Abstract
Metabolic disease is epidemiologically linked to severe complications upon influenza virus infection, thus vaccination is a priority in this high-risk population. Yet, vaccine responses are less effective in these same hosts. Here we examined how the timing of diet switching from a high-fat diet to a control diet affected influenza vaccine efficacy in diet-induced obese mice. Our results demonstrate that the systemic meta-inflammation generated by high-fat diet exposure limited T cell maturation to the memory compartment at the time of vaccination, impacting the recall of effector memory T cells upon viral challenge. This was not improved with a diet switch post-vaccination. However, the metabolic dysfunction of T cells was reversed if weight loss occurred 4 weeks before vaccination, restoring a functional recall response. This corresponded with changes in the systemic obesity-related biomarkers leptin and adiponectin, highlighting the systemic and specific effects of diet on influenza vaccine immunogenicity.
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Data availability
The data supporting the findings of this study are available within the Article and its supplementary materials. Per NIAID contract requirements, the datasets from these studies have been uploaded to the Statistical, Data Management and Coordination Center (SDMCC) where it will be released to the public upon publication. Source data are provided with this paper.
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Acknowledgements
We thank P. Freiden, K. Wiggins and B. Clark for expert technical assistance and scientific discussions, and P. Vogel for his pathological expertise (all of St Jude Children’s Research Hospital); D. Warren, C. Oudomvilay and C. Roberts (University of the Ozarks) for assisting in sample and assay preparation; the National Institutes of Health (NIH) Tetramer Core Facility (contract number 75N93020D00005) for providing the Influenza A NP tetramer; and the St Jude Animal Resource Center and Veterinary Pathology Core for helpful experimental assistance. This work was supported by ALSAC (American Lebanese Syrian Associated Charities), the National Institute of Allergy and Infectious Diseases (NIAID) at NIH under Department of Health and Human Services contract HHSN27220140006C for the St Jude Center of Excellence for Influenza Research and Surveillance (CEIRS), by the NIAID Collaborative Influenza Vaccine Innovation Centers (CIVIC) contracts 75N93019C00052 and 75N93021C00016 for the St Jude Center of Excellence for Influenza Research and Response (CEIRR) to S.S.-C. and P.G.T., NIAID NIH Award Number F31AI161986 to A.V.-P. and NIAID R01 AI140766-03 to S.S.-C. A.V.-P. and B.A.W. were supported by the St Jude Graduate School for Biomedical Sciences and A.H.M. was supported by NIAID T32AI106700-07. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
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R.H., A.V.-P. and S.S.-C. conceptualized the project. R.H., A.V.-P., S.S.-C. and P.G.T. developed the methodology. R.H., A.V.-P. and S.S.-C. performed validation. R.H., A.V.-P. and R.C.S. conducted formal analysis. R.H., A.V.-P., B.L., S.C., A.H.M., B.A.W., P.H.B., V.H., B.S., E.K.R., L.-A.V.d.V. and R.C.S. conducted investigations. R.H., A.V.-P., B.L., B.S., L.-A.V.d.V., P.G.T. and S.S.-C. procured resources. R.H. and A.V.-P. curated data. R.H., A.V.-P. and R.C.S. wrote the original draft. All authors reviewed and edited the paper. R.H. and A.V.-P. performed visualization. S.S.-C. supervised the project. R.H., A.V.-P and S.S.-C. administered the project. M.A.M., P.G.T. and S.S.-C. acquired funding.
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Extended data
Extended Data Fig. 1 Long-term weight loss after vaccination does not improve survival upon viral challenge.
(a) Timeline of diet administration, vaccination, and challenge for 12-week long-term diet protocol with diet composition breakdown by percent fat/protein/carbohydrate. (b) Weights of mice through short-term diet protocol and at (c) vaccination and challenge compared via one-way ANOVA (vaccination always lean p < 0.0001; H1N1 always lean p < 0.0001, mice that were formerly obese p < 0.0001). (d–f) Morbidity and mortality in vaccinated mice compared to mock vaccinated mice with n = 10 mice/group. (d) Weight curves post-challenge with statistical comparisons made via mixed-effects model. Grey dotted line indicates a 0% deviation from weight at baseline. (e) Clinical scores post-challenge with statistical comparisons made using a two-way ANOVA. (f) Survival post-challenge with statistical comparisons made using Mantel-Cox log-rank analysis. (g) Hemagglutination inhibition titers at indicated timepoints with n = 4 mice per diet group. Data in (b–e) are representative of two independent experiments and are graphed as means ± standard error and in (f) as surviving proportions with censored or event animals indicated by their respective symbols and in (g) as geometric means ± standard deviation with x indicating no mice surviving to time point. Statistical comparisons test between mice with obesity and indicated diet group (n = 10 mice/group) in (b, c) and between mock and vaccinated animals within a single diet group in (d–f).
Extended Data Fig. 2 Weight gain post-vaccination has modest impacts on survival at challenge.
(a) Timeline of diet administration, vaccination, and challenge for 4-week short-term or 12-week long-term reverse diet switch protocol with diet composition breakdown by percent fat/protein/carbohydrate. (b) Weights of formerly lean mice on short- and long-term reverse diet switch protocols at (c) vaccination and challenge compared via one-way ANOVA (short-term p < 0.0001, long-term p < 0.0010). Grey dotted lines represent the mean weight of mice with obesity at corresponding timepoints. (d-e) Morbidity and mortality in vaccinated mice compared to mock vaccinated mice with n = 10 mice/group for (d) short-term and (e) long-term reverse diet switch protocols. Weight curves post-challenge with statistical comparisons made via mixed-effects model. Grey dotted line indicates a 0% deviation from weight at baseline. Clinical scores post-challenge with statistical comparisons made using a two-way ANOVA. Survival post-challenge with statistical comparisons made using Mantel-Cox log-rank analysis. (f) Effector antibody levels in sera collected and quantified by hemagglutination inhibition (HAI). Grey dotted line represents lower limit of detection. Mice assayed longitudinally with n = 5 per group except for the day 21 post-influenza challenge timepoint in which only surviving mice were assayed. Data are representative of three independent experiments and are graphed as means ± standard error and, for survival graphs, as surviving proportions with censored or event animals indicated by their respective symbols. Statistical comparisons test between mice with obesity and indicated diet groups (n = 10 mice/group) in (b, c) and between mock and vaccinated animals within a single diet group in (d, e). These studies were done concurrently with data shown in Fig. 1 and Extended Data Fig. 1.
Extended Data Fig. 3 Similar responses to challenge post-diet switch in female mice.
(a) Timeline of diet administration, vaccination, and challenge in short-term diet and weight gain protocols with diet composition breakdown by percent fat/protein/carbohydrate. (b) Weights of female mice on diet protocols at (c) vaccination and challenge compared via one-way ANOVA (vaccination always lean p < 0.0001, formerly lean p < 0.0001; H1N1 always lean p < 0.0001, mice that were formerly obese p < 0.0001, formerly lean p < 0.0001). (d–f) Morbidity and mortality in vaccinated mice compared to mock vaccinated mice. (d) Weight curves post-challenge with statistical comparisons made via mixed-effects model. Grey dotted lines represent the mean weight of mice with obesity at corresponding timepoints. (e) Clinical scores post-challenge with statistical comparisons made using a two-way ANOVA. (f) Survival post-challenge with statistical comparisons made using Mantel-Cox log-rank analysis. Data in (b-e) are represented as means ± standard error and in (f) as surviving proportions with censored or event animals indicated by their respective symbols. (g) Effector antibody levels in sera collected and quantified by hemagglutination inhibition (HAI). Grey dotted line represents lower limit of detection. Mice assayed longitudinally with n = 5 per group except for the day 21 post-influenza challenge timepoint in which only surviving mice were assayed. Data displayed as geometric means ± standard deviation with x indicating no mice surviving to time point. Statistical comparisons test between mice with obesity and indicated diet group (n = 10 mice/group) in (b, c, g) and between mock and vaccinated animals within a single diet group in (d-f).
Extended Data Fig. 4 Frequency plots of primary responses to vaccination prior to diet switch.
Spleens were harvested and homogenized into single cell suspensions and 1 × 106 cells were stained for CD4+ T cells, CD8+ T cells, and B220+ B cells at 21 days post-vaccination and quantified via flow-cytometry. Frequency of (a) CD4+ (CD45i.v.− CD45+ CD3+ CD4+, p = 0.0021), (b) CD4+ effector memory (TEFM, CD45i.v.− CD45+ CD3+ CD4+ CD62L+ CD44−,) and (c) CD4+ central memory (TCM, CD45i.v.− CD3+ CD4+ CD62L+ CD44+, p = 0.0007) cells. Frequency of (d) CD8+ (CD45i.v.− CD45+ CD3+ CD8+), (e) CD8+ TEFM (CD45i.v.− CD45+ CD3+ CD8+ CD62L+ CD44−, p = 0.004), and (g) CD8+ TCM (CD45i.v.− CD3+ CD8+ CD62L+ CD44+) cells. Frequency of (g) B cells (CD3− B220+). Data are represented as boxplots as frequency of live singlets and analyzed with a two-tailed t-test used to compare groups. Note that samples were collected prior to diet switch. Corresponds to Fig. 4.
Extended Data Fig. 5 Recall responses are altered by HFD exposure at time of vaccination.
Lungs were harvested and homogenized into single cell suspensions and 1 × 106 cells were stained for tissue resident and circulating CD4+ and CD8+ T cells at 7 days post-challenge and quantified via flow-cytometry. (a) Absolute number or (b) frequency of tissue resident CD4+ T (CD45i.v.− CD45+ CD3+, CD4+), T effector memory (TEFM, CD45i.v.− CD45+ CD3+ CD4+ CD62L+ CD44−) and T central memory (TCM, CD45i.v.− CD45+ CD3+ CD4+ CD62L+ CD44+) cells or CD8+ T (CD45i.v.− CD45+ CD3+ CD8+), TEFM (CD45i.v.− CD45+ CD3+ CD4+ CD62L+ CD44−), and TCM (CD45i.v.− CD45+ CD3+ CD4+ CD62L+ CD44+) cells. (c) Absolute number or (d) frequency of circulating CD4+ T (CD45i.v.+ CD45− CD3+ CD4+), T effector memory (TEFM, CD45i.v.+ CD45− CD3+ CD4+ CD62L+ CD44−) and T central memory (TCM, CD45i.v.+ CD45− CD3+ CD4+ CD62L+ CD44+) cells or CD8+ T (CD45i.v.+ CD45− CD3+ CD8+), TEFM (CD45i.v.+ CD45− CD3+ CD4+ CD62L+ CD44−), and TCM (CD45i.v.+ CD45− CD3+ CD4+ CD62L+ CD44+) cells. Data include mice with obesity, always lean, and mice that were formerly obese (n = 2, n = 6, n = 4 for each group, respectively) and graphed as boxplots with comparisons made between always lean and formerly obese groups via one-way ANOVA. Frequency values are calculated as compared to live singlets.
Extended Data Fig. 6 Increased survival in phenotypic obese and mice that were formerly obese with 8-week HFD exposure.
(a) Timeline of diet administration, vaccination, and challenge in half-term diet switch studies. (b) Weights of mice through a half-term diet switch studies (n = 5–10 mice/group) at (c) vaccination and challenge (vaccination always lean p < 0.0001; H1N1 always lean p < 0.0001, formerly obese p < 0.0001). (d–f) Morbidity and mortality upon H1N1 virus challenge with n = 5–10 mice/group. (d) Weight curves with grey dotted line indicate a 0% deviation from baseline weight, (e) clinical scores and (f) survival. (g) Hemagglutination inhibition titers at indicated timepoints. The grey dotted line indicates the lower limit of detection. Data are represented in (b-e) as means ± standard error, in (f) as surviving proportions with censored or event animals indicated by their respective symbols, and in (g) as geometric mean ± standard deviation with x indicating no mice surviving to time point. Statistical comparisons test between mice with obesity and indicated diet groups (n = 10 mice/group) in (c).
Extended Data Fig. 7 Phenotyping of T cell subsets in pre-vaccination diet switch cohorts.
Mean fluorescent intensity (MFI) of splenic CD98, MitoTracker Red (MTR CMXRos) and MitoTracker Green (MTG) in (a) CD4+ effector memory (TEFM) T cells, (b) CD4+ central memory (TCM) T cells, (c) CD8+ TEFM, and (d) CD8+ TCM cells. Data include mice with obesity, always lean, and mice that were formerly obese (n = 7, n = 7, n = 8 for each group, respectively) and graphed as boxplots with comparisons made between via one-way ANOVA with CD4+ TEFM MTG formerly obese p = 0.0148; and CD8+ TEFM cells MTR formerly obese p = 0.0172, MTG formerly obese p = 0.0034.
Extended Data Fig. 8 Improved elicitation of memory T cell responses upon weight loss pre-vaccination.
Lungs were harvested and homogenized into single cell suspensions and 1 × 106 cells were stained for CD4+ and CD8+ T cells at 7 days post-challenge and quantified via flow-cytometry. (a) Absolute number or (b) frequency of tissue resident CD4+ T (CD45i.v.− CD45+ CD3+ CD4+), T effector memory (TEFM, CD45i.v.− CD45+ CD3+ CD4+ CD62L+ CD44−) and T central memory (TCM, CD45i.v.− CD45+ CD3+ CD4+ CD62L+ CD44+) cells or CD8+ T (CD45i.v.− CD45+ CD3+ CD8+, always lean p = 0.0473), TEFM (CD45i.v.− CD45+ CD3+ CD4+ CD62L+ CD44−), and TCM (CD45i.v.− CD45+ CD3+ CD4+ CD62L+ CD44+, formerly obese p = 0.0171) cells. (c) Absolute number or (d) frequency of circulating CD4+ T (CD45i.v.+ CD45− CD3+ CD4+, always lean p = 0.0253), T effector memory (TEFM, CD45i.v.+ CD45− CD3+ CD4+ CD62L+ CD44−, always lean p = 0.0069) and T central memory (TCM, CD45i.v.+ CD45− CD3+ CD4+ CD62L+ CD44+, always lean p = 0.0028, p = 0.0004; formerly obese p < 0.0001) cells or CD8+ T (CD45i.v.+ CD45− CD3+ CD8+, always lean p = 0.0038, formerly obese p = 0.0292), TEFM (CD45i.v.+ CD45− CD3+ CD4+ CD62L+ CD44−, always lean p = 0.0017), and TCM (CD45i.v.+ CD45− CD3+ CD4+ CD62L+ CD44+, always lean p = 0.0045, p = 0.0019; formerly obese p < 0.0001) cells. Data include always obese, always lean, and mice that were formerly obese (n = 8, n = 7, n = 7 for each group, respectively) and graphed in as boxplots with comparisons made between diet groups via one-way ANOVA. Frequency values are calculated as compared to live singlets.
Extended Data Fig. 9 Assessment of T-cell surface phenotype in lungs upon distinct diet regimens post-vaccination and post-influenza challenge.
At 4 weeks post-vaccination, mice were challenged with H1N1 virus. Lungs were harvested and homogenized into single-cell suspensions and 1 × 106 cells were stained for CD4+ and CD8+ T cells. (a) Mean fluorescent intensity (MFI) of CD98+ staining on CD4+ T, T effector memory (TEFM), and T central memory (TCM, always lean p = 0.0285) cells. (b) MFI of CD98+ staining on CD8+ TEFM (always lean p = 0.0391, formerly obese p = 0.0391) and TCM cells (always lean p = 0.0504, formerly obese p = 0.0280). (c) Frequency of PD1+ CD4+ T cells (CD44+ CD4+ CD98+, always lean p = 0.0015). MitoTracker Green (MTG) and MitoTracker Red (MTR CMXRos) staining in (d) CD4+ T cells, (e) CD4+ TEFM cells, (f) CD4+ TCM cells, (g) CD8+ TEFM cells (formerly obese MTG p = 0.0428, MTR p = 0.0025), (g) CD8+ TCM (always lean MTG p = 0.0121, formerly obese MTR p < 0.0001) cells. Data include mice with obesity, always lean, and mice that were formerly obese (n = 4, n = 8, n = 10 for each group, respectively) and graphed as boxplots with comparisons made between diet groups via one-way ANOVA. Corresponds to Fig. 6.
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Honce, R., Vazquez-Pagan, A., Livingston, B. et al. Diet switch pre-vaccination improves immune response and metabolic status in formerly obese mice. Nat Microbiol (2024). https://doi.org/10.1038/s41564-024-01677-y
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DOI: https://doi.org/10.1038/s41564-024-01677-y
