Immune Responses to SARS-CoV-2 cause severe COVID-19 in some and recovery in most

Clive Gray – Professor in Immunology
immunopaedia.org – useful web site for immunology resources.

Outline:

  • Basics of Immunology
  • A balance between inflammation and tolerance
  • What happens to people who progress to severe COVID-19?
  • What might be happening in SARS-CoV-2 infected people who remain asymtomatic, have few symptoms and recover?

Internal : External world

~99% of time the pathogen gets destructed, but the pathogen may survive in rare cases.

2 arms of immune responses:

Innate – evolutionary response – very rapid – elements of innate immunity are found in bacteria, plants, lower vertebrates, squids, fish etc.

Some pathogens survive ->

Adaptive immunity – much more targeted / focussed. The immune system targets more specifically the pathogens which survive the innate immunity.

Infection initially -> expansion (peak after maximal viral load) -> contraction with some residual immunity (Memo Maintenance) -> with secondary response (Recall) there is a more rapid expansion (and higher peak) of the specific immunity.

Immune regulation:

Predisposed conditions: DM, HPT, Obesity, would make an individual highly susceptible to inflammation due to in imbalance of Inflammation vs. Tolerance, see below.

The Yin Yang of immunology:

Yin – immune regulation; Yang – Inflammatory Process

Pro-inflammatory (Orange)

TH17 – inflammatory cells secreting the “calling signals” for leucocytes.

TH1 – secreting IFN gamma; IL-2 ; TNF-alpha – cytokines causing inflammation

Macrophage – presents antigens – in lymph nodes and germinal centres

T-Helper cells T-FH

Immune Regulation (Blue)

TH2 – hand in hand with TH1 (opposite)

Regulatory cells (nT and iT regulatory cells)

Actual pathogen is not causing disease – but the immune response – thus this is what should be focussed on to treat the disease.

Dose of the virus (viral load) is key to how you respond to the virus – Initial High dose in viral load likely will lead to high inflammatory response; Low dose (non-robust virus replication) may cause a less severe inflammatory response.

CCL’s allow leucocytes to migrate, hence in a cytokine storm, with high level of migration, the leucocytes causes severe local inflammation due to migration of leucocytes to local sites.

CCL5 blocking antibodies leads to rapid reduction of IL-6.

Dexamethasone is not so much an inhibitor of CCR5, but it prevents the hyperinflammation by inhibiting the majority of the inflammatory pathway.

CD8 cells

Within interstisium, the CD8 cells are present and

CD4 cells activates CD8 cells, hence called T-helper cells.

T-cell responses are very prevalent to COVID-19 exposed individuals. BUT CD4 cells and CD8 cells can also react to the SARS2 viral proteins in unexposed individuals.
RBD – receptor binding domain (Spike-protein); Orange is the amount of amino acids which are changeable.
Orange amino acids are those which are changeable – illustrating how the virus has mutated in a month.