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Coronavirus-specific antibody production in middle-aged mice requires phospholipase A2G2D
Jian Zheng, … , Makoto Murakami, Stanley Perlman
Jian Zheng, … , Makoto Murakami, Stanley Perlman
Published June 1, 2021
Citation Information: J Clin Invest. 2021;131(11):e147201. https://doi.org/10.1172/JCI147201.
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Research Article Virology Article has an altmetric score of 2

Coronavirus-specific antibody production in middle-aged mice requires phospholipase A2G2D

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Abstract

Worse outcomes occur in aged compared with young populations after infections with respiratory viruses, including pathogenic coronaviruses (SARS-CoV, MERS-CoV, and SARS-CoV-2), and are associated with a suboptimal lung milieu (“inflammaging”). We previously showed that a single inducible phospholipase, PLA2G2D, is associated with a proresolving/antiinflammatory response in the lungs, and increases with age. Survival was increased in naive Pla2g2d–/– mice infected with SARS-CoV resulting from augmented respiratory dendritic cell (rDC) activation and enhanced priming of virus-specific T cells. Here, in contrast, we show that intranasal immunization provided no additional protection in middle-aged Pla2g2d–/– mice infected with any of the 3 pathogenic human coronaviruses because virtually no virus-specific antibodies or follicular helper CD4+ T (Tfh) cells were produced. Using MERS-CoV–infected mice, we found that these effects did not result from T or B cell intrinsic factors. Rather, they resulted from enhanced, and ultimately, pathogenic rDC activation, as manifested most prominently by enhanced IL-1β expression. Wild-type rDC transfer to Pla2g2d–/– mice in conjunction with partial IL-1β blockade reversed this defect and resulted in increased virus-specific antibody and Tfh responses. Together, these results indicate that PLA2G2D has an unexpected role in the lungs, serving as an important modulator of rDC activation, with protective and pathogenic effects in respiratory coronavirus infections and immunization, respectively.

Authors

Jian Zheng, David Meyerholz, Lok-Yin Roy Wong, Michael Gelb, Makoto Murakami, Stanley Perlman

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Figure 5

Immunization induces increased accumulation of and IL-1β expression by CD11c+ rDCs in DLNs of hDPP4-Pla2g2d–/– mice.

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Immunization induces increased accumulation of and IL-1β expression by C...
Five-month-old hDPP4 and hDPP4-Pla2g2d–/– mice were immunized with VRP-MERS-S or PBS i.n. on day 0 and day 28, followed by a lethal dose (750 pfu) of MERS-CoV i.n. on day 70. Mice were treated intranasally with CFSE at day 0 after infection to track the migration of lung DCs. (A) The number of DCs in lung DLNs or spleens of VRP-MERS-S–immunized and infected middle-aged hDPP4 or hDPP4-Pla2g2d–/– mice was determined by flow cytometry at the indicated dpi, n = 4/group. (B) Expression of cytokines (pro-IL-1β, IL-6, IL-10, IL-12, and TNF), MHC molecules, and costimulatory molecules (CD80, CD83, CD86) by lung and DLN DCs harvested from immunized hDPP4 or hDPP4-Pla2g2d–/– mice is shown. Data are shown as mean ± SEM and are representative of 3 independent experiments, n = 4/group. (C) An in vitro Tfh cell differentiation culture system was established as described in Methods. Percentage of CXCR5+Bcl-6+, IL-2+, and IL-17+ CD4+ T cells at day 4 of culture with different concentrations of exogenous IL-1β is shown, n = 5/group. (D) DC adoptive transfer was carried out as shown in protocol. The survival of mice and production of neutralizing antibody were determined after challenge, n = 5/group. (A–D) Data are shown as mean ± SEM and are representative of 3 independent experiments. Data shown in A and B were analyzed using Student’s t test, while the percentages of CXCR5+Bcl-6+, IL-2+, and IL-17+ CD4+ T cells shown in C were analyzed in an IL-1β dose-dependent manner using 1-way ANOVA. *P < 0.05.

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