Mice with diverse microbial exposure histories as a model for preclinical vaccine testing

Jessica K. Fiege, Katharine E. Block, Mark J Pierson, Hezkiel Nanda, Frances K. Shepherd, Clayton K Mickelson, J. Michael Stolley, William E. Matchett, Sathi Wijeyesinghe, David K. Meyerholz, Vaiva Vezys, Steven Shen, Sara E Hamilton Hart, David Masopust, Ryan A. Langlois

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Laboratory mice comprise an expeditious model for preclinical vaccine testing; however, vaccine immunogenicity in these models often inadequately translates to humans. Reconstituting physiologic microbial experience to specific pathogen-free (SPF) mice induces durable immunological changes that better recapitulate human immunity. We examined whether mice with diverse microbial experience better model human responses post vaccination. We co-housed laboratory mice with pet-store mice, which have varied microbial exposures, and then assessed immune responses to influenza vaccines. Human transcriptional responses to influenza vaccination are better recapitulated in co-housed mice. Although SPF and co-housed mice were comparably susceptible to acute influenza infection, vaccine-induced humoral responses were dampened in co-housed mice, resulting in poor control upon challenge. Additionally, protective heterosubtypic T cell immunity was compromised in co-housed mice. Because SPF mice exaggerated humoral and T cell protection upon influenza vaccination, reconstituting microbial experience in laboratory mice through co-housing may better inform preclinical vaccine testing.

Original languageEnglish (US)
Pages (from-to)1815-1827.e6
JournalCell Host and Microbe
Volume29
Issue number12
DOIs
StatePublished - Dec 8 2021

Bibliographical note

Funding Information:
This work was supported by NIH R01 AI132962 to R.A.L. and NIH R01 AI150600 to R.A.L. and D.M. NIH CIVIC contract no. 75N93019C00051 to D.M. and R.A.L. NIH R01 AI116678 to S.E.H. J.K.F. K.E.B. and W.E.M. were supported by T32 HL007741. This project was also funded in part with federal funds from NIAID, NIH and the department of Health and Human Services, under CEIRS contract no. HHSN272201400005C. We acknowledge the NIH Tetramer Core Facility for providing H-2Db-PA224 and H-2Db-NP366 tetramers. We thank Dr. Thomas Griffith for I-Ab NP311 tetramer. We also thank the UMN Flow Cytometry Resource Facility, UMN Genomics Center, CFI Dirty Mouse Colony and BSL-3 Program for support. We thank Dr. Steve Jameson for discussions during early stages of the work. J.K.F. and K.E.B. designed, performed, and analyzed experiments. M.J.P. C.K.M. J.M.S. and S.W. performed experiments. F.K.S. H.N. W.E.M. and S.S.S. performed computational and statistical analyses. D.K.M. performed histological analyses. V.V. was involved in study design. R.A.L. D.M. and S.E.H. supervised the study. J.K.F. and R.A.L. wrote the manuscript with input from all co-authors. J.K.F. and K.E.B. contributed equally. The authors declare no competing interests. We worked to ensure sex balance in the selection of non-human subjects. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list.

Funding Information:
This work was supported by NIH R01 AI132962 to R.A.L. and NIH R01 AI150600 to R.A.L. and D.M. NIH CIVIC contract no. 75N93019C00051 to D.M. and R.A.L. NIH R01 AI116678 to S.E.H. J.K.F., K.E.B., and W.E.M. were supported by T32 HL007741 . This project was also funded in part with federal funds from NIAID , NIH and the department of Health and Human Services , under CEIRS contract no. HHSN272201400005C . We acknowledge the NIH Tetramer Core Facility for providing H-2D b -PA 224 and H-2D b -NP 366 tetramers. We thank Dr. Thomas Griffith for I-A b NP 311 tetramer. We also thank the UMN Flow Cytometry Resource Facility, UMN Genomics Center, CFI Dirty Mouse Colony and BSL-3 Program for support. We thank Dr. Steve Jameson for discussions during early stages of the work.

Publisher Copyright:
© 2021 Elsevier Inc.

Keywords

  • T cell immunity
  • dirty mice
  • humoral immunity
  • influenza virus
  • preclinical models
  • vaccine

PubMed: MeSH publication types

  • Journal Article

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