A focused salivary gland infection with attenuated MCMV: An animal model with prevention of pathology associated with systemic MCMV infection

Pilgrim, Mark J.; Kasman, Laura; Grewal, Jasmaninder Singh; Bruorton, Mary E.; Werner, Phil; London, Lucille; London, Steven D.

doi:10.1016/j.yexmp.2006.12.010

Cited by 16 publications

(43 citation statements)

References 33 publications

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“…Nevertheless, since mouse CMV (mCMV) has many features in common with hCMV, and mCMV infection of mice resembles its human counterpart with respect to pathogenesis, the mouse animal model ( in vitro and in vivo ) has been extensively used to understand the pathogenesis of acute, latent, and recurrent infections (e.g. Reynolds et al, 1993; Lagenaur et al, 1994; Schmader et al, 1995; Krmpotic et al, 2003; Melnick et al, 2006; Pilgrim et al, 2007; Jaskoll et al, 2008a, 2008b; Bai et al, 2008; Kasman et al, 2009). As with humans, the SMG is the major target organ for mCMV replication in the infected mouse.…”

Section: Introductionmentioning

confidence: 99%

Small molecule inhibitors of the host cell COX/AREG/EGFR/ERK pathway attenuate cytomegalovirus-induced pathogenesis

Melnick¹,

Abichaker²,

Htet³

et al. 2011

Experimental and Molecular Pathology

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As with other herpesviruses, human cytomegalovirus (hCMV) has the ability to establish lifelong persistence and latent infection following primary exposure, salivary glands (SMGs) being the primary site of both. In the immunocompromised patient, hCMV is a common cause of opportunistic infections, and subsequent morbidity and mortality. Elucidating the molecular pathogenesis of CMV-induced disease is critical to the development of more effective and safer drug therapies. In the present study, we used a novel mouse postnatal SMG organ culture model of mCMV-induced dysplasia to investigate a candidate signaling network suggested by our prior studies (COX-2/AREG/EGFR/ERK). The objective was to employ small molecule inhibitors to target several key steps in the autocrine loop, and in this way ameliorate pathology. Our results indicate that upregulation of ERK phosphorylation is necessary for initial mCMV-induced pathogenesis, and that ErbB receptor family phosphorylation and downstream signaling are highly relevant targets for drug discovery.

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Section: Introductionmentioning

confidence: 99%

Small molecule inhibitors of the host cell COX/AREG/EGFR/ERK pathway attenuate cytomegalovirus-induced pathogenesis

Melnick¹,

Abichaker²,

Htet³

et al. 2011

Experimental and Molecular Pathology

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confidence: 99%

“…We previously described a model of a focused salivary gland infection, which we used to investigate the hypothesis that the salivary gland acts as a mucosal inductive site, as well as its known function as an effector site in oral mucosal immunity (8, 9). We demonstrated that intraglandular inoculation with tissue culture‐derived murine cytomegalovirus (tcMCMV), which is attenuated with respect to its ability to infect systemic tissues, limited infection to the salivary gland without high viral titers and pathology in other organs and stimulated a local host immune response (8, 9). This immunization protocol also induced salivary gland ectopic follicles that displayed both functional and phenotypic characteristics of mucosal inductive site germinal centers (GCs) including cognate interactions of B and T cells with follicular dendritic cells, proliferating cells, class switching, plasma cell differentiation, and protection against a lethal systemic challenge with MCMV (8, 9).…”

mentioning

confidence: 99%

“…We demonstrated that intraglandular inoculation with tissue culture‐derived murine cytomegalovirus (tcMCMV), which is attenuated with respect to its ability to infect systemic tissues, limited infection to the salivary gland without high viral titers and pathology in other organs and stimulated a local host immune response (8, 9). This immunization protocol also induced salivary gland ectopic follicles that displayed both functional and phenotypic characteristics of mucosal inductive site germinal centers (GCs) including cognate interactions of B and T cells with follicular dendritic cells, proliferating cells, class switching, plasma cell differentiation, and protection against a lethal systemic challenge with MCMV (8, 9). This data provided direct evidence that the salivary glands can act as a mucosal inductive site, which may be dependent, at least in part, on lymphoid neogenesis within the salivary gland.…”

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confidence: 99%

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Protective MCMV immunity by vaccination of the salivary glandviaWharton's duct: replication‐deficient recombinant adenovirus expressing individual MCMV genes elicits protection similar to that of MCMV

et al. 2014

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Salivary glands, a major component of the mucosal immune system, confer antigen-specific immunity to mucosally acquired pathogens. We investigated whether a physiological route of inoculation and a subunit vaccine approach elicited MCMV-specific and protective immunity. Mice were inoculated by retrograde perfusion of the submandibular salivary glands via Wharton's duct with tcMCMV or MCMV proteins focused to the salivary gland via replication-deficient adenovirus expressing individual MCMV genes (gB, gH, IE1; controls: saline and replication deficient adenovirus without MCMV inserts). Mice were evaluated for MCMV-specific antibodies, T-cell responses, germinal center formation, and protection against a lethal MCMV challenge. Retrograde perfusion with tcMCMV or adenovirus expressed MCMV proteins induced a 2- to 6-fold increase in systemic and mucosal MCMV-specific antibodies, a 3- to 6-fold increase in GC marker expression, and protection against a lethal systemic challenge, as evidenced by up to 80% increased survival, decreased splenic pathology, and decreased viral titers from 10(6) pfu to undetectable levels. Thus, a focused salivary gland immunization via a physiological route with a protein antigen induced systemic and mucosal protective immune responses. Therefore, salivary gland immunization can serve as an alternative mucosal route for administering vaccines, which is directly applicable for use in humans.

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“…Because we demonstrated that both intraglandular inoculation (5, 6) and retrograde perfusion of the submandibular salivary gland (7) with tcMCMV generated MCMV‐specific T‐cell immunity, we evaluated the T h 1/T h 2/T h 17 immune responses after both tcMCMV inoculation and a lethal MCMV challenge. BALB/cByJ mice were inoculated with saline or 10 5 PFU/mouse tcMCMV via retrograde perfusion of the submandibular gland.…”

Section: Resultsmentioning

confidence: 99%

Salivary gland immunization via Wharton's duct activates differential T‐cell responses within the salivary gland immune system

et al. 2019

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Salivary glands are a major component of the mucosal immune system that confer adaptive immunity to mucosal pathogens. As previously demonstrated, immunization of the submandibular gland with tissue culture–derived murine cytomegalovirus (tcMCMV) or replication‐deficient adenoviruses expressing individual murine cytomegalovirus (MCMV) genes protected mice against a lethal MCMV challenge. Here, we report that salivary gland inoculation of BALB/cByJ mice with tcMCMV or recombinant adenoviruses differentially activates T helper (Th)1, ‐2, and ‐17 cells in the salivary glands vs. the associated lymph nodes. After inoculation with tcMCMV, lymphocytes from the submandibular gland preferentially express the transcription factor T‐cell–specific T‐box transcription factor (T‐bet), which controls the expression of the hallmark Th1 cytokine, IFN‐γ. Lymphocytes from the periglandular lymph nodes (PGLNs) express both T‐bet and GATA‐binding protein 3 (GATA3), which promotes the secretion of IL‐4, ‐5, and ‐10 from Th2 cells. In contrast, after inoculation with replication‐deficient adenoviruses, lymphocytes from the submandibular gland express T‐bet, GAT A3, and RAR‐related orphan receptor γ, thymus‐specific isoform (ROR/γt) (required for differentiation of Th17 cells) and forkhead box P3 (Foxp3) (required for the differentiation of regulatory T cells). Lymphocytes from the PGLNs were not activated. The differential induction of Th responses in the salivary gland vs. the PGLNs after inoculation with attenuated virus vs. a nominal protein antigen supports the use of the salivary as an alternative mucosal route for administering vaccines.—Liu, G., Zhang, F., Wang, R., London, S. D., London, L. Salivary gland immunization via Wharton's duct activates differential T‐cell responses within the salivary gland immune system. FASEB J. 33, 6011–6022 (2019). http://www.fasebj.org

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A focused salivary gland infection with attenuated MCMV: An animal model with prevention of pathology associated with systemic MCMV infection

Cited by 16 publications

References 33 publications

Small molecule inhibitors of the host cell COX/AREG/EGFR/ERK pathway attenuate cytomegalovirus-induced pathogenesis

Small molecule inhibitors of the host cell COX/AREG/EGFR/ERK pathway attenuate cytomegalovirus-induced pathogenesis

Protective MCMV immunity by vaccination of the salivary glandviaWharton's duct: replication‐deficient recombinant adenovirus expressing individual MCMV genes elicits protection similar to that of MCMV

Salivary gland immunization via Wharton's duct activates differential T‐cell responses within the salivary gland immune system

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