Natural Killer Cells and COVID-19 (L7)

Natural Killer Cells and COVID-19

• Natural killer cell activation and maturation increase as COVID-19 severity increases.
• Natural killer cell numbers decrease as the infection becomes more severe.
• mRNA-based vaccines trigger a spike in natural killer cell activation, which eventually decreases in the days following vaccination.

Neutrophils and COVID-19

• Neutrophils are short-lived, but their life can be extended by infection.
• Neutrophils are phagocytic cells, playing a key role in the early immune response.
• Neutrophilia (increased neutrophils) is common in COVID-19 patients.
• Neutropenia (decreased neutrophils) can also occur, contributing to a lower white blood cell count.
• Neutrophil infiltrates in the lungs have been observed during autopsies of COVID-19 patients.
• Neutrophil netosis (release of DNA and cell contents) is associated with IL-6 and is a mechanism for trapping infectious agents.

Monocytes and COVID-19

• Monocytes differentiate into macrophages and play a significant role in the immune response.
• Increased levels of circulating monocytes are observed during acute COVID-19 infection and can persist after recovery or even in individuals with post-acute sequelae of COVID-19 (PASC).
• Monocytes/macrophages contribute to the cytokine storm during COVID-19.
• Changes in monocyte subpopulations can persist for months after COVID-19, even in individuals without PASC.

CD169+ Monocytes in COVID-19

• CD169+ is a marker for a specific monocyte subpopulation.
• CD169+ monocytes are most affected in COVID-19 compared to the general monocyte marker CD14.
• In healthy individuals, monocytes represent 5-10% of circulating cells.
• In recovered COVID-19 patients, the percentage of circulating monocytes remains high.
• Patients with PASC have significantly higher monocyte counts that persist.

Type 1 Interferons and Viral Infections

• Type 1 interferons are antiviral cytokines produced by various cell types.
• Changes in dendritic cell numbers are observed in COVID-19.
• Plasmacytoid dendritic cells are the most potent producers of type 1 interferons.

Plasmacytoid Dendritic Cells: Specialized Virus Experts

• Plasmacytoid dendritic cells are factories for type 1 interferon production.
• These cells express Toll-like receptors 7 and 9, recognizing viral RNA and DNA, respectively.
• They have high constitutive levels of transcription factor IRF-7, enabling rapid interferon alpha production upon viral encounter.
• Plasmacytoid dendritic cells have an extensive endoplasmic reticulum.

Plasmacytoid Dendritic Cells and COVID-19

• Studies have observed decreased numbers of plasmacytoid dendritic cells in COVID-19 patients, potentially contributing to the low type 1 interferon production seen in this disease.
• Dexamethasone, a corticosteroid used to dampen immune responses, can further impact plasmacytoid dendritic cell numbers and function in COVID-19.

Coronaviruses Inhibit Type 1 Interferons

• Coronaviruses have evolved mechanisms to evade the antiviral effects of type 1 interferons.
• They can hide within double-membraned structures inside cells, evading key pattern recognition receptors (RIG-1 and endosomal Toll-like receptors).
• Coronaviruses can inhibit the activation of RIG-1, a receptor for double-stranded RNA.
• They can also inhibit the induction and signaling of type 1 interferons.
• ORF3b, a protein from SARS-CoV-2, is a potent interferon antagonist.

T Cell Dynamics in COVID-19

• In uninfected individuals, CD4 and CD8 T cells circulate normally without causing symptoms.
• In moderate COVID-19, the immune response is functioning well, leading to epithelial damage and cytokine production (TNF-alpha, IL-6, IL-10, and interferon gamma).
• Lymphocyte production declines as these cells become activated in the lymph nodes.
• During severe COVID-19, there is a large decrease in lymphocytes (including CD4 and CD8 T cells), accompanied by an increase in white blood cell count due to increased neutrophils. This is consistent with a cytokine storm.

Trained Immunity

• Innate immune cells do not exhibit classical memory like T and B cells.
• However, evidence suggests that innate immune responses can be enhanced based on prior exposure to antigens. This is known as "trained immunity" or "innate memory".
• Trained immunity can be demonstrated by increased resistance to infections after vaccination or exposure to particular antigens.
• Trained immunity is not as long-lasting as classic memory from T and B cells, potentially persisting for months or sometimes longer.