The SARS-CoV-2 Nucleoprotein Induces Innate Memory in Human Monocytes

Area of Science:

• Immunology
• Virology
• Infectious Diseases

Background:

• Monocytes and macrophages are key innate immune cells crucial for managing infections.
• SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection outcomes depend on host immune interactions.
• The concept of 'innate memory,' where initial immune encounters alter responses to future challenges, is not well understood in the context of SARS-CoV-2.

Purpose of the Study:

• To investigate if SARS-CoV-2 or its components can induce innate memory in human monocytes.
• To explore the potential long-term immune sequelae of COVID-19 related to innate immune cell responses.

Main Methods:

• Human monocytes were cultured *in vitro* and exposed to SARS-CoV-2 components (Spike protein subunits S1/S2, nucleocapsid N protein, heat-inactivated virus).
• Following initial exposure, monocytes were re-challenged with viral or bacterial stimuli.
• Immune responses, including cytokine production (e.g., IL-1Ra), were measured to assess innate memory induction.

Main Results:

• Exposure to SARS-CoV-2 Spike protein subunits (S1, S2) and heat-inactivated virus did not significantly alter monocyte reactivity.
• Pre-exposure of monocytes to the SARS-CoV-2 nucleocapsid (N) protein resulted in an enhanced production of anti-inflammatory Interleukin-1 receptor antagonist (IL-1Ra) upon subsequent challenge.
• This altered cytokine profile suggests a modified innate immune response, potentially indicating a milder reaction to new infections.

Conclusions:

• The SARS-CoV-2 nucleocapsid (N) protein, but not Spike proteins or inactivated virus, can induce a form of innate memory in human monocytes *in vitro*.
• This innate memory is characterized by an increased production of IL-1Ra, suggesting a potentially dampened inflammatory response to subsequent infections.
• These findings contribute to understanding the long-term immune consequences of COVID-19 and the role of innate memory in disease pathogenesis.