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The role of peripheral blood neutrophils in the pathogenesis of SARS-CoV-2 infection and associated adverse outcomes


   School of Dentistry

  , , Dr Adrian Shields,  Wednesday, June 30, 2021  Funded PhD Project (European/UK Students Only)

Birmingham United Kingdom Biochemistry Cell Biology Immunology Molecular Biology

About the Project

Background:

Accumulated evidence suggests that patients with severe COVID‐19 may have a dysregulation of their immune response that allows the development of hyper-inflammation and consequent immunothrombosis. Severe courses of SARS and MERS have been consistently reported to be accompanied by increased cytokine and chemokine responses, measureable in lung tissues and in serum in humans and animals 1-3. Another reported marker is the neutrophil‐to‐lymphocyte ratio (NLR), which was shown to reflect systemic inflammatory responses and to predict severity of the disease 4, 5. This was confirmed in a recent meta‐analysis reporting that NLR values increased significantly in patients with severe COVID‐19 disease 6.

Neutrophils are the most abundant leukocytes in blood and constitute the first line of defence against numerous infectious pathogens, including bacteria and viruses. They are highly heterogeneous with marked inter-individual variability in neutrophil numbers and behaviour. Genetic and epigenetic factors underlie most of this inter-individual variability 7. Neutrophils migrate from the blood stream to injured or infected sites to kill pathogens and to remove cellular debris prior to healing. They employ different antimicrobial mechanisms, which are also known to cause substantial collateral host tissue damage under certain circumstances, which in itself acts as a trigger of inflammation 8. This neutrophil-mediated tissue damage has been reported in the context of a variety of diseases, including acute respiratory distress syndrome (ARDS) and multiple organ failure 9.

Since neutrophils respond to cytokine signalling and release a variety of pro-inflammatory mediators themselves, it is plausible that the reported “cytokine storm” in some COVID-19 patients is directly related to neutrophil attraction to lung tissues and their subsequent activation and consequent neutrophil-mediated tissue damage and disease exacerbation. Importantly, severe COVID-19 is characterised by a highly pronounced neutrophil extracellular trap (NET) formation inside small blood vessels. Intravascular aggregation of NETs leads to rapid vascular occlusion, followed by disturbed microcirculation and organ damage. In severe COVID-19, neutrophil granulocytes are strongly activated and adopt a phenotype prone to spontaneous NET formation 10.

PhD Objectives:

1)      To understand whether inherent inter-individual differences in neutrophil phenotype may, in part, determine the course and severity of COVID-19.

2)      To analyse plasma from convalescent COVID-19 patients and its impact on neutrophils from unaffected, systemically health volunteers.

3)      To better understand the mechanism of action of currently proposed anti-cytokine therapies and to identify additional cytokine/chemokine targets.

Methods/techniques:

The proposed studies comprise ex vivo assays of neutrophils from two cohorts: healthy donors who were never infected with SARS-CoV-2 and healthy donors previously infected with SARS-CoV-2, confirmed by serum antibody testing and stratified by severity of disease.

Isolated peripheral blood neutrophils will be exposed to cytokines, acute serum, or SARS-CoV-2 virus fragments. This will be followed by functional assays to assess the release of cytokines and reactive oxygen species, formation of NETs, neutrophil chemotactic accuracy and phagocytosis (fluorescence- and luminescence-based approaches, flow cytometry, multiplex assays and live cell tracking 11-15). Apoptosis and necrosis assays will also be carried out. In addition, neutrophil gene expression arrays will be conducted for any relevant stimuli, and serum-mediated NET degradation will be assessed. Neutrophil responses to serum from convalescent patients who experienced outcomes of variable severity to SARS-CoV-2 exposure will also be examined.

We will consider applications from prospective students with a very good biomedical, biology or similar Masters degree and with prior experience in immunology research. Experience in some or all of the above methods is desirable.

For more information regarding the project, please contact Dr J. Hirschfeld ().

To be considered for this studentship, please send the following documents to Viktorija Ziabliceva ():

•             A detailed CV, including your nationality and country of birth;

•             Names and addresses of two referees;

•             A covering letter highlighting your research experience/capabilities;

•             Copies of your degree certificates with transcripts;

•             Evidence of your proficiency in the English language, if applicable.


Funding Notes

University tuition fees and bench fees at the Home rate will be met by the University for the 3 years of the studentship.
Bursary p.a.: Bursary equivalent to UKRI national minimum stipend (2020/21 bursary rate is £15,285)
Eligibility: Permanent UK Residence status as the fees will be paid at the Home rate.

References

1. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the `Cytokine Storm' in COVID-19. J Infect 2020;80(6):607-613.
2. Pedersen SF, Ho YC. SARS-CoV-2: a storm is raging. J Clin Invest.
2020;130(5):2202-2205.
3. Chen J, Lau YF, Lamirande EW, Paddock CD, Bartlett JH, Zaki SR, et al. Cellular immune responses to severe acute respiratory syndrome coronavirus (SARS-CoV) infection in senescent BALB/c mice: CD4+ T cells are important in control of SARS-CoV infection. J Virol 2010; 84:1289-301.
4. Liu Y, Du X, Chen J, Jin Y, Peng L, Wang HHX, et al. Neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with COVID-19. J Infect.2020; 81(1):e6-e12.
5. Liu J, Liu Y, Xiang P, Pu L, Xiong H, Li C, et al. Neutrophil-to-Lymphocyte Ratio Predicts Severe Illness Patients with 2019 Novel Coronavirus in the Early Stage. medRxiv 2020:2020.02.10.20021584.
6. Lagunas-Rangel FA. Neutrophil-to-lymphocyte ratio and lymphocyte-to-C-reactive protein ratio in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis. J Med Virol; 2020;92(10):1733-1734.
7. Ng LG, Ostuni R, Hidalgo A. Heterogeneity of neutrophils. Nat Rev Immunol 2019; 19:255-65.
8. Leliefeld PHC, Wessels CM, Leenen LPH, Koenderman L, Pillay J. The role of neutrophils in immune dysfunction during severe inflammation. Crit Care (London, England) 2016; 20:73.
9. Summers C, Singh NR, White JF, Mackenzie IM, Johnston A, Solanki C, et al. Pulmonary retention of primed neutrophils: a novel protective host response, which is impaired in the acute respiratory distress syndrome. Thorax 2014; 69:623-9.
10. Leppkes M, Knopf J, Naschberger E, Lindemann A, Singh J, Herrmann I, Stürzl M, Staats L, Mahajan A, Schauer C, Kremer AN, Völkl S, Amann K, Evert K, Falkeis C, Wehrfritz A, Rieker RJ, Hartmann A, Kremer AE, Neurath MF, Muñoz LE, Schett G, Herrmann M. Vascular occlusion by neutrophil extracellular traps in COVID-19. EBioMedicine. 2020;58:102925.
11. Ling MR, Chapple IL, Matthews JB. Peripheral blood neutrophil cytokine hyper-reactivity in chronic periodontitis. Innate Immun 2015; 21:714-25.
12. Dias IH, Matthews JB, Chapple IL, Wright HJ, Dunston CR, Griffiths HR. Activation of the neutrophil respiratory burst by plasma from periodontitis patients is mediated by pro-inflammatory cytokines. J Clin Periodontol 2011;38:1-7.
13. Moonen CGJ, Hirschfeld J, Cheng L, Chapple ILC, Loos BG, Nicu EA. Oral Neutrophils Characterized: Chemotactic, Phagocytic, and Neutrophil Extracellular Trap (NET) Formation Properties. Front Immunol 2019;10:635.
14. Hirschfeld J, White PC, Milward MR, Cooper PR, Chapple ILC. Modulation of Neutrophil Extracellular Trap and Reactive Oxygen Species Release by Periodontal Bacteria. Infect Immun 2017; 85.
15. Hirschfeld J, Roberts HM, Chapple IL, Parcina M, Jepsen S, Johansson A, et al. Effects of Aggregatibacter actinomycetemcomitans leukotoxin on neutrophil migration and extracellular trap formation. J Oral Microbiol 2016; 8:33070.

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