YopJ-Promoted Cytotoxicity and Systemic Colonization Are Associated with High Levels of Murine Interleukin-18, Gamma Interferon, and Neutrophils in a Live Vaccine Model of Yersinia pseudotuberculosis Infection

ABSTRACT Several Yersinia species have been utilized as live attenuated vaccines to prime protective immunity against yersiniae and other pathogens. A type III secretion system effector known as YopJ in Y. pseudotuberculosis and Y. pestis and YopP in Y. enterocolitica has been shown to regulate host immune responses to live Yersinia vaccines. YopJ/P kills macrophages and dendritic cells, reduces their production of tumor necrosis factor alpha (TNF-α) and interleukin-12 (IL-12), and promotes systemic colonization in mouse models of intestinal Yersinia infection. Furthermore, YopP activity decreases antigen presentation by dendritic cells, and a yopP mutant of a live Y. enterocolitica carrier vaccine elicited effective priming of CD8 T cells to a heterologous antigen in mice. These results suggest that YopJ/P activity suppresses both innate and adaptive immune responses to live Yersinia vaccines. Here, a sublethal intragastric mouse infection model using wild-type and catalytically inactive yopJ mutant strains of Y. pseudotuberculosis was developed to further investigate how YopJ action impacts innate and adaptive immune responses to a live vaccine. Surprisingly, YopJ-promoted cytotoxicity and systemic colonization were associated with significant increases in neutrophils in spleens and the proinflammatory cytokines IL-18 and gamma interferon (IFN-γ) in serum samples of mice vaccinated with Y. pseudotuberculosis. Secretion of IL-18 accompanied YopJ-mediated killing of macrophages infected ex vivo with Y. pseudotuberculosis, suggesting a mechanism by which this effector directly increases proinflammatory cytokine levels in vivo. Mice vaccinated with the wild-type strain or the yopJ mutant produced similar levels of antibodies to Y. pseudotuberculosis antigens and were equally resistant to lethal intravenous challenge with Y. pestis. The findings indicate that a proinflammatory, rather than anti-inflammatory, process accompanies YopJ-promoted cytotoxicity, leading to increased systemic colonization by Y. pseudotuberculosis and potentially enhancing adaptive immunity to a live vaccine.

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The Inability of Wild-Type Rabies Virus To Activate Dendritic Cells Is Dependent on the Glycoprotein and Correlates with Its Low Level of theDe Novo-Synthesized Leader RNA

Journal of Virology ◽

10.1128/jvi.02092-14 ◽

2014 ◽

Vol 89 (4) ◽

pp. 2157-2169 ◽

Cited By ~ 16

Author(s):

Yang Yang ◽

Ying Huang ◽

Clement W. Gnanadurai ◽

Shengbo Cao ◽

Xueqin Liu ◽

...

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Rabies Virus ◽

Adoptive Transfer ◽

Viral Infections ◽

De Novo ◽

Wild Type ◽

Adaptive Immune Responses ◽

Low Level ◽

Adaptive Immune

ABSTRACTDendritic cells (DCs) are the most efficient antigen-presenting cells, playing a key role in the adaptive immune responses to viral infections. Our studies demonstrate that wild-type (wt) rabies virus (RABV) does not activate DCs. Adoptive transfer of DCs primed with wt RABV did not activate DCs, stimulate virus neutralizing antibodies (VNA), or protect recipients against challenge. However, adoptive transfer of DCs primed with laboratory-attenuated RABV resulted in DC activation, production of VNA, and protection against challenge.In vitrostudies with recombinant RABV (laboratory-attenuated RABV expressing the glycoprotein or the phosphoprotein from wt RABV) demonstrate that DC activation is dependent on the glycoprotein and involves the IPS-1 pathway. Furthermore, binding to and entry into DCs by wt RABV is severely blocked, and the copy number ofde novo-synthesized leader RNA was two logs lower in DCs infected with the wt than in DCs treated with laboratory-attenuated RABV. However, transient transfection of DCs with synthesized leader RNA from either wt or attenuated RABV is capable of activating DCs in a dose-dependent manner. Thus, the inability of wt RABV to activate DCs correlates with its low level of thede novo-synthesized leader RNA.IMPORTANCERabies remains a public health threat, with more than 55,000 fatalities each year around the world. Since DCs play a key role in the adaptive immune responses to viral infections, we investigated the ability of rabies virus (RABV) to activate DCs. It was found that the adoptive transfer of DCs primed with wt RABV did not activate DCs, stimulate VNA, or protect mice against lethal challenge. However, laboratory-attenuated RABV mediates the activation of DCs via the IPS-1 pathway and is glycoprotein dependent. We further show that wt RABV evades DC-mediated immune activation by inefficient binding/entry into DCs and as a result of a reduced level ofde novo-synthesized leader RNA. These findings may have important implications in the development of efficient rabies vaccines.

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CD8+lineage dendritic cells determine adaptive immune responses to inflammasome activation upon sterile skin injury

Experimental Dermatology ◽

10.1111/exd.13436 ◽

2017 ◽

Vol 27 (1) ◽

pp. 71-79 ◽

Cited By ~ 2

Author(s):

Rituparna Chakraborty ◽

Janin Chandra ◽

Shuai Cui ◽

Lynn Tolley ◽

Matthew A. Cooper ◽

...

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Inflammasome Activation ◽

Adaptive Immune Responses ◽

Skin Injury ◽

Adaptive Immune

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Dendritic Cells in Innate and Adaptive Immune Responses against Influenza Virus

Viruses ◽

10.3390/v1031022 ◽

2009 ◽

Vol 1 (3) ◽

pp. 1022-1034 ◽

Cited By ~ 12

Author(s):

Artur Summerfield ◽

Kenneth McCullough

Keyword(s):

Dendritic Cells ◽

Influenza Virus ◽

Immune Responses ◽

Adaptive Immune Responses ◽

Adaptive Immune

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Dendritic Cells/Macrophages-Targeting Feature of Ebola Glycoprotein and its Potential as Immunological Facilitator for Antiviral Vaccine Approach

Microorganisms ◽

10.3390/microorganisms7100402 ◽

2019 ◽

Vol 7 (10) ◽

pp. 402

Author(s):

Titus Abiola Olukitibi ◽

Zhujun Ao ◽

Mona Mahmoudi ◽

Gary A. Kobinger ◽

Xiaojian Yao

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Ebola Virus ◽

Vaccine Development ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Immunological Approach ◽

Vaccine Approach ◽

Acquired Immune Responses ◽

Diverse Virus

In the prevention of epidemic and pandemic viral infection, the use of the antiviral vaccine has been the most successful biotechnological and biomedical approach. In recent times, vaccine development studies have focused on recruiting and targeting immunogens to dendritic cells (DCs) and macrophages to induce innate and adaptive immune responses. Interestingly, Ebola virus (EBOV) glycoprotein (GP) has a strong binding affinity with DCs and macrophages. Shreds of evidence have also shown that the interaction between EBOV GP with DCs and macrophages leads to massive recruitment of DCs and macrophages capable of regulating innate and adaptive immune responses. Therefore, studies for the development of vaccine can utilize the affinity between EBOV GP and DCs/macrophages as a novel immunological approach to induce both innate and acquired immune responses. In this review, we will discuss the unique features of EBOV GP to target the DC, and its potential to elicit strong immune responses while targeting DCs/macrophages. This review hopes to suggest and stimulate thoughts of developing a stronger and effective DC-targeting vaccine for diverse virus infection using EBOV GP.

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Toxic adjuvants alter the function and phenotype of dendritic cells to initiate adaptive immune responses induced by oralHelicobacter pylorivaccines

Helicobacter ◽

10.1111/hel.12536 ◽

2018 ◽

Vol 23 (6) ◽

Cited By ~ 6

Author(s):

Shuanghui Luo ◽

Wei Liu ◽

Zhiqin Zeng ◽

Feng Ye ◽

Chupeng Hu ◽

...

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Adaptive Immune Responses ◽

Adaptive Immune

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Crosstalk between Dendritic Cells and Immune Modulatory Agents against Sepsis

Genes ◽

10.3390/genes11030323 ◽

2020 ◽

Vol 11 (3) ◽

pp. 323 ◽

Cited By ~ 1

Author(s):

Guoying Wang ◽

Xianghui Li ◽

Lei Zhang ◽

Abualgasim Elgaili Abdalla ◽

Tieshan Teng ◽

...

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Immune Responses ◽

Critical Role ◽

Innate Immune ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Th2 Responses ◽

Novel Strategy

Dendritic cells (DCs) play a critical role in the immune system which sense pathogens and present their antigens to prime the adaptive immune responses. As the progression of sepsis occurs, DCs are capable of orchestrating the aberrant innate immune response by sustaining the Th1/Th2 responses that are essential for host survival. Hence, an in-depth understanding of the characteristics of DCs would have a beneficial effect in overcoming the obstacle occurring in sepsis. This paper focuses on the role of DCs in the progression of sepsis and we also discuss the reverse sepsis-induced immunosuppression through manipulating the DC function. In addition, we highlight some potent immunotherapies that could be used as a novel strategy in the early treatment of sepsis.

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Dendritic cells and C‐type lectin receptors: coupling innate to adaptive immune responses

Immunology and Cell Biology ◽

10.1038/icb.2008.55 ◽

2008 ◽

Vol 86 (7) ◽

pp. 580-587 ◽

Cited By ~ 102

Author(s):

Sandra J Vliet ◽

Juan J García‐Vallejo ◽

Yvette Kooyk

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Adaptive Immune Responses ◽

Lectin Receptors ◽

Adaptive Immune

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Type I Interferons Mediate the Innate Cytokine Response to Recombinant Fowlpox Virus but Not the Induction of Plasmacytoid Dendritic Cell-Dependent Adaptive Immunity

Journal of Virology ◽

10.1128/jvi.02618-09 ◽

2010 ◽

Vol 84 (13) ◽

pp. 6549-6563 ◽

Cited By ~ 7

Author(s):

Erin L. Lousberg ◽

Cara K. Fraser ◽

Michael G. Tovey ◽

Kerrilyn R. Diener ◽

John D. Hayball

Keyword(s):

Immune Responses ◽

Plasmacytoid Dendritic Cell ◽

Type I Interferons ◽

Interleukin 12 ◽

Type I ◽

Adaptive Immune Responses ◽

Fowlpox Virus ◽

Adaptive Immune ◽

Type I Ifns

ABSTRACT Type I interferons (IFNs) are considered to be important mediators of innate immunity due to their inherent antiviral activity, ability to drive the transcription of a number of genes involved in viral clearance, and their role in the initiation of innate and adaptive immune responses. Due to the central role of type I IFNs, we sought to determine their importance in the generation of immunity to a recombinant vaccine vector fowlpox virus (FPV). In analyzing the role of type I IFNs in immunity to FPV, we show that they are critical to the secretion of a number of innate and proinflammatory cytokines, including type I IFNs themselves as well as interleukin-12 (IL-12), tumor necrosis factor-alpha (TNF-α), IL-6, and IL-1β, and that deficiency leads to enhanced virus-mediated antigen expression. Interestingly, however, type I IFNs were not required for adaptive immune responses to recombinant FPV even though plasmacytoid dendritic cells (pDCs), the primary producers of type I IFNs, have been shown to be requisite for this to occur. Furthermore, we provide evidence that the importance of pDCs may lie in their ability to capture and present virally derived antigen to T cells rather than in their capacity as professional type I IFN-producing cells.

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