Multifaceted Defects in Monocytes in Different Phases of Chronic Hepatitis B Virus Infection: Lack of Restoration after Antiviral Therapy

• Published in: Microbiology spectrum 2022-12, Vol.10 (6), p.e0193922-e0193922
• Main Authors: Dey, Debangana, Pal, Sourina, Chakraborty, Bidhan Chandra, Baidya, Ayana, Bhadra, Soham, Ghosh, Ranajoy, Banerjee, Soma, Ahammed, S K Mahiuddin, Chowdhury, Abhijit, Datta, Simanti
• Format: Article
• Language: English
• Subjects: Antiviral Agents - therapeutic use; beta Catenin - metabolism; beta Catenin - therapeutic use; Cytokines - metabolism; Hepatitis B e Antigens - metabolism; Hepatitis B Surface Antigens - analysis; hepatitis B virus surface antigen; Hepatitis B, Chronic - drug therapy; Host-Microbial Interactions; Humans; IL-4; Interleukin-4 - metabolism; Interleukin-4 - therapeutic use; monocyte subsets; Monocytes - metabolism; Monocytes - pathology; Research Article; tenofovir; Tenofovir - therapeutic use; Treg; β-catenin
• ISSN: 2165-0497; 2165-0497
• DOI: 10.1128/spectrum.01939-22

Monocytes play an important role in the control of microbial infection, but monocyte biology during chronic hepatitis B virus (HBV) infection (CHI) remains inadequately studied. We investigated the frequency, phenotype, and functions of monocyte subsets in different phases of CHI, namely, immune tolerance (IT), hepatitis B early antigen (HBeAg)-positive/HBeAg-negative chronic hepatitis B (EP-/EN-CHB, respectively), and inactive carrier (IC), identified factors responsible for their functional alterations, and determined the impact of antiviral therapy on these cells. Flow cytometric analysis indicated that HLA-DR CD14 CD16 classical monocytes were significantly reduced while HLA-DR CD14 CD16 intermediate and HLA-DR CD14 CD16 nonclassical monocytes were expanded in IT and EP-/EN-CHB compared with those in IC and healthy controls (HC). In comparison to IC/HC, monocytes in IT and CHB exhibited diminished expression of Toll-like receptor 2 (TLR-2)/TLR-4/TLR-9 and cytokines interleukin-12 (IL-12)/tumor necrosis factor alpha (TNF-α)/IL-6 but produced higher levels of IL-10/transforming growth factor β (TGF-β). Further, monocytes in CHB/IT showed impaired phagocytosis and oxidative response relative to those in IC/HC. assays indicated that high titers of hepatitis B surface antigen (HBsAg) present in IT/CHB and of IL-4 in CHB triggered the functional defects in monocytes via induction of β-catenin. Additionally, monocyte-derived M1 macrophages of CHB/IT produced fewer proinflammatory and more anti-inflammatory cytokines than those of IC/HC, while in CHB/IT, the monocytes skewed the differentiation of CD4 T cells more toward regulatory T cells and a Th2 phenotype. Moreover, monocytes in CHB and IT overexpressed chemokine receptor CCR2, which coincided with increased intrahepatic accumulation of β-catenin CD14 cells. One year of tenofovir therapy failed to normalize monocyte functions or reduce serum HBsAg/IL-4 levels. Taken together, monocytes are functionally perturbed mostly in IT and EP-/EN-CHB phases. Targeting intramonocytic β-catenin or reducing HBsAg/IL-4 levels might restore monocyte function and facilitate viral clearance. Chronic HBV infection (CHI) is a major cause of end-stage liver disease for which pharmacological treatments currently available are inadequate. Chronically HBV-infected patients fail to mount an efficient immune response to the virus, impeding viral clearance and recovery from hepatitis. Monocytes represent a central part of innate imm