Protective MCMV immunity by vaccination of the salivary gland<i>via</i>Wharton's duct: replication‐deficient recombinant adenovirus expressing individual MCMV genes elicits protection similar to that of MCMV

Liu, Guangliang; Zhang, Fangfang; London, Lucille; London, Steven D.

doi:10.1096/fj.13-244178

Cited by 10 publications

(22 citation statements)

References 42 publications

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“…In protection studies, saline‐inoculated BALB/cByJ mice were challenged systemically (intraperitoneally) with 2 × 10 4 PFU/mouse MCMV (100 µl), and tcMCMV‐inoculated mice were challenged intraperitoneally with 5 × 10 4 PFU/mouse MCMV (100 µl). A total of 2 × 10 4 PFU/mouse MCMV was used in saline‐inoculated mice because challenge with a lethal inoculum of MCMV (5 × 10 4 PFU/mouse) resulted in the death of all mice by d 8 postchallenge (7). In experiments utilizing replication‐deficient recombinant adenoviruses, BALB/ cByJ mice were inoculated and boosted on d 30, with 10 6 PFU/mouse replication‐deficient recombinant adenovirus expressing a combination of MCMV genes gpB, gpH, and IE1 (Ad‐Combo) (10 6 PFU/mouse of each recombinant virus).…”

Section: Methodsmentioning

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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Section: Methodsmentioning

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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“…The strict tropism of HCMV to humans urged the study of homologous cytomegaloviruses (CMVs) in other animal species. There is vast literature regarding murine CMV (MCMV) and also several reports about rhesus monkey CMV (RhCMV) models (for a brief overview, see Table 1) [20][21][22][23][24][25][26][27][28]. This wealth of work contributes extensively to the understanding of basic aspects of the interactions between CMV and the host.…”

Section: Mouse Models Of Hcmv Infections and Human Immune Responsesmentioning

confidence: 99%

Modeling Human Cytomegalovirus in Humanized Mice for Vaccine Testing

2020

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Human cytomegalovirus (HCMV or HHV-5) is a globally spread pathogen with strictly human tropism that establishes a life-long persistence. After primary infection, high levels of long-term T and B cell responses are elicited, but the virus is not cleared. HCMV persists mainly in hematopoietic reservoirs, whereby occasional viral reactivation and spread are well controlled in immunocompetent hosts. However, when the immune system cannot control viral infections or reactivations, such as with newborns, patients with immune deficiencies, or immune-compromised patients after transplantations, the lytic outbursts can be severely debilitating or lethal. The development of vaccines for immunization of immune-compromised hosts has been challenging. Several vaccine candidates did not reach the potency expected in clinical trials and were not approved. Before anti-HCMV vaccines can be tested pre-clinically in immune-compromised hosts, reliable in vivo models recapitulating HCMV infection might accelerate their clinical translation. Therefore, immune-deficient mouse strains implanted with human cells and tissues and developing a human immune system (HIS) are being explored to test anti-HCMV vaccines. HIS-mice resemble immune-compromised hosts as they are equipped with antiviral human T and B cells, but the immune reactivity is overall low. Several groups have independently shown that HCMV infections and reactivations can be mirrored in HIS mice. However, these models and the analyses employed varied widely. The path forward is to improve human immune reconstitution and standardize the analyses of adaptive responses so that HIS models can be forthrightly used for testing novel generations of anti-HCMV vaccines in the preclinical pipeline.

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“… Adenovirus +++ ++++ [ 15 ] Rats SGid; Repeated pre-exposure to inactivated adenovirus induced immune tolerance. tcMCMV +++ ++++ [ 34 ] Mice SGid imzn resulted in protection from a lethal challenge. pDNA: fimbriae from P. ginigivalis ++++ +++ [ 23 ] Mice TSG > IM; Greater IgA seen with TSG imzn, than with IM imzn.…”

Section: Introductionmentioning

confidence: 99%

“…A subsequent comprehensive study by the same group employed the gentler route of intraductal instillation. Here, instilling either a replication-deficient recombinant adenovirus expressing individual MCMV genes or tcMCMV resulted in protection against a lethal systemic challenge with MCMV [ 34 ]. Due to its broad tropism and relative safety, the adenovirus is a common vector used to deliver vaccine antigens and other transgenes, and its potent immune reactions in the SG can be tolarized through pre-exposure [ 35 ].…”

Section: Introductionmentioning

confidence: 99%

“…Due to its broad tropism and relative safety, the adenovirus is a common vector used to deliver vaccine antigens and other transgenes, and its potent immune reactions in the SG can be tolarized through pre-exposure [ 35 ]. Using a recombinant replication-deficient adenovirus to deliver MSMV genes resulted in strong systemic neutralizing MCMV-specific IgG in the serum [ 34 ]. Additionally, immunization with the adenovirus induced mucosal neutralizing MCMV-specific IgA at the primary immunization site (saliva), as well as distal mucosal sites (feces and vagina).…”

Section: Introductionmentioning

confidence: 99%

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The salivary gland as a target for enhancing immunization response

Ponzio

Sanders

2017

Trop Dis Travel Med Vaccines

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BackgroundAn organism’s immune response to a vaccine is dependent on a number of factors, including the site of immunization. While muscle is the most common site for vaccine administration, other sites, including the salivary gland, are poised to confer stronger and broader immunoprotection.FindingsStudies exploring the salivary gland as an immunization site have involved protein antigens, as well as live pathogens and DNA vaccines. While intraductal instillation of protein antigens into the salivary gland may result in a relatively transient increase in antibody production, DNA or attenuated pathogen vaccination appear to confer a lasting widespread mucosal immune response that includes robust salivary and enteric IgA, as well as high levels of circulating IgG. Furthermore, vaginal and lung antibodies are also seen. For enteric pathogens, a common class of pathogen encountered by travelers, this type of immune response provides for a level of redundant protection against foreign microbes with mucosal targets.ConclusionThe strength of immune response conferred by salivary gland vaccination is generally stronger than that seen in response to the same vaccine at a comparison site. For example, where other routes fail, immunization of the salivary gland has been shown to confer protection in lethal challenge models of infectious pathogens. A host of vaccines currently under development suffer from immunogenicity challenges, adding to the widespread interest and search for novel routes and adjuvants. With its capability to facilitate a strong and broad immune response, the salivary gland warrants consideration as an immunization site, especially for vaccines with immunogenicity challenges, as well as vaccines that would benefit from combined systemic and mucosal immunity.

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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

Cited by 10 publications

References 42 publications

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

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

Modeling Human Cytomegalovirus in Humanized Mice for Vaccine Testing

The salivary gland as a target for enhancing immunization response

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