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Vaccination mitigates influenza-induced muscular declines in aged mice.

ABSTRACT: Influenza (flu) infection increases the risk for disability, falls, and broken bones in older adults. We have employed a preclinical model to examine the impact of flu on muscle function, which has a direct impact on fall risk. In mice, flu causes mobility and strength impairments with induction of inflammatory and muscle degradation genes that are increased and prolonged with aging. To determine if vaccination could reduce flu-induced muscle decrements, mice were vaccinated with flu nucleoprotein, infected, and muscle parameters were measured. Vaccination of aged mice resulted in significant protection from functional decrements, muscle gene expressions alterations, and morphological damage. Vaccination also improved protection from lung localized and systemic inflammation in aged mice. Despite documented decreased vaccine efficacy with aging, vaccination still provided partial protection to aged mice and represents a potential strategy to prevent flu-induced disability. These findings provide translational insight on ways to reduce flu-induced disability with aging. Graphical abstract .

SUBMITTER: Keilich SR

PROVIDER: S-EPMC7732952 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Vaccination mitigates influenza-induced muscular declines in aged mice.

Keilich Spencer R SR Lorenzo Erica C EC Torrance Blake L BL Harrison Andrew G AG Bartley Jenna M JM Haynes Laura L

GeroScience 20200529 6

Influenza (flu) infection increases the risk for disability, falls, and broken bones in older adults. We have employed a preclinical model to examine the impact of flu on muscle function, which has a direct impact on fall risk. In mice, flu causes mobility and strength impairments with induction of inflammatory and muscle degradation genes that are increased and prolonged with aging. To determine if vaccination could reduce flu-induced muscle decrements, mice were vaccinated with flu nucleoprote ...[more]

PMID: 32472355

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Project description:Elderly individuals are highly susceptible to influenza virus (IAV) infection and respond poorly to influenza vaccines. Although the generally accepted correlate of protection following influenza vaccination is neutralizing antibody titers, cytotoxic T cell activity has been found to be a better correlate in the elderly. This suggests that vaccines designed to protect against influenza in the elderly should induce both humoral and cellular immunity. The co-induction of T cell immunity is additionally advantageous, as virus-specific T cells are frequently cross-reactive against different strains of IAV. Here, we tested the capacity of a synthetic TLR-4 adjuvant, SLA-SE (second-generation lipid adjuvant formulated in a squalene-based oil-in-water emulsion) to elicit T cell immunity to a recombinant influenza nucleoprotein (rNP), in both young and aged mice. IAV challenge of vaccinated mice resulted in a modest increase in the numbers of NP-specific CD4 and CD8 effector T cells in the spleen, but did not increase numbers of memory phenotype CD8 T cells generated following viral clearance (compared to control vaccinated mice). Cytotoxic activity of CD8, but not CD4 T cells was increased. In addition, SLA-SE adjuvanted vaccination specifically enhanced the production of NP-specific IgG2c antibodies in both young and aged mice. Although NP-specific antibodies are not neutralizing, they can cooperate with CD8 T cells and antigen-presenting cells to enhance protective immunity. Importantly, SLA-SE adjuvanted rNP-vaccination of aged mice resulted in significantly enhanced viral clearance. In addition, vaccination of aged mice resulted in enhanced survival after lethal challenge compared to control vaccination, that approached statistical significance. These data demonstrate the potential of SLA-SE adjuvanted rNP vaccines to (i) generate both cellular and humoral immunity to relatively conserved IAV proteins and (ii) elicit protective immunity to IAV in aged mice.

Project description:Histone H4 lysine16 acetylation (H4K16Ac) modulates chromatin structure by serving as a switch from a repressive to a transcriptionally active state. This euchromatin mark is associated with active transcription. In this study, we investigated the effects of H4K16Ac on the expression of pro-fibrotic genes in lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) and in an aging murine model of lung fibrosis. Methods: The lung tissues and fibroblasts from human IPF/non-IPF donors and from aged mice with/without bleomycin induced lung fibrosis were used in this study. The H4K16Ac levels were examined by immunohistochemistry or western blots. RNA silencing of H4K16Ac acetyltransferase Mof was used to reduce H4K16Ac levels in IPF fibroblasts. The effects of reduced H4K16Ac on pro-fibrotic gene expression were examined by western blots and real-time PCR. The association of H4K16Ac with these genes' promoter region were evaluated by ChIP assays. The gene expression profile in siRNA Mof transfected IPF cells were determined by RNA-Seq. The impact of H4K16Ac levels on lung fibrosis was evaluated in an aging murine model. Results: Aged mice with bleomycin induced lung fibrosis showed increased H4K16Ac levels. Human lung fibroblasts with siRNA Mof silencing demonstrated reduced H4K16Ac, and significantly down-regulated profibrotic genes, such as α-smooth muscle actin (α-SMA), collagen I, Nox4, and survivin. ChIP assays confirmed the associations of these pro-fibrotic genes' promoter region with H4K16Ac, while in siRNA Mof transfected cells the promoter/H4K16Ac associations were depleted. RNA-seq data demonstrated that Mof knockdown altered gene expression and cellular pathways, including cell damage and repair. In the aging mice model of persistent lung fibrosis, 18-month old mice given intra-nasal siRNA Mof from week 3 to 6 following bleomycin injury showed improved lung architecture, decreased total hydroxyproline content and lower levels of H4K16Ac. Conclusions: These results indicate a critical epigenetic regulatory role for histone H4K16Ac in the pathogenesis of pulmonary fibrosis, which will aid in the development of novel therapeutic strategies for age-related diseases such as IPF.

Dataset Information

Vaccination mitigates influenza-induced muscular declines in aged mice.

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Vaccination mitigates influenza-induced muscular declines in aged mice.

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