The Nucleocapsid Protein of Rift Valley Fever Virus Is a Potent Human CD8+ T Cell Antigen and Elicits Memory Responses

Weidong Xu, Douglas M. Watts, Margaret C. Costanzo, Xiaolei Tang, Leon A. Venegas, Feng Jiao, Alessandro Sette, John Sidney, Andrew K. Sewell, Linda Wooldridge, Shinji Makino, John C. Morrill, Clarence J. Peters, June Kan-Mitchell

Research output: Contribution to journalArticle

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Abstract

There is no licensed human vaccine currently available for Rift Valley Fever Virus (RVFV), a Category A high priority pathogen and a serious zoonotic threat. While neutralizing antibodies targeting the viral glycoproteins are protective, they appear late in the course of infection, and may not be induced in time to prevent a natural or bioterrorism-induced outbreak. Here we examined the immunogenicity of RVFV nucleocapsid (N) protein as a CD8+ T cell antigen with the potential for inducing rapid protection after vaccination. HLA-A*0201 (A2)-restricted epitopic determinants were identified with N-specific CD8+ T cells from eight healthy donors that were primed with dendritic cells transduced to express N, and subsequently expanded in vitro by weekly re-stimulations with monocytes pulsed with 59 15mer overlapping peptides (OLPs) across N. Two immunodominant epitopes, VT9 (VLSEWLPVT, N121-129) and IL9 (ILDAHSLYL, N165-173), were defined. VT9- and IL9-specific CD8+ T cells identified by tetramer staining were cytotoxic and polyfunctional, characteristics deemed important for viral control in vivo. These peptides induced specific CD8+ T cell responses in A2-transgenic mice, and more importantly, potent N-specific CD8+ T cell reactivities, including VT9- and IL9-specific ones, were mounted by mice after a booster vaccination with the live attenuated RVF MP-12. Our data suggest that the RVFV N protein is a potent human T cell immunogen capable of eliciting broad, immunodominant CD8+ T cell responses that are potentially protective. Understanding the immune responses to the nucleocapsid is central to the design of an effective RVFV vaccine irrespective of whether this viral protein is effective as a stand-alone immunogen or only in combination with other RVFV antigens.

Original languageEnglish (US)
Article numbere59210
JournalPLoS One
Volume8
Issue number3
DOIs
StatePublished - Mar 18 2013

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Rift Valley fever virus
nucleocapsid proteins
Nucleocapsid Proteins
T-cells
Viral Tumor Antigens
Viruses
T-lymphocytes
antigens
T-Lymphocytes
Antigens
Data storage equipment
Interleukin-9
Nucleocapsid
nucleocapsid
varespladib methyl
Vaccination
Vaccines
Bioterrorism
immune response
peptides

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Xu, W., Watts, D. M., Costanzo, M. C., Tang, X., Venegas, L. A., Jiao, F., ... Kan-Mitchell, J. (2013). The Nucleocapsid Protein of Rift Valley Fever Virus Is a Potent Human CD8+ T Cell Antigen and Elicits Memory Responses. PLoS One, 8(3), [e59210]. https://doi.org/10.1371/journal.pone.0059210

The Nucleocapsid Protein of Rift Valley Fever Virus Is a Potent Human CD8+ T Cell Antigen and Elicits Memory Responses. / Xu, Weidong; Watts, Douglas M.; Costanzo, Margaret C.; Tang, Xiaolei; Venegas, Leon A.; Jiao, Feng; Sette, Alessandro; Sidney, John; Sewell, Andrew K.; Wooldridge, Linda; Makino, Shinji; Morrill, John C.; Peters, Clarence J.; Kan-Mitchell, June.

In: PLoS One, Vol. 8, No. 3, e59210, 18.03.2013.

Research output: Contribution to journalArticle

Xu, W, Watts, DM, Costanzo, MC, Tang, X, Venegas, LA, Jiao, F, Sette, A, Sidney, J, Sewell, AK, Wooldridge, L, Makino, S, Morrill, JC, Peters, CJ & Kan-Mitchell, J 2013, 'The Nucleocapsid Protein of Rift Valley Fever Virus Is a Potent Human CD8+ T Cell Antigen and Elicits Memory Responses', PLoS One, vol. 8, no. 3, e59210. https://doi.org/10.1371/journal.pone.0059210
Xu, Weidong ; Watts, Douglas M. ; Costanzo, Margaret C. ; Tang, Xiaolei ; Venegas, Leon A. ; Jiao, Feng ; Sette, Alessandro ; Sidney, John ; Sewell, Andrew K. ; Wooldridge, Linda ; Makino, Shinji ; Morrill, John C. ; Peters, Clarence J. ; Kan-Mitchell, June. / The Nucleocapsid Protein of Rift Valley Fever Virus Is a Potent Human CD8+ T Cell Antigen and Elicits Memory Responses. In: PLoS One. 2013 ; Vol. 8, No. 3.
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abstract = "There is no licensed human vaccine currently available for Rift Valley Fever Virus (RVFV), a Category A high priority pathogen and a serious zoonotic threat. While neutralizing antibodies targeting the viral glycoproteins are protective, they appear late in the course of infection, and may not be induced in time to prevent a natural or bioterrorism-induced outbreak. Here we examined the immunogenicity of RVFV nucleocapsid (N) protein as a CD8+ T cell antigen with the potential for inducing rapid protection after vaccination. HLA-A*0201 (A2)-restricted epitopic determinants were identified with N-specific CD8+ T cells from eight healthy donors that were primed with dendritic cells transduced to express N, and subsequently expanded in vitro by weekly re-stimulations with monocytes pulsed with 59 15mer overlapping peptides (OLPs) across N. Two immunodominant epitopes, VT9 (VLSEWLPVT, N121-129) and IL9 (ILDAHSLYL, N165-173), were defined. VT9- and IL9-specific CD8+ T cells identified by tetramer staining were cytotoxic and polyfunctional, characteristics deemed important for viral control in vivo. These peptides induced specific CD8+ T cell responses in A2-transgenic mice, and more importantly, potent N-specific CD8+ T cell reactivities, including VT9- and IL9-specific ones, were mounted by mice after a booster vaccination with the live attenuated RVF MP-12. Our data suggest that the RVFV N protein is a potent human T cell immunogen capable of eliciting broad, immunodominant CD8+ T cell responses that are potentially protective. Understanding the immune responses to the nucleocapsid is central to the design of an effective RVFV vaccine irrespective of whether this viral protein is effective as a stand-alone immunogen or only in combination with other RVFV antigens.",
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