Intravenous immunoglobulin recalibrates monocyte responses to abortive SARS-CoV-2 infection across viral variants.
TL;DR
These findings identify primary human monocytes as targets of abortive yet immunologically active SARS-CoV-2 infection and demonstrate that IVIg modulate monocyte stress and inflammatory responses through Fc-dependent mechanisms rather than direct viral neutralization.
Abstract
Monocytes contribute to inflammation during coronavirus disease 2019 (COVID-19), yet their capacity to support productive infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the impact of viral evolution on their responses, remain unclear. Here, we investigated the interaction between primary human monocytes and three SARS-CoV-2 variants representing distinct evolutionary stages (Wuhan, Delta, and Omicron), and evaluated the modulatory effects of intravenous immunoglobulin (IVIg). All variants efficiently entered monocytes and persisted as intracellular viral RNA and protein, but failed to generate infectious progeny, indicating abortive infection. Despite the absence of productive replication, infected monocytes exhibited marked ultrastructural remodeling and mounted robust innate immune responses. Omicron infection was associated with enhanced replication-related signatures compared with Wuhan and Delta. IVIg did not prevent viral entry or RNA persistence but significantly reduced infection-induced vacuolization and selectively modulated cytokine responses. Notably, high-dose IVIg enhanced TNF-associated responses and reduced IL10 expression, suggesting a recalibration of monocyte inflammatory set-points. These effects occurred independently of neutralizing activity. Together, these findings identify primary human monocytes as targets of abortive yet immunologically active SARS-CoV-2 infection and demonstrate that IVIg modulate monocyte stress and inflammatory responses through Fc-dependent mechanisms rather than direct viral neutralization.