Non‐structural protein 1‐specific antibodies directed against Zika virus in humans mediate antibody‐dependent cellular cytotoxicity

L, Vargas; Adam, Awadalkareem; Masterson, M.D. James F.; Smith, Madison; Lyski, Zoë L; Dowd, Kimberly A.; Pierson, Theodore C.; Messer, William B.; Currier, Jeffrey R.; Mathew, Anuja

doi:10.1111/imm.13380

Cited by 12 publications

(11 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…NS1 is predominantly secreted as a hexamer by flavivirus-infected cells, but the protein can also be found on the cellular plasma membrane in a dimeric configuration ( 33 , 34 ). The biological function of surface-restricted NS1 is unclear, but the antigen can facilitate opsonization of infected cells by NS1-reactive antibodies, thereby allowing NK cells, monocytes, and other phagocytic cells to recognize and clear infected cells via Fc receptor–mediated mechanisms such as antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis ( 35 , 36 ). To measure the abundance of opsonizing NS1-specific antibodies, we used a CEM.NK R cell line that was engineered to stably express DENV-1 NS1 (fig.…”

Section: Resultsmentioning

confidence: 99%

Evolution of inflammation and immunity in a dengue virus 1 human infection model

Waickman

Fang

et al. 2022

Sci. Transl. Med.

View full text Add to dashboard Cite

Dengue virus (DENV) infections are major causes of morbidity and mortality throughout the tropics and subtropics. More than 400 million infections are estimated to occur every year, resulting in nearly 100 million symptomatic infections and more than 20,000 deaths. Early immune response kinetics to infection remain unclear, in large part due to the variable incubation period exhibited by the DENVs after introduction into a susceptible host. To fill this knowledge gap, we performed a comprehensive virologic and immunologic analysis of individuals experimentally infected with the underattenuated DENV-1 strain 45AZ5. This analysis captured both the kinetics and composition of the innate, humoral, and cellular immune responses elicited by experimental DENV-1 infection, as well as virologic and clinical features. We observed a robust DENV-specific immunoglobulin A (IgA) antibody response that manifested between the appearance of DENV-specific IgM and IgG in all challenged individuals, as well as the presence of a non-neutralizing/NS1-specific antibody response that was delayed relative to the appearance of DENV virion–specific humoral immunity. RNA sequencing analysis revealed discrete and temporally restricted gene modules that correlated with acute viremia and the induction of adaptive immunity. Our analysis provides a detailed description, in time and space, of the evolving matrix of DENV-elicited human inflammation and immunity and reveals several previously unappreciated immunological aspects of primary DENV-1 infection that can inform countermeasure development and evaluation.

show abstract

Section: Resultsmentioning

confidence: 99%

Evolution of inflammation and immunity in a dengue virus 1 human infection model

Waickman

Fang

et al. 2022

Sci. Transl. Med.

View full text Add to dashboard Cite

show abstract

“…NS1 is predominantly secreted as a hexamer by flavivirus infected cells, but the protein can also be found on the cellular plasma membrane in a dimeric configuration [33, 34]. While the biological function of surface-restricted NS1 is unclear, the antigen can facilitate opsonization of infected cells by NS1-reactive antibodies, thereby allowing NK cells, monocytes and other phagocytic cells to recognize and clear infected cells via Fc receptor mediated mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) [35, 36]. To measure the abundance of opsonizing NS-1 specific antibodies we utilized a CEM.NKR cell line that was engineered to stably express DENV-1 NS1 ( Supplemental Figure 2 ) and quantified the abundance of anti-NS1 opsonizing antibodies using flow cytometry.…”

Section: Resultsmentioning

confidence: 99%

Evolution of inflammation and immunity in a dengue virus 1 human infection model

Waickman

Fang

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Dengue virus (DENV) infections are significant sources of morbidity and mortality throughout the tropics and subtropics. Over 400 million infections are estimated to occur every year, resulting in nearly 100 million symptomatic infections and over 20,000 deaths. Early immune response kinetics to infection remain unclear, in large part due to the variable incubation period exhibited by the DENVs after introduction into a susceptible host. To fill this knowledge gap, we performed a comprehensive virologic and immunologic analysis of individuals experimentally infected with the under-attenuated DENV-1 strain 45AZ5. This analysis captured both the kinetics and composition of the innate, humoral, and cellular immune responses elicited by experimental DENV-1 infection, as well as virologic and clinical features. Revealed in this analysis was a robust DENV-specific IgA antibody response that manifested between the appearance of DENV-specific IgM and IgG in all challenged individuals, as well as the presence of a non-neutralizing/NS1-specific antibody response that was delayed relative to the appearance of DENV-virion specific humoral immunity. RNAseq analysis also revealed several distinct and temporally-restricted gene modules that allowed for the identification and differentiation of the innate and adaptive immune response to DENV-infection. Our analysis provides a detailed description, in time and space, of the evolving matrix of DENV-elicited human inflammation and immunity and reveals several previously unappreciated immunological aspects of primary DENV-1 infection that can inform countermeasure development and evaluation.

show abstract

“…While our study focuses on DENV, NS1-reactive antibodies have been observed in circulation after infection with numerus other flavivirus including Zika virus (ZIKV) (40–43). Notably, ZIKV NS1-reactive antibodies have been shown to be capable of facilitating NK cell degranulation and lysis of NS1 expressing cells using a system similar to that presented in our study (40).…”

Section: Discussionmentioning

confidence: 99%

Soluble NS1 antagonizes IgG- and IgA-mediated monocytic phagocytosis of DENV infected cells

Waldran

Wegman

Bahr

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Dengue virus (DENV) is endemic in over 100 countries, infecting an estimated 400 million individuals every year. Infection with DENV raises a significant antibody response, primarily consisting of antibodies targeting viral (structural) proteins. However, not all DENV antigens are part of the virion itself, as the DENV genome encodes several non-structural (NS) proteins. One of these, NS1, has been shown to be antigenic and is expressed on the membrane of DENV-infected cells. IgG and IgA isotype antibodies that bind NS1 are detectable in serum following DENV infection and are also capable of interacting with Fc receptors expressed on professional phagocytes. Our study aims to determine if NS1-binding IgG and IgA isotype antibodies contribute to the clearance of DENV-infected cells by professional phagocytes through antibody mediated phagocytosis/trogocytosis. Using an in vitro model of trogocytosis we observed that both IgG and IgA isotype antibodies can facilitate facilitating monocytic uptake of DENV NS1 expressing plasma membrane in an additive fashion. This process was dependent on the expression of FcγRI (CD64) and FcαR (CD89) for IgG and IgA mediated membrane uptake, respectively. Furthermore, this process was antagonized by the presence of soluble NS1, suggesting that the production of soluble NS1 by infected cells may serve as an immunological chaff, thereby antagonizing opsonization and clearance of infected cells by NS1-specific IgG and IgA isotype antibodies.

show abstract

Non‐structural protein 1‐specific antibodies directed against Zika virus in humans mediate antibody‐dependent cellular cytotoxicity

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 12 publications

References 41 publications

Evolution of inflammation and immunity in a dengue virus 1 human infection model

Evolution of inflammation and immunity in a dengue virus 1 human infection model

Evolution of inflammation and immunity in a dengue virus 1 human infection model

Soluble NS1 antagonizes IgG- and IgA-mediated monocytic phagocytosis of DENV infected cells

Contact Info

Product

Resources

About