Exploring antiviral effector cells in vaccinia virus-infected tissues

Vaccinia virus (VACV) is a large, double-stranded DNA virus belonging to the Poxviridae family that was used as the live vaccine leading to the eradication of smallpox. Despite eradication through global vaccination, the precise immune mechanisms underlying recovery from infection are incompletely understood. VACV is commonly studied after infection of the lung to model human smallpox vaccination; however, most current VACV infection models lack information on the anatomical organisation of immune cells interacting with virus-infected cells in tissues. To understand antiviral immunity in critical barrier tissues, this study investigated the spatial organisation of both leukocytes and VACV-infected cells in two different models: epicutaneous infection of the skin and a newly developed model of mouse lip (labial mucosal) infection. After epicutaneous infection of the skin, T cells traffic into the dermis and eliminate VACV- infected inflammatory monocytes. During the course of infection, VACV replication leads to a marked increase in the permeability of local blood vessels that occurs prior to the entry of CD8+ T cells. Pharmacological Inhibition of VEGF receptor (VEGFR)-signalling abrogated VACV-induced vascular leakage. Furthermore, CD8+ T cell-mediated clearance of infected monocytes also reduced vascular permeability. After mucosal infection in the lip, VACV replicates to high titres and both group 1 innate lymphoid cells (ILCs) and T cells are recruited to infected tissue. Intravital imaging revealed that group 1 ILCs continuously patrol the epithelium in both naïve and infected tissues and are the major immune force limiting oral mucosal viral infection at early timepoints. Unexpectedly, group 1 ILCs produce interferon gamma (IFN-γ) irrespective of contact with virus-infected cells, even in the uninfected epithelium, invoking an antiviral state independent of infection. Elimination of group 1 ILCs or neutralisation of IFN-γ decreased the expression of several key antiviral genes in the uninfected oral mucosa. Although ILC1s play an early critical role in restricting VACV spread in the labial mucosa, these cells are not sufficient alone to clear labial VACV infection as *Rag1-/-* mice (which lack T and B cells, but retain ILCs) have prolonged viral replication which can be reduced by adoptively transferred T cells. Together, these findings illustrate the complexities of immune-cell-mediated interactions and protection in the tissue, from the kinetics of leukocyte entry and elimination of virus-infected cells to the amplification of antiviral signals.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2023

Author dc:creator

• Shannon, John

Advisors dc:contributor.advisor

• Smith, Geoffrey
• Hickman, Heather

• Innate lymphoid cells
• T cells
• Tissue immunity
• Vaccinia virus
• Viral immunology

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/18d3ed63-bb0c-40fa-a432-3805152de40e/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.101824

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/357843