HEV ORF3 downregulatesCD14 and CD64 to impair macrophages phagocytosis through inhibiting JAK/STAT pathway

Abstract

Hepatitis E virus (HEV) could induce chronic hepatitis and liver failure with high mortality through unknown mechanisms. The previous study showed that the HEV open reading frames 3 (ORF3) could inhibit macrophages inflammatory response. Impaired macrophages phagocytosis was also found in patients infected with HEV and its nucleic acids could be detected in macrophages. To elucidate the role of HEV ORF3 on phagocytosis, the phagocytosis activation was measured by phagocytosis test, flow cytometry, and phalloidin staining. Meanwhile, the expression of key phagocytic receptors and the activation of transduction pathway were investigated by using reverse transcription real‐time quantitative polymerase chain reaction (RT‐qPCR) and Western blot analysis. Results of phagocytosis test showed that the HEV ORF3 could significantly impair the absorption capacity of latex beads. Furthermore, results of RT‐qPCR and Western blot analysis showed that the expression of CD14 and CD64 decreased. Afterward, the present study showed that the activation of Janus kinase‐signal transducer and activator of transcription (JAK/STAT) signaling pathway was inhibited by HEV ORF3 and downregulation of CD14 and CD64 could be reversed by interferon γ, one activator of the JAK1/STAT1 signaling pathway. In conclusion, HEV ORF3 could significantly impair the phagocytosis of macrophage by downregulating expression of CD14 and CD64, which may function by inhibiting the activation of the JAK1/STAT1 signaling pathway.

Interplay between Hepatitis E Virus and Host Cell Pattern Recognition Receptors

“…HEV ORF3-mediated regulation of LPS-induced signaling [106] might be attenuating the endotoxemia in the liver during the natural course of infection as proposed for HCV NS5A protein [108]. HEV ORF3 mediated the impairment of phagocytosis by downregulation of phagocytic receptors CD14 and CD64 through the inhibition of JAK/STAT signaling is also demonstrated [109]. Overall, these findings implicate the role of ORF3 in curtailing cellular antiviral response and favoring virus replication.…”

CD14 Is Involved in the Interferon Response of Human Macrophages to Rubella Virus Infection

“…The role played by CD14 in host defence mechanisms is always protective through activation of an immune response [ 41 ], whereas the level of CD14 expression in MΦs during infection depends on the type of the virus and bacterium. Comparable to infection with RuV, the expression of ORF3 of hepatitis E virus (HEV) reduced CD14 expression [ 50 ]. In the case of human monocyte-derived MΦ CMV infection is associated with a maintained high expression level of CD14 as compared to the decline in mock infection over time of cultivation [ 51 ].…”

Enhancing Fatty Acid Catabolism of Macrophages Within Aberrant Breast Cancer Tumor Microenvironment Can Re-establish Antitumor Function

“…Currently, it is widely believed that the JAK1/STAT1 signaling pathway is one of the major pathways of M1 macrophage activation (Gough et al, 2008). When this pathway is deregulated, phagocytosis of macrophages is inhibited (Lei et al, 2019). Indeed, we identified the involvement of the JAK1-STAT1 pathway in the above process.…”