Natural Killer Cell Dysfunction during Acute Infection with Foot-and-Mouth Disease Virus

Toka, Felix N.; Nfon, Charles; Dawson, Harry; Golde, William T.

doi:10.1128/cvi.00280-09

Cited by 39 publications

(38 citation statements)

References 57 publications

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“…We have previously demonstrated that, in vitro, WT FMDV interferes with full induction of transcription of IFN-␤ (19). However, in vivo, IFN-␣ mRNA or protein has been detected in WT FMDV-infected bovine and swine (8,65,72). We did not detect significant differences in the amount of IFN-␣ protein in the serum of animals inoculated with A12-WT or A12-SAP.…”

Section: Discussionmentioning

confidence: 50%

Inoculation of Swine with Foot-and-Mouth Disease SAP-Mutant Virus Induces Early Protection against Disease

Segundo

Weiss

Pérez-Martín

et al. 2012

J Virol

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Foot-and-mouth disease virus (FMDV) leader proteinase (L pro ) cleaves itself from the viral polyprotein and cleaves the translation initiation factor eIF4G. As a result, host cell translation is inhibited, affecting the host innate immune response. We have demonstrated that L pro is also associated with degradation of nuclear factor B (NF-B), a process that requires L pro nuclear localization. Additionally, we reported that disruption of a conserved protein domain within the L pro coding sequence, SAP mutation, prevented L pro nuclear retention and degradation of NF-B, resulting in in vitro attenuation. Here we report that inoculation of swine with this SAP-mutant virus does not cause clinical signs of disease, viremia, or virus shedding even when inoculated at doses 100-fold higher than those required to cause disease with wild-type (WT) virus. Remarkably, SAP-mutant virus-inoculated animals developed a strong neutralizing antibody response and were completely protected against challenge with WT FMDV as early as 2 days postinoculation and for at least 21 days postinoculation. Early protection correlated with a distinct pattern in the serum levels of proinflammatory cytokines in comparison to the levels detected in animals inoculated with WT FMDV that developed disease. In addition, animals inoculated with the FMDV SAP mutant displayed a memory T cell response that resembled infection with WT virus. Our results suggest that L pro plays a pivotal role in modulating several pathways of the immune response. Furthermore, manipulation of the L pro coding region may serve as a viable strategy to derive live attenuated strains with potential for development as effective vaccines against foot-and-mouth disease.

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Section: Discussionmentioning

confidence: 50%

Inoculation of Swine with Foot-and-Mouth Disease SAP-Mutant Virus Induces Early Protection against Disease

Segundo

Weiss

Pérez-Martín

et al. 2012

J Virol

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“…Translocation of lysosome-associated membrane protein 1 (LAMP1/CD107a) to the cell membrane has been confirmed as a marker of cytotoxic degranulation by CD8 T and NK cells (34). While CD107a mobilization has been reported as a marker for porcine NK cell degranulation (35), this is the first report of its application to assess porcine CD8 T cell degranulation. PBMC isolated 5 days postchallenge were stimulated with CSFV.…”

Section: Cd8␣mentioning

confidence: 93%

Assessment of the Phenotype and Functionality of Porcine CD8 T Cell Responses following Vaccination with Live Attenuated Classical Swine Fever Virus (CSFV) and Virulent CSFV Challenge

Franzoni

Kurkure

Edgar

et al. 2013

Clin. Vaccine Immunol.

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Vaccination with live attenuated classical swine fever virus (CSFV) induces solid protection after only 5 days, which has been associated with virus-specific T cell gamma interferon (IFN-␥) responses. In this study, we employed flow cytometry to characterize T cell responses following vaccination and subsequent challenge infections with virulent CSFV. The CD3 ؉ CD4 ؊ CD8 hi T cell population was the first and major source of CSFV-specific IFN-␥. A proportion of these cells showed evidence for cytotoxicity, as evidenced by CD107a mobilization, and coexpressed tumor necrosis factor alpha (TNF-␣). To assess the durability and recall of these responses, a second experiment was conducted where vaccinated animals were challenged with virulent CSFV after 5 days and again after a further 28 days. While virus-specific CD4 T cell (CD3 ؉ CD4 ؉ CD8␣ ؉ ) responses were detected, the dominant response was again from the CD8 T cell population, with the highest numbers of these cells being detected 14 and 7 days after the primary and secondary challenges, respectively. These CD8 T cells were further characterized as CD44 hi CD62L؊ and expressed variable levels of CD25 and CD27, indicative of a mixed effector and effector memory phenotype. The majority of virus-specific IFN-␥ ؉ CD8 T cells isolated at the peaks of the response after each challenge displayed CD107a on their surface, and subpopulations that coexpressed TNF-␣ and interleukin 2 (IL-2) were identified. While it is hoped that these data will aid the rational design and/or evaluation of next-generation marker CSFV vaccines, the novel flow cytometric panels developed should also be of value in the study of porcine T cell responses to other pathogens/vaccines.

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“…In vitro, natural killer (NK) cells have been shown to lyse FMDV-infected cells (56). However, analysis of cells from FMDV-infected animals shows a loss of NK cell function during the acute phase of infection (55) (reviewed in reference 16).…”

mentioning

confidence: 99%

Induction of Foot-and-Mouth Disease Virus-Specific Cytotoxic T Cell Killing by Vaccination

Patch

Pedersen

Toka

et al. 2011

Clin Vaccine Immunol

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Foot-and-mouth disease (FMD) continues to be a significant threat to the health and economic value of livestock species. This acute infection is caused by the highly contagious FMD virus (FMDV), which infects cloven-hoofed animals, including large and small ruminants and swine. Current vaccine strategies are all directed toward the induction of neutralizing antibody responses. However, the role of cytotoxic T lymphocytes (CTLs) has not received a great deal of attention, in part because of the technical difficulties associated with establishing a reliable assay of cell killing for this highly cytopathic virus. Here, we have used recombinant human adenovirus vectors as a means of delivering FMDV antigens in a T cell-directed vaccine in pigs. We tested the hypothesis that impaired processing of the FMDV capsid would enhance cytolytic activity, presumably by targeting all proteins for degradation and effectively increasing the class I major histocompatibility complex (MHC)/FMDV peptide concentration for stimulation of a CTL response. We compared such a T cell-targeting vaccine with the parental vaccine, previously shown to effectively induce a neutralizing antibody response. Our results show induction of FMDV-specific CD8؉ CTL killing of MHC-matched target cells in an antigen-specific manner. Further, we confirm these results by MHC tetramer staining. This work presents the first demonstration of FMDV-specific CTL killing and confirmation by MHC tetramer staining in response to vaccination against FMDV.

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Natural Killer Cell Dysfunction during Acute Infection with Foot-and-Mouth Disease Virus

Cited by 39 publications

References 57 publications

Inoculation of Swine with Foot-and-Mouth Disease SAP-Mutant Virus Induces Early Protection against Disease

Inoculation of Swine with Foot-and-Mouth Disease SAP-Mutant Virus Induces Early Protection against Disease

Assessment of the Phenotype and Functionality of Porcine CD8 T Cell Responses following Vaccination with Live Attenuated Classical Swine Fever Virus (CSFV) and Virulent CSFV Challenge

Induction of Foot-and-Mouth Disease Virus-Specific Cytotoxic T Cell Killing by Vaccination

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