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Key Publications associated with this project |
https://www.biorxiv.org/content/10.1101/2024.09.16.613292v1 |
| https://www.biorxiv.org/content/10.1101/2020.05.04.075119v3 |