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Coronavirus-specific antibody production in middle-aged mice requires phospholipase A2G2D
Jian Zheng1, David Meyerholz2, Lok-Yin Roy Wong1
1Department of Microbiology and Immunology and.
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.
Insights
PLA2G2D offers protection against pathogenic coronaviruses by enhancing immune cell activation. However, its absence during immunization leads to detrimental immune responses, highlighting its dual role in respiratory virus infections.
Area of Science:
- Immunology
- Virology
- Aging Research
Background:
- Aging exacerbates respiratory virus infections, particularly pathogenic coronaviruses, due to lung inflammation ('inflammaging').
- PLA2G2D, a phospholipase increasing with age, was previously linked to beneficial lung inflammation resolution.
- PLA2G2D deficiency improved survival in SARS-CoV infected mice via enhanced dendritic cell (DC) activation and T cell priming.
Purpose of the Study:
- To investigate the role of PLA2G2D in pathogenic coronavirus infections and immunization in aged mice.
- To determine the mechanisms underlying the differential effects of PLA2G2D in infection versus immunization.
- To explore the impact of PLA2G2D on respiratory dendritic cell (rDC) activation and adaptive immune responses.
Main Methods:
- Utilized Pla2g2d-/- mice and wild-type (WT) mice, infected with SARS-CoV, MERS-CoV, or SARS-CoV-2.
- Administered intranasal immunization to assess adaptive immune responses, including virus-specific antibodies and follicular helper T (Tfh) cells.
- Conducted experiments involving WT rDC transfer and partial IL-1β blockade in Pla2g2d-/- mice.
- Analyzed immune cell activation, cytokine expression (IL-1β), and viral load.
Main Results:
- Pla2g2d-/- mice showed no enhanced protection upon immunization against any of the three coronaviruses, with impaired antibody and Tfh cell production.
- This lack of response was attributed to pathogenic rDC activation, characterized by increased IL-1β expression, not T or B cell intrinsic defects.
- Transferring WT rDCs and partially blocking IL-1β in Pla2g2d-/- mice restored protective adaptive immunity, including antibody and Tfh responses.
Conclusions:
- PLA2G2D plays a critical, dual role in respiratory coronavirus infections, acting protectively during infection and detrimentally during immunization.
- Pathogenic rDC activation, driven by IL-1β, underlies the failure of immunization in PLA2G2D-deficient aged mice.
- Targeting IL-1β or modulating rDC function could be therapeutic strategies for improving vaccine efficacy and outcomes in aged populations.
