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Persistent viral replication and the development of T-cell responses after intranasal infection by MCMV

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Abstract

Natural transmission of cytomegalovirus (CMV) has been difficult to observe. However, recent work using the mouse model of murine (M)CMV demonstrated that MCMV initially infects the nasal mucosa after transmission from mothers to pups. We found that intranasal (i.n.) inoculation of C57BL/6J mice resulted in reliable recovery of replicating virus from the nasal mucosa as assessed by plaque assay. After i.n. inoculation, CD8+ T-cell priming occurred in the mandibular, deep-cervical, and mediastinal lymph nodes within 3 days of infection. Although i.n. infection induced “memory inflation” of T cells specific for the M38316–323 epitope, there were no detectable CD8+ T-cell responses against the late-appearing IE3416–423 epitope, which contrasts with intraperitoneal (i.p.) infection. MCMV-specific T cells migrated into the nasal mucosa where they developed a tissue-resident memory (TRM) phenotype and this could occur independently of local virus infection or antigen. Strikingly however, virus replication was poorly controlled in the nasal mucosa and MCMV was detectable by plaque assay for at least 4 months after primary infection, making the nasal mucosa a second site for MCMV persistence. Unlike in the salivary glands, the persistence of MCMV in the nasal mucosa was not modulated by IL-10. Taken together, our data characterize the development of local and systemic T-cell responses after intranasal infection by MCMV and define the nasal mucosa, a natural site of viral entry, as a novel site of viral persistence.

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Acknowledgements

This work was supported by Grant AI106810 awarded to C.M.S.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University, 19107, Philadelphia, PA, USA

    Shunchuan Zhang, Sofia Caldeira-Dantas, Corinne J. Smith & Christopher M. Snyder

  2. Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal

    Sofia Caldeira-Dantas

  3. PT Government Associate Laboratory, ICVS/3B’s, Braga/Guimarães, Portugal

    Sofia Caldeira-Dantas

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  1. Shunchuan Zhang
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This article is part of the Special Issue on Immunological Imprinting during Chronic Viral Infection.

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430_2019_589_MOESM1_ESM.pptx

Supplementary material 1 Representative gating strategies. Representative gates show the analyses of dividing CD8+ T cells to identify the sites of priming (data shown in Fig. 2), the identification of CD8+ TRM in the i.v. antibody-negative fraction of the nasal mucosa and salivary glands (data shown in Fig. 4), and phenotypic analyses of circulating virus-specific CD8+ T cells (data shown in Fig. 3). (PPTX 5387 KB)

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Zhang, S., Caldeira-Dantas, S., Smith, C.J. et al. Persistent viral replication and the development of T-cell responses after intranasal infection by MCMV. Med Microbiol Immunol 208, 457–468 (2019). https://doi.org/10.1007/s00430-019-00589-7

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