Soluble NS1 Antagonizes IgG- and IgA- Mediated Monocytic Phagocytosis of DENV Infected Cells

Abstract

Dengue virus (DENV) is endemic in over 100 countries, infecting an estimated 400 million individuals every year. Infection with DENV raises an antibody response primarily targeting viral structural proteins. However, DENV encodes several immunogenic non-structural (NS) proteins, one of which, NS1, is expressed on the membrane of DENV-infected cells. IgG and IgA isotype antibodies that bind NS1 are abundant in serum following DENV infection. Our study aims to determine if NS1-binding IgG and IgA isotype antibodies contribute to the clearance of DENV-infected cells by antibody-mediated cellular phagocytosis. We observed that both IgG and IgA isotype antibodies can facilitate monocytic uptake of DENV NS1 expressing cells in a FcγRI and FcαRI dependent fashion. Interestingly, this process was antagonized by the presence of soluble NS1, suggesting that the production of soluble NS1 by infected cells may serve as immunological chaff, antagonizing opsonization and clearance of DENV infected cells.

Roles of NS1 Protein in Flavivirus Pathogenesis

“…257 Thus, the authors suggest that circulating sNS1 acts as a decoy and binds with NS1-reactive antibodies to prevent them from recognizing the DENV-infected cells, leading to immune evasion, which facilitates viral replication and spread of virions within the host. 257 While the authors have only explored the DENV NS1 protein, it is quite possible that this phenomenon is common to all flaviviruses that secrete NS1 to the circulation in abundance. Further experiments with other flaviviruses must be conducted to confirm whether all flavivirus NS1 proteins facilitate immune evasion by functioning as a decoy.…”

“…142 A recent study suggested a potential explanation for the secretion of circulating sNS1 from DENV-infected cells, which is to serve as a form of immunological distraction, shielding the infected cells from recognition and subsequent elimination by NK cells and phagocytes. 257 The authors showed that DENVinfected cells expressing NS1 protein on their cell surface (membrane-bound NS1) can be opsonized by NS1-reactive IgG and IgA isotype antibodies, facilitating their phagocytic clearance using in vitro assays that included cells infected with DENV-2 and cells that were stably expressing membranebound NS1. However, the addition of soluble recombinant DENV-2 NS1 to the cell culture media prevented the monocytic antibody-dependent phagocytosis of the cells expressing the DENV NS1 proteins on their cell surface.…”

“…However, the addition of soluble recombinant DENV-2 NS1 to the cell culture media prevented the monocytic antibody-dependent phagocytosis of the cells expressing the DENV NS1 proteins on their cell surface. 257 Thus, the authors suggest that circulating sNS1 acts as a decoy and binds with NS1-reactive antibodies to prevent them from recognizing the DENV-infected cells, leading to immune evasion, which facilitates viral replication and spread of virions within the host. 257 While the authors have only explored the DENV NS1 protein, it is quite possible that this phenomenon is common to all flaviviruses that secrete NS1 to the circulation in abundance.…”

“…Therefore, the relevance of sNS1 for immune evasion during a primary DENV infection may not be significant. 257…”

“…The authors showed that DENV-infected cells expressing NS1 protein on their cell surface (membrane-bound NS1) can be opsonized by NS1-reactive IgG and IgA isotype antibodies, facilitating their phagocytic clearance using in vitro assays that included cells infected with DENV-2 and cells that were stably expressing membrane-bound NS1. However, the addition of soluble recombinant DENV-2 NS1 to the cell culture media prevented the monocytic antibody-dependent phagocytosis of the cells expressing the DENV NS1 proteins on their cell surface . Thus, the authors suggest that circulating sNS1 acts as a decoy and binds with NS1-reactive antibodies to prevent them from recognizing the DENV-infected cells, leading to immune evasion, which facilitates viral replication and spread of virions within the host .…”