Induction of Th1 type response by DNA vaccinations with N, M, and E genes against SARS-CoV in mice

Jin, Huali; Xiao, Cheng; Chen, Ze; Kang, Youmin; Ma, Yijie; Zhu, Ke-Cheng; Xie, Qiaoli; Tu, Yixian; Yu, Yang; Wang, Bin

doi:10.1016/j.bbrc.2005.01.048

Cited by 64 publications

(64 citation statements)

References 31 publications

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“…In contrast, our current data suggest that N protein-immunized mice exhibit activation of both Th1 and Th2 responses after SARS-CoV infection. In agreement with our data, Jin et al (54) have demonstrated that prior immunization with N protein generates stronger Ag-specific Th1 and Th2 responses than immunization with M or E protein.…”

Section: Discussionsupporting

confidence: 94%

Prior Immunization with Severe Acute Respiratory Syndrome (SARS)-Associated Coronavirus (SARS-CoV) Nucleocapsid Protein Causes Severe Pneumonia in Mice Infected with SARS-CoV

Yasui¹,

Kai

Kitabatake³

et al. 2008

The Journal of Immunology

251

240

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The details of the mechanism by which severe acute respiratory syndrome-associated coronavirus (SARS-CoV) causes severe pneumonia are unclear. We investigated the immune responses and pathologies of SARS-CoV-infected BALB/c mice that were immunized intradermally with recombinant vaccinia virus (VV) that expressed either the SARS-CoV spike (S) protein (LC16m8rVV-S) or simultaneously all the structural proteins, including the nucleocapsid (N), membrane (M), envelope (E), and S proteins (LC16m8rVV-NMES) 7–8 wk before intranasal SARS-CoV infection. The LC16m8rVV-NMES-immunized group exhibited as severe pneumonia as the control groups, although LC16m8rVV-NMES significantly decreased the pulmonary SARS-CoV titer to the same extent as LC16m8rVV-S. To identify the cause of the exacerbated pneumonia, BALB/c mice were immunized with recombinant VV that expressed the individual structural proteins of SARS-CoV (LC16mOrVV-N, -M, -E, -S) with or without LC16mOrVV-S (i.e., LC16mOrVV-N, LC16mOrVV-M, LC16mOrVV-E, or LC16mOrVV-S alone or LC16mOrVV-N + LC16mOrVV-S, LC16mOrVV-M + LC16mOrVV-S, or LC16mOrVV-E + LC16mOrVV-S), and infected with SARS-CoV more than 4 wk later. Both LC16mOrVV-N-immunized mice and LC16mOrVV-N + LC16mOrVV-S-immunized mice exhibited severe pneumonia. Furthermore, LC16mOrVV-N-immunized mice upon infection exhibited significant up-regulation of both Th1 (IFN-γ, IL-2) and Th2 (IL-4, IL-5) cytokines and down-regulation of anti-inflammatory cytokines (IL-10, TGF-β), resulting in robust infiltration of neutrophils, eosinophils, and lymphocytes into the lung, as well as thickening of the alveolar epithelium. These results suggest that an excessive host immune response against the nucleocapsid protein of SARS-CoV is involved in severe pneumonia caused by SARS-CoV infection. These findings increase our understanding of the pathogenesis of SARS.

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Section: Discussionsupporting

confidence: 94%

Prior Immunization with Severe Acute Respiratory Syndrome (SARS)-Associated Coronavirus (SARS-CoV) Nucleocapsid Protein Causes Severe Pneumonia in Mice Infected with SARS-CoV

Yasui¹,

Kai

Kitabatake³

et al. 2008

The Journal of Immunology

251

240

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“…We assume that antigen-specific CD8 + T cells reveal a direct killing of virus-infected cells and CD4 + T cells may provide help for antibody isotype switching and generation of memory B cells and memory CD8 + T cells [23,26]. In support of our expectation, other studies of animal coronavirus have suggested that both cellular and humoral immunity contribute to protection during persistent infection [27][28][29][30][31].…”

Section: Discussionsupporting

confidence: 73%

Immunization with SARS-CoV S DNA vaccine generates memory CD4+ and CD8+ T cell immune responses

Huang¹,

Ma²,

Wu³

2006

Vaccine

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An effective vaccine for severe acute respiratory syndrome (SARS) will probably require the generation and maintenance of both humoral and cellular immune responses. It has been reported that after natural infection in humans and immunization in animals with SARS-CoV vaccine, antibody is produced and persistent for a long period of time. In the present study, mice were immunized i.m. with SARS-CoV S DNA vaccine, and three different methods (ELISA, ELISPOT and FACS) were used to evaluate the immune responses when the cells were stimulated in vitro with a pool of peptides overlapping entire SARS spike protein. The results show that prime-immunization with SARS-CoV S DNA vaccine can induce both CD4(+) and CD8(+) T cell responses. Boosting with the same vaccine enhances CD4(+) and CD8(+) T cell responses in both lymphoid and nonlymphoid organs and were persistent over two months. The SARS-CoV S-specific CD4(+) and CD8(+) T cells were CD62L(-), a marker for memory cells, and -30 to 50% of the cells expressed IL-7Ralpha (CD127), a marker for the capacity of effector cells to develop into memory cells. In addition, immunization with the DNA vaccine elicited high levels of antibody production. Taken together, these data demonstrate that immunization with SARS-CoV S DNA vaccine can generate antigen-specific humoral and cellular immune responses that may contribute to long-term protection.

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“…In previous study, N protein is a representative antigen for the T-cell response in vaccine setting (Gao et al, 2003), and the mice vaccinated with calreticulin (CRT)/N DNA were capable of significantly reducing the titer of challenging vaccinia virus expressing the N protein of SARS virus (Kim et al, 2004). It has been reported that N DNA vaccine could induce SARS-specific T-cell proliferation and cytotoxic T cells activity, further experiments demonstrate that SARS-N administration could induce virus-specific cellular responses in human cells using SCID-PBL/hu mouse model (Jin et al, 2005;Okada et al, 2005). Although more than 90% of sera obtained from convalescent SARS patients have antibodies against N (Tan et al, 2004), N antigen did not induce a detectable serum SARS-CoV-neutralizing antibody response in mice (Buchholz et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

The expression of membrane protein augments the specific responses induced by SARS-CoV nucleocapsid DNA immunization

Jing

Qin

et al. 2006

Molecular Immunology

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Nucleocapsid protein plays a critical role in SARS-CoV pathogenesis, and high-level anti-nucleocapsid antibodies are detected in the patients infected by severe acute respiratory syndrome-associated coronavirus (SARS-CoV). Several studies have shown that there exists an interaction between nucleocapsid (N) and membrane (M) protein. In this paper, we investigate whether the expression of membrane protein can affect the immune responses induced by nucleocapsid DNA immunization. Two recombinant plasmids containing M and N coding sequence were constructed. Moreover, in order to get the antigen for ELISA and in vitro stimulation assay, N protein were expressed and purified from E. coli bacteria. Injection of 20mug of the mixture of pVAX1-M and pVAX1-N into the Balb/c mice could elicit the humoral and cellular responses. The ELISA analysis using the N antigen or inactivated SARS-CoV particles as capture antigen showed that co-injection of SARS-M could enhance N-induced antibody production, especially IgG2a subclass. After lymphocytes were stimulated with 10mug/ml purified N antigen, The CD4+ and CD8+ T cells of N and M plus N group were increased compared with those of control groups, and the M protein could augment the activation of lymphocytes induced by N DNA vaccine. Cytokine ELISA analysis revealed that co-injection of M could enhance the levels of IFN-gamma, IL-2 release induced by N antigen. Further experiments in field mouse also support the claim that membrane protein can augment the N-specific immune responses. Virus challenge test was conducted in BSL3 bio safety laboratory with Brandt's vole SARS-CoV model, and the results indicated that co-immunization of M and N antigens could reduce the mortality and pathological changes in lung from the virus infection.

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Induction of Th1 type response by DNA vaccinations with N, M, and E genes against SARS-CoV in mice

Cited by 64 publications

References 31 publications

Prior Immunization with Severe Acute Respiratory Syndrome (SARS)-Associated Coronavirus (SARS-CoV) Nucleocapsid Protein Causes Severe Pneumonia in Mice Infected with SARS-CoV

Prior Immunization with Severe Acute Respiratory Syndrome (SARS)-Associated Coronavirus (SARS-CoV) Nucleocapsid Protein Causes Severe Pneumonia in Mice Infected with SARS-CoV

Immunization with SARS-CoV S DNA vaccine generates memory CD4+ and CD8+ T cell immune responses

The expression of membrane protein augments the specific responses induced by SARS-CoV nucleocapsid DNA immunization

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