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Role of alveolar macrophages in Covid19 pathology


   Sir William Dunn School of Pathology

  Prof W S James, Dr S Cowley  Friday, December 03, 2021  Competition Funded PhD Project (Students Worldwide)

Oxford United Kingdom Biochemistry Cell Biology Genetics Immunology Microbiology Molecular Biology Pathology Virology

About the Project

For most people infected with SARS-CoV-2, infection is only mildly symptomatic, transient and limited to the upper airways and epithelia of the nasopharynx. However, more serious disease involves the lung epithelium, in which infection of Type 2 pneumocytes results in a damaging inflammatory response, resulting in pneumonitis, infiltration by blood monocytes, endothelial leakage, intravascular coagulation and disseminated pathology in multiple organs. A critical step from mild to severe disease appears to be the replication of the virus in the alveolar cells, and it is unclear to what extent in vivo the resident macrophages protect the pneumocytes from infection, on the one hand, or promote deleterious inflammatory reactions to infection, on the other. Understanding how the molecular cell biology of macrophages regulates this balance between defence and disease is critical to rational approaches to combat Covid19 disease, and has implications for other lung infections. To address these questions, we have developed a genetically tractable, yet pathophysiologically authentic human alveolar tissue-in-a-dish model using induced pluripotent stem cell differentiation to generate both macrophages and type 2 pneumocytes in coculture. You will work with other members of the James Lab, under the supervision of Dr Sally Cowley, Head of the James and Lillian Martin Centre for stem cell research and William James, Professor of Virology and Hon Director of the Centre, to investigate the involvement of specific pathways of macrophage sensing and response in relation to SARS-CoV-2 infection. You will be trained in Containment Level 3 techniques for safe working with SARS-CoV-2, and in techniques of stem cell mutagenesis and differentiation.


Funding Notes

4 Year DPhil Prize Studentships cover full University fees, a tax free enhanced stipend of ~£17,609 pa, and up to £5,300 pa for research costs and travel. The competition is open to applicants from all countries. See View Website for full details and to apply.

References

1. Cahill, T. J. et al. Tissue-resident macrophages regulate lymphatic vessel growth and patterning in the developing heart. Development 148, dev194563 (2021).
2. Vaughan-Jackson, A. et al. Differentiation of human induced pluripotent stem cells to authentic macrophages using a defined, serum-free, open-source medium. Stem Cell Reports 16, 1735–1748 (2021).
3. Matthews, P. C. C. et al. SARS-CoV-2 RNA detected in blood products from patients with COVID-19 is not associated with infectious virus. Wellcome Open Res. 5, (2020).
4. Lee, H. et al. LRRK2 Is Recruited to Phagosomes and Co-recruits RAB8 and RAB10 in Human Pluripotent Stem Cell-Derived Macrophages. Stem Cell Reports 14, 940–955 (2020).
5. Honarmand Ebrahimi, K., Vowles, J., Browne, C., McCullagh, J. & James, W. S. ddhCTP produced by the radical-SAM activity of RSAD2 (viperin) inhibits the NAD+-dependent activity of enzymes to modulate metabolism. FEBS Lett. 594, 1631–1644 (2020).
6. Skelly, D. et al. Two doses of SARS-CoV-2 vaccination induce robust immune responses to emerging SARS-CoV-2 variants of concern. Nat. Commun. (2021).
7. Mendonça, L. et al. Correlative multi-scale cryo-imaging unveils SARS-CoV-2 assembly and egress. Nat. Commun. 12, 1–10 (2021).
8. Wing, P. A. C. et al. Hypoxic and pharmacological activation of HIF inhibits SARS-CoV-2 infection of lung epithelial cells. Cell Rep. 35, (2021).
9. Folegatti, P. M. P. M. et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet 396, 467–478 (2020).
10. Zhou, D. et al. Structural basis for the neutralization of SARS-CoV-2 by an antibody from a convalescent patient. Nat. Struct. Mol. Biol. 27, 950–958 (2020).
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