Influenza A induces dysfunctional immunity and death in MeCP2-overexpressing mice
James C. Cronk, Jasmin Herz, Taeg S. Kim, Antoine Louveau, Emily K. Moser, Ashish K. Sharma, Igor Smirnov, Kenneth S. Tung, Thomas J. Braciale, Jonathan Kipnis
James C. Cronk, Jasmin Herz, Taeg S. Kim, Antoine Louveau, Emily K. Moser, Ashish K. Sharma, Igor Smirnov, Kenneth S. Tung, Thomas J. Braciale, Jonathan Kipnis
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Research Article Immunology Inflammation

Influenza A induces dysfunctional immunity and death in MeCP2-overexpressing mice

Abstract

Loss of function or overexpression of methyl-CpG-binding protein 2 (MeCP2) results in the severe neurodevelopmental disorders Rett syndrome and MeCP2 duplication syndrome, respectively. MeCP2 plays a critical role in neuronal function and the function of cells throughout the body. It has been previously demonstrated that MeCP2 regulates T cell function and macrophage response to multiple stimuli, and that immune-mediated rescue imparts significant benefit in Mecp2-null mice. Unlike Rett syndrome, MeCP2 duplication syndrome results in chronic, severe respiratory infections, which represent a significant cause of patient morbidity and mortality. Here, we demonstrate that MeCP2Tg3 mice, which overexpress MeCP2 at levels 3- to 5-fold higher than normal, are hypersensitive to influenza A/PR/8/34 infection. Prior to death, MeCP2Tg3 mice experienced a host of complications during infection, including neutrophilia, increased cytokine production, excessive corticosterone levels, defective adaptive immunity, and vascular pathology characterized by impaired perfusion and pulmonary hemorrhage. Importantly, we found that radioresistant cells are essential to infection-related death after bone marrow transplantation. In all, these results demonstrate that influenza A infection in MeCP2Tg3 mice results in pathology affecting both immune and nonhematopoietic cells, suggesting that failure to effectively respond and clear viral respiratory infection has a complex, multicompartment etiology in the context of MeCP2 overexpression.

Authors

James C. Cronk, Jasmin Herz, Taeg S. Kim, Antoine Louveau, Emily K. Moser, Ashish K. Sharma, Igor Smirnov, Kenneth S. Tung, Thomas J. Braciale, Jonathan Kipnis

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Figure 1

MeCP2Tg3 mice are highly susceptible to influenza A infection, with late adaptive immune failure and uncontrolled viral titers.

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MeCP2Tg3 mice are highly susceptible to influenza A infection, with late...
(A) Survival of 12-week-old FVB/C57BL6 F1 male MeCP2Tg3 and wild-type littermates infected with a dose of influenza A/PR/8/34 previously determined as LD100 for MeCP2Tg3 mice, representative of greater than 3 experiments. n = 4 mice per group. **P = 0.0091 by log-rank (Mantel-Cox) test. (B) Weight loss kinetics as measured by percentage of body weight lost ± SEM during infection, representative of greater than 3 experiments. (C) Lung immune cell counts ± SEM as measured by flow cytometry on day 3 post infection (p.i.). n = 3 mice per group. *P = 0.0225 by 2-tailed Student’s t test. (D) Lung immune cell counts ± SEM as measured by flow cytometry on day 8 p.i., representative of 2 experiments. n = 3 mice per group. *P < 0.05, **P < 0.01 by 2-tailed Student’s t test. (E and F) Influenza A/PR/8–specific IgG and IgM antibody titers ± SEM as measured by ELISA in bronchoalveolar lavage (BAL) fluid from day 8 p.i. n = 3 mice per group. *P < 0.05, **P < 0.01, ***P < 0.001 by 2-way ANOVA with Bonferroni post test. (G) Viral titers ± SEM from BAL fluid measured on day 8 p.i. by tissue culture infectious dose (TCID50). n = 4 mice per group. *P = 0.0211 by Mann-Whitney test.