Immune cell interactions and lung damage in SARS-CoV-2 special attention on monocytes/macrophages, T and B lymphocytes, dendritic cells and Toll-like receptors in SARS-CoV-2.

Coronavirus disease 2019 (COVID-19) is caused by a novel human virus - SARS-CoV-2, is characterized in severe cases by dysregulated innate and adaptive immune responses leading to lung injury and systemic hyperinflammation. This review summarizes the roles of monocyte/macrophages, T and B lymphocytes, dendritic cells, and Toll-like receptor signaling in the immunopathogenesis of severe COVID-19. Severe COVID-19 is characterized by light neutrophilia, reduced numbers of transitional and non-classical monocytes, lymphopenia and diminished conventional and plasmacytoid dendritic cells (DCs). Inflammatory monocytes/macrophage activation and excessive cytokine production contribute to alveolar damage and cytokine storm. Alveolar macrophages (AMs) are abortively infected by the virus in an ACE2-dependent manner, but still no virus replication has been detected. AMs produce high quantities of IL-6 TNF-α, and IL-1β promoting cytokine storm. T lymphocytes dysregulation is associated with lymphopenia, impaired antiviral responses, and T-cell exhaustion. Severe COVID-19 infection causes a disproportionate decrease of CD4+ T cells, reduced CD8+ T cells and alteration of T cell subsets i.e. Tregs decrease and stimulation of Th1, Th2 and Th17. TLR3 and TLR7 are broadly expressed on human immune cells and recognize dsRNA and ssRNA in the endosome. Since TLR7 duplicated genes are localized on the X-chromosome, the disease is more expressed in men. B cell responses are characterized by impaired germinal center formation and extrafollicular antibody production. B cells produce neutralizing antibodies having little somatic hypermutations (SHM) that block the virus in the extra-follicular space. The activation of B cells via contact with Tfh cells antigen and BCR antigen is described. The reduction of germinal centers in thoracic lymph nodes and spleen is discussed. DCs depletion and dysfunction reduce antigen-presentation and interferon responses. A significant reduction of conventional DCs1 and DCs2 and of pDCs in blood is detected. Simultaneously, CD1c+ DCs are recruited and increased in the lung in severe COVID-19. Toll-like receptor pathways further amplify inflammatory signaling and immune imbalance. Collectively, these immune alterations contribute to defective viral clearance and progressive lung injury. Understanding the interactions between innate and adaptive immune responses in COVID-19 may support the development of targeted immunomodulatory therapies and provide broader insights into viral immunopathology.