Modulating Cell Migration During Viral Encephalitis to Protect the Central Nervous System

 

Supervisor: Dr Marieke Pingen, School of Infection & Immunity

 

Rotation project:

Many viruses can infect our central nervous system (CNS), resulting in severe neurological damage caused not only by the virus per se, but also the immune system’s attempts to clear the virus from the nervous system. Viral encephalitis has a high mortality rate (estimated 10-40%) and survivors can experience substantial sequala. For many patients, the viral cause of encephalitis cannot be identified, and very few antivirals are available for treatment. Thus, there is an urgent need for pan-viral treatment strategies limiting morbidity and mortality due to viral encephalitis.

Due to the limited capacity for self-renewal, the immune response in the CNS must be delicately balanced between limiting viral infection without causing irreparable damage. Migratory immune cells, which are primarily recruited by chemotactic cytokines (chemokines), are critical for viral clearance but also contribute to immune-mediated damage to the CNS. Whilst we have previously characterised the migratory immune response, it is not fully understood which immune cells are beneficial or harmful.

In this project we will study the role of chemokine-mediated recruitment of immune cells on viral clearance and pathology during viral encephalitis. We have several strains of chemokine receptor deficient mice, and chemokine receptor reporter mice to characterise the migratory immune response. Using these mice and our model virus Semliki Forest virus (SFV), we will investigate the impact of the chemokine-mediated recruitment on pathology. Once we have a better understanding of the impact of the various immune cell populations, we will use chemokine blockers to modify the recruitment of key immune cell populations. This way we will investigate whether we can modulate the migratory immune response, skewing the balance towards protecting the CNS.

Within this project, students will use flow cytometry, imaging and molecular techniques to investigate the immune response to viral encephalitis. The supervisory team is interdisciplinary, benefitting from expertise in chemokine biology (Gerry Graham), viral infection (Marieke Pingen) and neuroimmunology (Jonathan Cavanagh). We have close collaborations within the Centre for Virus Research and Neuroscience.

Key references:

  • Daniela Michlmayr et al, Defining the chemokine basis for leukocyte recruitment during viral encephalitis, J Virol 2014. DOI: 1128/JVI.03421-13
  • Laura Medina-Ruiz et al, Analysis of combinatorial chemokine receptor expression dynamics using multi-receptor reporter mice. eLife 2022 DOI: 7554/eLife.72418
  • Doug Dyer et al, Chemokine Receptor Redundancy and Specificity Are Context Dependent. Immunity, 2019. doi: 10.1016/j.immuni.2019.01.009.