Dissecting the immunological mechanisms of vascular pathology in pre-clinical patients with chronic inflammation and its link to atherosclerosis

A PhD project for the 2022 doctoral clinical fellows programme with Venizelos Papagiannopoulos (primary supervisor, Crick), Francesco D’Aiuto (UCL) and John Deanfield (UCL). 

Project description

Cardiovascular diseases develop over many years during what is termed as the pre-clinical phase through mechanisms that are not well characterised. Most clinical work has focused on the pathological mechanisms driving active disease, but much less attention has been invested in understanding and treating the early stages of disease development during the pre-clinical phase. This is particularly important since atherosclerosis is an irreversible disease.

Francesco D'Aiuto

Chair / Honorary Consultant in Periodontology (Monospecialty) or Restorative Dentistry, Eastman Dental Institute, Faculty of Medical Sciences, UCL

John Deanfield

Professorial Research Fellow, Clinical Science, Institute of Cardiovascular Science, Faculty of Pop Health Sciences, UCL

Recent studies have shown that vascular dysfunction develops many years before active atherosclerosis and can be a potent predictor of pre-clinical atherosclerosis. However, the mechanisms driving vascular dysfunction remain unclear. Furthermore, cardiovascular disease and its associated risk factors were the predominant elements dictating the development of immune pathology during severe infection as recently observed in SARS-COVID-2 patients.

Chronic inflammation is a major driver of vascular dysfunction. Our project will aim at understanding the mechanisms driving vascular inflammation by examining the impact on myeloid cells such as neutrophils, monocytes and macrophages. The cross-talk between these cells is an important driver of pathology during the clinical phase of atherosclerosis (Warnatsch et al.m 2015).

We have recently established several readouts that allow us to dissect novel aspects of the functional impact of patient plasmas on neutrophil function and correlate it to proteomic and cytokine analysis to uncover novel mechanisms of pathology. Using these strategies, we have already uncovered functional alterations in neutrophils as well as deficiencies that are linked to vascular pathologies (unpublished). During these studies, we have also observed comparable deficiencies in a lower proportion of healthy donors, suggesting these mechanisms of pathology might be relevant in chronic inflammatory conditions as well.

To address this fundamental question, we will employ our functional and systems platform to characterize pathological mechanisms by studying the plasma and myeloid cells of patients with chronic pre-clinical inflammation. In addition, periodontitis has been shown to be linked to vascular endothelial dysfunction and type-2 diabetes and non-pharmacological treatment reverses pathology in these patients (D'Aiuto et al., 2018; D'Aiuto et al., 2008; Masi et al., 2018). We will also evaluate the impact on-neutrophil-associated pathogenic mechanisms of treatments that have been found to reverse the vascular pathology associated with pre-clinical atherosclerosis. These studies will uncover whether the mechanisms we have identified in sepsis and SARS-COV-2 patients are more prevalent in “healthy” patients with low levels of chronic inflammation.

The partner institution for this project is UCL.

References

  1. Warnatsch, A., Ioannou, M., Wang, Q., and Papayannopoulos, V. (2015). Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science 349, 316-320.
  2. D'Aiuto, F., Gkranias, N., Bhowruth, D., Khan, T., Orlandi, M., Suvan, J., Masi, S., Tsakos, G., Hurel, S., Hingorani, A.D., et al. (2018). Systemic effects of periodontitis treatment in patients with type 2 diabetes: a 12 month, single-centre, investigator-masked, randomised trial. Lancet Diabetes Endocrinol 6, 954-965.
  3. D'Aiuto, F., Sabbah, W., Netuveli, G., Donos, N., Hingorani, A.D., Deanfield, J., and Tsakos, G. (2008). Association of the metabolic syndrome with severe periodontitis in a large U.S. population-based survey. J Clin Endocrinol Metab 93, 3989-3994.
  4. Masi, S., Orlandi, M., Parkar, M., Bhowruth, D., Kingston, I., O'Rourke, C., Virdis, A., Hingorani, A., Hurel, S.J., Donos, N., et al. (2018). Mitochondrial oxidative stress, endothelial function and metabolic control in patients with type II diabetes and periodontitis: A randomised controlled clinical trial. Int J Cardiol 271, 263-268.