Week 11 Part 1 - COVID-19 Flashcards
B Cell Responses to SARS-CoV-2
Most COVID-19 patients mount IgG, IgM (and IgA) responses to the virus
Many mount neutralising antibodies
Magnitude of antibody response can correlate with disease severity
Anitgens:
- spike protein
- nucleocapsid (abundant during viral replication)
Neutralising Antibodies that Target the Spike Protein
RBD
S1
Ectodomain (S2P)
B Cells and the Germinal Centre of the Spleen
B:T cell interactions critical for:
- proliferation of B cells
- expansion of B cells
- isotype switching
- aaffinity maturation
B cells with the highest affinity are selected to survive
- antibody secreting B cells
- or memory B cells
Spleen and Lymph Nodes in COVID-19
Germinal centres are lost in lymph nodes and spleen
Loss of white pulp in spleens
Biphasic Course for COVID-19
Viral and host inflammatory response phases
Viral evasion of host immunity precedes hyper-inflammatory phase
Delayed interferon-type-I response similar to macrophage activation syndrome
Phasic Therapy with ‘Double Hit’
Virus-directed therapy e.g. Paxlovid, Molnupivar, Remdesivir (inhibits virus)
Host-directed agents e.g. dexamethasone (inhibits inflammation)
Interferon Responses
Early IFN response = rapid viral clearance -> mild disease
Delayed IFN response = viral persistence, inflammation -> severe disease
Low or no IFN response = no viral control, inflammation -> severe disease
Injection of recombinant IFN = viral clearance -> milder disease
Delayed IFN Response Leading to Hyperinflammatory Response - Low Viral Load vs High Viral Load
Low viral load → IFN response engaged early → mild disease
High viral load → virus replication delays IFN response → cytokine storm before adaptive response can clear the virus → severe disease
Myeloid Cells and Hyperinflammatory Response
IL-6, IL-1b and interferons secreted by infected epithelial cells
Increase inflammation in resident macrophages and recruit inflammatory monocytes
Recruited myeloid cells drive further inflammation: IL-6, and TNF
Dysfunctional responses are amplified: increased neutrophils and eosinophils
- NETosis
- thrombocytosis
Also involve plasmacytoid dendritic cells and recruitment of NK cells
CD4 and CD8 T Cell Responses in COVID-19
CD4+ T cells provide B cell help (in the germinal centres)
CD8+ T cells kill infected cells to reduce viral burden
Reduced CD4+ T cells and CD8+ T cells in peripheral blood of COVID-19 patients
Highest reduction in CD8+ T cells in severe cases
Mild symptoms: patients have normal or slightly elevated T cells
Reduced Circulating T Cells in COVID-19
Inflammatory milieu e.g. TNF inhibits T cell recirculation
Extensive T cell death in spleens and lymph nodes
T cell recruitment to the pulmonary site of infection
Other T Cell Responses in COVID-19
Increased number of activated T cells expressing an exhausted phenotype
Upregulation of co-stimulatory markers
Upregulation of inhibitory markers e.g. PD-1, CTLA-4, TIM-3
Reduced regulatory T cells
Production of inflammatory cytokines by CD4+ T cells
- GM-CSF which recruits myeloid cells
CD8+ T cells may have increased or reduced cytotoxic activity
Common Lab Diagnostics in COVID-19
Leukopaenia
Lymphopaenia
Elevated ALT, LDH, CRP, and erythrocyte sedimentation rate
Increased neutrophil to lymphocyte ratio
Thrombocytopaenia
Hypoalbuminaemia
RT-PCR Testing for COVID-19
Targeting the spike (S) gene of SARS-CoV-2
US FDA screens viral nucleocapsids N1 and N2
Cycle threshold <40 for only one of the two nucleocapsid proteins - indeterminant
Overall, good specificity and considered the most sensitive
How can RT-PCR for COVID be Improved?
By addition of RdRp/Helicase (Hel), Nucleocapsid (N) and Envelope (E) genes
