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Lack of evidence for intergenerational inheritance of immune resistance to infections

Nature Immunology volume 23, pages 203–207 (2022)Cite this article

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Matters Arising to this article was published on 20 January 2022

The Original Article was published on 18 October 2021

arising from Katzmarski et al. Nature Immunology https://doi.org/10.1038/s41590-021-01052-7 (2021)

Epigenetic-mediated memory capacity of the innate immune system, coined trained immunity, is an evolutionarily conserved trait, which enhances host immune responses to subsequent homologous or heterologous infections1. Trained immunity was first discovered in plants and invertebrates that lack an adaptive immune system2,3; however, trained immunity is also a conserved mechanism in higher species like verteberates1. Interestingly, vertical transmission of trained immunity provides protection for up to two subsequent generations in plants and invertebrates2,3,4. Although recent epidemiological studies suggest that the protection of vaccination-mediated trained immunity (e.g., Bacille Calmette–Guérin (BCG)) may also be vertically transmitted to the offspring in humans5,6,7, supporting experimental data for these observations were lacking. Now, a study using murine models of Candida albicans infection or a pathogen-associated molecular pattern (PAMP; zymosan) reports that trans- and intergenerational inheritance of trained immunity provides heterologous protection against infections in offspring8. However, we find that using similar mouse models of trained immunity induced by live vaccination (BCG), PAMPs (β-glucan) or infection (C. albicans), the protection against viral (influenza virus), bacterial (Mycobacterium tuberculosis (Mtb)) or fungal (C. albicans) infections was the same between the offspring of trained and nontrained parents.

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Fig. 1: Parental BCG vaccination does not generate intergenerational resistance against infections in offspring.
Fig. 2: Paternal fungal infection or β-glucan treatment does not generate intergenerational resistance in offspring.

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Authors and Affiliations

  1. Department of Medicine, Department of Pathology, Department of Microbiology & Immunology, McGill University Health Centre, McGill International TB Centre, Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada

    Eva Kaufmann, Marija Landekic, Jeffrey Downey, Julia Chronopoulos, Sara Teimouri Nezhad, Kim Tran, Donald C. Vinh & Maziar Divangahi

  2. Genetics, Genomics, and Systems Biology, University of Chicago, Chicago, IL, USA

    Luis B. Barreiro

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Contributions

E.K., M.L., J.D., J.C., S.T.N. and K.T. performed experiments and analyzed data. E.K., D.C.V., L.B.B. and M.D. designed experiments and discussed results and strategy. E.K., L.B.B. and M.D. wrote the manuscript.

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Correspondence to Luis B. Barreiro or Maziar Divangahi.

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The authors declare no competing interests.

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Zoltan Fehervari was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Antibiotic treatment of BCG i.v.–vaccinated mice does not unmask intergenerational resistance.

a, Mice were iv-vaccinated with BCG-Tice (1 × 106 CFU). After one-month BCG vaccination, to eliminate live BCG, mice were treated with Antibiotics (INH + Rifampicin) for 4wks, followed by a 2wks wash-out period. Subsequently, naïve or BCG-vaccinated mice were mated and the adult offspring were infected with M. tuberculosis (~50 CFU, H37Rv aerosol, male offspring) or IAV sublethal (50PFU) or lethal (90PFU) dose (intranasally; female offspring). b, Lung and spleen CFU at 4wks post Mtb infection. c, Lung PFU 3d post sublethal IAV infection. d, F1.2 and F1.3 offspring from BCG-vaccinated and unvaccinated mice were treated with the antibitics and then were infected with Mtb or IAV. e, Survival after lethal IAV infection in F1.2 and F1.3. F1.2 (f) and F1.3 (g) Lung and spleen CFU 4wks post Mtb infection. All CFU data are displayed in log scale. There was no statistically significant difference between groups.

Extended Data Fig. 2 BCG vaccination in the offspring of vaccinated parents does not enhance trained immunity in macrophages.

a, Mice were vaccinated with BCG-iv (1 × 106 CFU) for one month and mated with vaccinated or naive counterparts. 6–8 week-old F1.1 and F1.3 offspring were then vaccinated or not with BCG-iv (1 × 106 CFU). b,c, At 1 month post BCG vaccination, protective capacities of BMDM from BCG-iv vaccinated and nonvaccinated F1.1 (b), or F1.3 (c) offspring from naïve or BCG-iv vaccinated parents were assessed against M. tuberculosis (H37Rv, MOI 1) infection. * p < 0.05.

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Kaufmann, E., Landekic, M., Downey, J. et al. Lack of evidence for intergenerational inheritance of immune resistance to infections. Nat Immunol 23, 203–207 (2022). https://doi.org/10.1038/s41590-021-01102-0

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