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Cross-protection against a human enteric coronavirus and a virulent bovine enteric coronavirus in gnotobiotic calves.

ABSTRACT: A group 2 human coronavirus designated HECV-4408 was isolated from a child with acute diarrhea and is antigenically and genetically more closely related to bovine coronavirus (BCoV) than to human coronavirus OC43 (X. M. Zhang, W. Herbst, K. G. Kousoulas, and J. Storz, J. Med. Virol. 44:152-161, 1994). To determine whether HECV-4408 infects gnotobiotic calves and induces cross-protective immunity against the virulent enteric BCoV DB2 strain, gnotobiotic calves (n = 4) were orally inoculated with HECV-4408 and then challenged with BCoV DB2 at postinoculation day (PID) 21. All calves inoculated with HECV-4408 developed diarrhea at PID 3 to 4 lasting 5 to 9 days. Fecal and nasal virus shedding were first detected by reverse transcription-PCR at PID 3 to 4 and at PID 2 to 4, respectively. After challenge with bovine coronavirus, no diarrhea or virus shedding was detected in calves inoculated with HECV-4408, but a mock-inoculated calf developed diarrhea and fecal and nasal shedding. Fecal immunoglobulin A (IgA) and serum IgG antibodies were first detected at PID 7 and PID 14, respectively. At postchallenge day 7, serum IgG and fecal IgA antibody titers remained the same or increased only twofold compared to prechallenge titers. An additional two gnotobiotic calves were inoculated with HECV-4408 and euthanized at PID 5. Moderate villous atrophy was observed in the small intestines, and viral antigen was detected in villous enterocytes of the small and large intestines by immunohistochemistry. These results support and extend the previous report that HECV-4408 is likely a variant of bovine coronavirus. They confirm its infectivity for calves and complete cross-protection against a bovine coronavirus (DB2 strain) showing 98.2% amino acid identity to HECV-4408 in the S protein.

SUBMITTER: Han MG

PROVIDER: S-EPMC1676286 | biostudies-literature | 2006 Dec

REPOSITORIES: biostudies-literature

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Cross-protection against a human enteric coronavirus and a virulent bovine enteric coronavirus in gnotobiotic calves.

Han Myung Guk MG Cheon Doo-Sung DS Zhang Xuming X Saif Linda J LJ

Journal of virology 20060913 24

A group 2 human coronavirus designated HECV-4408 was isolated from a child with acute diarrhea and is antigenically and genetically more closely related to bovine coronavirus (BCoV) than to human coronavirus OC43 (X. M. Zhang, W. Herbst, K. G. Kousoulas, and J. Storz, J. Med. Virol. 44:152-161, 1994). To determine whether HECV-4408 infects gnotobiotic calves and induces cross-protective immunity against the virulent enteric BCoV DB2 strain, gnotobiotic calves (n = 4) were orally inoculated with ...[more]

PMID: 16971444

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Project description:UnlabelledNoroviruses (NoVs) are the leading cause of nonbacterial acute gastroenteritis worldwide in people of all ages. The P particle is a novel vaccine candidate derived from the protruding (P) domain of the NoV VP1 capsid protein. This study utilized the neonatal gnotobiotic pig model to evaluate the protective efficacies of primary infection, P particles, and virus-like particles (VLPs) against NoV infection and disease and the T cell responses to these treatments. Pigs either were vaccinated intranasally with GII.4/1997 NoV (VA387)-derived P particles or VLPs or were inoculated orally with a GII.4/2006b NoV variant. At postinoculation day (PID) 28, pigs either were euthanized or were challenged with the GII.4/2006b variant and monitored for diarrhea and virus shedding for 7 days. The T cell responses in intestinal and systemic lymphoid tissues were examined. Primary NoV infection provided 83% homologous protection against diarrhea and 49% homologous protection against virus shedding, while the P particle and VLP vaccines provided cross-variant protection (47% and 60%, respectively) against diarrhea. The protection rates against diarrhea are significantly inversely correlated with T cell expansion in the duodenum and are positively correlated with T cell expansion in the ileum and spleen. The P particle vaccine primed for stronger immune responses than VLPs, including significantly higher numbers of activated CD4+ T cells in all tissues, gamma interferon-producing (IFN-γ+) CD8+ T cells in the duodenum, regulatory T cells (Tregs) in the blood, and transforming growth factor β (TGF-β)-producing CD4+ CD25- FoxP3+ Tregs in the spleen postchallenge, indicating that P particles are more immunogenic than VLPs at the same dose. In conclusion, the P particle vaccine is a promising vaccine candidate worthy of further development.ImportanceThe norovirus (NoV) P particle is a vaccine candidate derived from the protruding (P) domain of the NoV VP1 capsid protein. P particles can be easily produced in Escherichia coli at high yields and thus may be more economically viable than the virus-like particle (VLP) vaccine. This study demonstrated, for the first time, the cross-variant protection (46.7%) of the intranasal P particle vaccine against human NoV diarrhea and revealed in detail the intestinal and systemic T cell responses by using the gnotobiotic pig model. The cross-variant protective efficacy of the P particle vaccine was comparable to that of the VLP vaccine in pigs (60%) and to the homologous protective efficacy of the VLP vaccine in humans (47%). NoV is now the leading cause of pediatric dehydrating diarrhea, responsible for approximately 1 million hospital visits for U.S. children and 218,000 deaths in developing countries. The P particle vaccine holds promise for reducing the disease burden and mortality.

Project description:BackgroundBovine coronavirus (BCoV) is a widely distributed pathogen, causing disease and economic losses in the cattle industry worldwide. Prevention of virus spread is impeded by a lack of basic knowledge concerning viral shedding and transmission potential in individual animals. The aims of the study were to investigate the duration and quantity of BCoV shedding in feces and nasal secretions related to clinical signs, the presence of virus in blood and tissues and to test the hypothesis that seropositive calves are not infectious to naïve in-contact calves three weeks after BCoV infection.MethodsA live animal experiment was conducted, with direct contact between animal groups for 24 h as challenge procedure. Four naïve calves were commingled with a group of six naturally infected calves and sequentially euthanized. Two naïve sentinel calves were commingled with the experimentally exposed group three weeks after exposure. Nasal swabs, feces, blood and tissue samples were analyzed for viral RNA by RT-qPCR, and virus isolation was performed on nasal swabs. Serum was analyzed for BCoV antibodies.ResultsThe calves showed mild general signs, and the most prominent signs were from the respiratory system. The overall clinical score corresponded well with the shedding of viral RNA the first three weeks after challenge. General depression and cough were the signs that correlated best with shedding of BCoV RNA, while peak respiratory rate and peak rectal temperature appeared more than a week later than the peak shedding. Nasal shedding preceded fecal shedding, and the calves had detectable amounts of viral RNA intermittently in feces through day 35 and in nasal secretions through day 28, however virus isolation was unsuccessful from day six and day 18 from the two calves investigated. Viral RNA was not detected in blood, but was found in lymphatic tissue through day 42 after challenge. Although the calves were shedding BCoV RNA 21 days after infection the sentinel animals were not infected.ConclusionsProlonged shedding of BCoV RNA can occur, but detection of viral RNA does not necessarily indicate a transmission potential. The study provides valuable information with regard to producing scientifically based biosecurity advices.

Project description:Accumulating evidence indicates that antibodies can protect against some intracellular pathogens. Mycobacterium bovis is an intracellular bacterium, and its cell wall (CW) is essential for its virulence and survival. However, the questions of whether antibodies play a protective role in immunity against M. bovis infection and what effects antibodies specific to the CW of M. bovis have still remain unclear. Here, we report that antibodies targeting the CW of an isolated pathogenic M. bovis strain and that of an attenuated bacillus Calmette-Guérin (BCG) strain could induce protection against virulent M. bovis infection in vitro and in vivo. Further research found that the antibody-induced protection was mainly achieved by promoting Fc gamma receptor (FcγR)-mediated phagocytosis, inhibiting bacterial intracellular growth, and enhancing the fusion of phagosomes and lysosomes, and it also depended on T cells for its efficacy. Additionally, we analyzed and characterized the B-cell receptor (BCR) repertoires of CW-immunized mice via next-generation sequencing. CW immunization stimulated BCR changes in the complementarity determining region 3 (CDR3) isotype distribution, gene usage, and somatic hypermutation. Overall, our study validates the idea that antibodies targeting the CW induce protection against virulent M. bovis infection. This study highlights the importance of antibodies targeting the CW in the defense against tuberculosis. IMPORTANCE M. bovis is the causative agent of animal tuberculosis (TB) and human TB. Research on M. bovis is of great public health significance. Currently, TB vaccines are mainly aimed at eliciting protection by enhancement of cell-mediated immunity, and there are few studies on protective antibodies. This is the first report of protective antibodies against M. bovis infection, and the antibodies had both preventive and even therapeutic effects in an M. bovis infection mouse model. Additionally, we reveal the relationship between CDR3 gene diversity and the immune characteristics of the antibodies. These results will provide valuable advice for the rational development of TB vaccines.

Dataset Information

Cross-protection against a human enteric coronavirus and a virulent bovine enteric coronavirus in gnotobiotic calves.

Publications

Cross-protection against a human enteric coronavirus and a virulent bovine enteric coronavirus in gnotobiotic calves.

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