Gr-1+ cells, but not neutrophils, limit virus replication and lesion development following flank infection of mice with herpes simplex virus type-1

Wojtasiak, Magdalena; Pickett, Danielle L.; Tate, Michelle D.; Bedoui, Sammy; Job, Emma R.; Whitney, Paul G.; Brööks, Andrëw G.; Reading, Patrick C.

doi:10.1016/j.virol.2010.08.001

Cited by 33 publications

(44 citation statements)

References 72 publications

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“…Our study targeted Ly6G specifically using a different antibody (clone 1A8) that does not recognize significant populations of activated T or B lymphocytes (55). Gr-1-expressing cells, but not Ly6G ϩ cells, have previously been implicated in protection against herpes simplex virus 1 (HSV-1) infection (56,57), indicating a clear difference in the antiviral roles of these different populations of cells.…”

Section: Discussionmentioning

confidence: 99%

Redundant Function of Plasmacytoid and Conventional Dendritic Cells Is Required To Survive a Natural Virus Infection

Kaminsky

Sei

Parekh

et al. 2015

J Virol

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Viruses that spread systemically from a peripheral site of infection cause morbidity and mortality in the human population. Innate myeloid cells, including monocytes, macrophages, monocyte-derived dendritic cells (mo-DC), and dendritic cells (DC), respond early during viral infection to control viral replication, reducing virus spread from the peripheral site. Ectromelia virus (ECTV), an orthopoxvirus that naturally infects the mouse, spreads systemically from the peripheral site of infection and results in death of susceptible mice. While phagocytic cells have a requisite role in the response to ECTV, the requirement for individual myeloid cell populations during acute immune responses to peripheral viral infection is unclear. In this study, a variety of myeloid-specific depletion methods were used to dissect the roles of individual myeloid cell subsets in the survival of ECTV infection. We showed that DC are the primary producers of type I interferons (T1-IFN), requisite cytokines for survival, following ECTV infection. DC, but not macrophages, monocytes, or granulocytes, were required for control of the virus and survival of mice following ECTV infection. Depletion of either plasmacytoid DC (pDC) alone or the lymphoid-resident DC subset (CD8␣ ؉ DC) alone did not confer lethal susceptibility to ECTV. However, the function of at least one of the pDC or CD8␣ ؉ DC subsets is required for survival of ECTV infection, as mice depleted of both populations were susceptible to ECTV challenge. The presence of at least one of these DC subsets is sufficient for cytokine production that reduces ECTV replication and virus spread, facilitating survival following infection. IMPORTANCEPrior to the eradication of variola virus, the orthopoxvirus that causes smallpox, one-third of infected people succumbed to the disease. Following successful eradication of smallpox, vaccination rates with the smallpox vaccine have significantly dropped. There is now an increasing incidence of zoonotic orthopoxvirus infections for which there are no effective treatments. Moreover, the safety of the smallpox vaccine is of great concern, as complications may arise, resulting in morbidity. Like many viruses that cause significant human diseases, orthopoxviruses spread from a peripheral site of infection to become systemic. This study elucidates the early requirement for innate immune cells in controlling a peripheral infection with ECTV, the causative agent of mousepox. We report that there is redundancy in the function of two innate immune cell subsets in controlling virus spread early during infection. The viral control mediated by these cell subsets presents a potential target for therapies and rational vaccine design. P rior to the induction of the adaptive immune response, cells of the innate immune system are deployed early during viral infection to control the pathogen and limit its spread from the site of infection. Effector cells of the innate immune system include myeloid cell subsets: granulocytes (neutrophils, eosinophils, and b...

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Section: Discussionmentioning

confidence: 99%

Redundant Function of Plasmacytoid and Conventional Dendritic Cells Is Required To Survive a Natural Virus Infection

Kaminsky

Sei

Parekh

et al. 2015

J Virol

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“…In an HSV-1 skin flank infection model, mice depleted of GR1 + cells had increased viral loads and lesion severity. This effect was not observed in mice depleted of Ly6G + cells (including neutrophils and G-MDSCs) (164), suggesting that Ly6C…”

Section: Direct Targeting Of Mdscs In Vivomentioning

confidence: 93%

“…During HSV-1 and HSV-2 infection of mice, cells phenotypically resembling MDSCs infiltrated the cornea (34) and skin (40,164). In one study, increased herpes simplex keratitis (HSK) and viral titers were observed in HSV-1-infected Kit W-sh mice (that lack CD31 + mast cells), compared to wildtype mice (130).…”

Section: Dna Virusesmentioning

confidence: 99%

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The Role of Myeloid-Derived Suppressor Cells in Viral Infection

2017

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Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cells that are well described as potent immune regulatory cells during human cancer and murine tumor models. Reports of MDSCs during viral infections remain limited, and their association with immunomodulation of viral diseases is still being defined. Here, we provide an overview of MDSCs or MDSC-like cells identified during viral infections, including murine viral models and human viral diseases. Understanding the similarities and/or differences of virally induced versus tumor-derived MDSCs will be important for designing future immunotherapeutic approaches.

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“…These cell types share effector mechanisms, and both are recruited to sites of infection, but they differ in their mechanisms of activation and recruitment; recently, they have been shown to make differential contributions to the control of Listeria monocytogenes and herpes simplex virus 1 (33,34). The antibody depletion of Gr-1 ϩ cells is unable to distinguish the contribution of each cell type given the affinity of RB6-8C5 for Ly-6C and Ly-6G, with Ly-6G being found selectively on neutrophils and Ly-6C being No antibody C57BL/6 Background *** *** found on neutrophils, subsets of CCR2 ϩ inflammatory monocytes, myeloid suppressor cells, and memory subsets of CD8 ϩ T cells (35,36).…”

Section: Discussionmentioning

confidence: 99%

Role for Gr-1⁺Cells in the Control of High-Dose Mycobacterium bovis Recombinant BCG

Panas

Letvin

2014

Clin. Vaccine Immunol.

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Mycobacterium bovis bacillus Calmette-Guérin (BCG) is an attractive target for development as a live vaccine vector delivering transgenic antigens from HIV and other pathogens. Most studies aimed at defining the clearance of BCG have been performed at doses between 10 2 and 10 4 CFU. Interestingly, however, recombinant BCG (rBCG) administered at doses of >10 6 CFU effectively generates antigen-specific T-cell responses and primes for heterologous boost responses. Thus, defining clearance at high doses might aid in the optimization of rBCG as a vector. In this study, we used bioluminescence imaging to examine the kinetics of rBCG transgene expression and clearance in mice immunized with 5 ؋ 10 7 CFU rBCG expressing luciferase. Similar to studies using low-dose rBCG, our results demonstrate that the adaptive immune response is necessary for long-term control of rBCG beginning 9 days after immunizing mice. However, in contrast to these reports, we observed that the majority of mycobacterial antigen was eliminated prior to day 9. By examining knockout and antibody-mediated depletion mouse models, we demonstrate that the rapid clearance of rBCG occurs in the first 24 h and is mediated by Gr-1 ؉ cells. As Gr-1 ؉ granulocytes have been described as having no impact on BCG clearance at low doses, our results reveal an unappreciated role for Gr-1 ؉ neutrophils and inflammatory monocytes in the clearance of high-dose rBCG. This work demonstrates the potential of applying bioluminescence imaging to rBCG in order to gain an understanding of the immune response and increase the efficacy of rBCG as a vaccine vector. Mycobacterium bovis bacillus Calmette-Guérin (BCG) is an attenuated mycobacterial vaccine administered to newborns for the prevention of childhood miliary tuberculosis. BCG possesses several attributes that make it a highly favorable candidate for development as a recombinant vaccine vector. These include its ability (i) to express transgenic antigens from pathogens, such as HIV, (ii) to induce strong T-cell responses associated with the release of gamma interferon (IFN-␥) and other Th 1 cytokines, and (iii) to generate T-cell responses specific for transgenic antigens, which can ultimately be increased by heterologous boost vaccination (1-8). The aforementioned responses are generated with high doses of recombinant BCG (rBCG). Specifically, rBCG administered to mice at a dose equal to 10 6 CFU rapidly induces the development of transgene product-specific T cells, a response not observed using lower doses of 10 3 to 10 6 CFU (9-11). Furthermore, rBCG doses of Ͼ10 7 CFU induce detectable primary T-cell responses directed against the foreign transgenic epitope in rhesus macaque studies, responses that are not observed at lower doses (5,12).Despite the fact that transgene-product specific T cells are generated in response to high doses of rBCG, very few experiments have been performed to determine the clearance of high-dose BCG. Instead, experiments determining the clearance of BCG have been done using lower doses of...

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Gr-1+ cells, but not neutrophils, limit virus replication and lesion development following flank infection of mice with herpes simplex virus type-1

Cited by 33 publications

References 72 publications

Redundant Function of Plasmacytoid and Conventional Dendritic Cells Is Required To Survive a Natural Virus Infection

Redundant Function of Plasmacytoid and Conventional Dendritic Cells Is Required To Survive a Natural Virus Infection

The Role of Myeloid-Derived Suppressor Cells in Viral Infection

Role for Gr-1⁺Cells in the Control of High-Dose Mycobacterium bovis Recombinant BCG

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Gr-1+ cells, but not neutrophils, limit virus replication and lesion development following flank infection of mice with herpes simplex virus type-1

Cited by 33 publications

References 72 publications

Redundant Function of Plasmacytoid and Conventional Dendritic Cells Is Required To Survive a Natural Virus Infection

Redundant Function of Plasmacytoid and Conventional Dendritic Cells Is Required To Survive a Natural Virus Infection

The Role of Myeloid-Derived Suppressor Cells in Viral Infection

Role for Gr-1+Cells in the Control of High-Dose Mycobacterium bovis Recombinant BCG

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Product

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Role for Gr-1⁺Cells in the Control of High-Dose Mycobacterium bovis Recombinant BCG