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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, January 08, 2021 Competition Funded PhD Project (Students Worldwide)

About the Project

For most people infected with SARS-CoV-2, infection appears to be only mildly symptomatic, transient and limited to the upper airways and epithelia of the nasopharynx. However, more serious disease involves the alveolar cells of the lung, including Type 2 pneumocytes and alveolar macrophages, 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, particularly with Dr Sally Cowley, Head of the James Martin Stem Cell 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 ~£17,285 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. Karlsson, K. R. et al. Homogeneous monocytes and macrophages from human embryonic stem cells following coculture-free differentiation in M-CSF and IL-3. Exp. Hematol. 36, 1167–1175 (2008).
2. Van Wilgenburg, B., Moore, M. D., James, W. S. & Cowley, S. A. The productive entry pathway of HIV-1 in macrophages is dependent on endocytosis through lipid rafts containing CD4. PLoS One 9, (2014).
3. van Riet, S. et al. In vitro modelling of alveolar repair at the air-liquid interface using alveolar epithelial cells derived from human induced pluripotent stem cells. Sci. Rep. 10, 5499 (2020).
4. Borrmann, H. et al. Pharmacological activation of the circadian component REV-ERB inhibits HIV-1 replication. Sci. Rep. 10, 13271 (2020).
5. Zhou, D. et al. Structural basis for the neutralization of SARS-CoV-2 by an antibody from a convalescent patient. Nat. Struct. Mol. Biol. (2020). doi:10.1038/s41594-020-0480-y
6. Andersson, M. I. et al. SARS-CoV-2 RNA detected in blood products from patients with COVID-19 is not associated with infectious virus [version 1; peer review: 1 approved with reservations]. Wellcome Open Res. 5, (2020).
7. Folegatti, 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).
8. Miao, X. et al. A novel biparatopic hybrid antibody-ACE2 fusion that blocks SARS-CoV-2 infection: implications for therapy. MAbs 12, 1804241 (2020).
9. Ebrahimi, K. H. et al. Viperin, through its radical‐SAM activity, depletes cellular nucleotide pools and interferes with mitochondrial metabolism to inhibit viral replication. FEBS Lett. 1873-3468.13761 (2020). doi:10.1002/1873-3468.13761
10. 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).
11. Huo, J. et al. Neutralizing nanobodies bind SARS-CoV-2 spike RBD and block interaction with ACE2. Nat. Struct. Mol. Biol. (2020). doi:10.1038/s41594-020-0469-6
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