Project description:RNA interference (RNAi) is a key antiviral immune mechanism in eukaryotes. However, in vertebrates such as birds and mammals, antiviral RNAi has only been observed in cells with poor interferon systems (stem cells and oocytes) or in viral suppressors of RNAi (VSR) deficiency virus infections. Our research originally discovered that infecting macrophages with wild-type coronavirus (Infectious bronchitis virus, IBV) and influenza viruses (Avian influenza virus, AIV) can trigger RNAi antiviral immunity and produce a certain amount of virus-derived siRNA (vsiRNA). These vsiRNAs have an inhibitory effect on the virus and carry out targeted silencing along the Dicer-Ago2-vsiRNA axis. Notably, these vsiRNAs are distributed throughout of the virus’s entire genome, with a predilection for A/U at the 5’ and 3’ termini of vsiRNA. In addition, Dicer cleavage produces vsiRNA based on the RWM motif, where R represents A/G, W represents A/C, and M represents A/U. Additionally, we discovered that avian LGP2 and MDA5 proteins positively impact the expression of the Dicer protein and the Dicer subtype “DicerM”, which exhibits a potent antiviral activity compared to Dicer itself. Most importantly, the psilencer4.1-plasmid constructed based on vsiRNA combined with nanomaterial polyetherimide (PEI) showed excellent anti-virus activity in specific-pathogen-free (SPF) chickens. These findings show that RNA viruses trigger the production of the vsiRNA in avian somatic cells, which is of great significance for the application of therapeutic vaccines in poultry.
Project description:RNA interference (RNAi) is a key antiviral immune mechanism in eukaryotes. However, in vertebrates such as birds and mammals, antiviral RNAi has only been observed in cells with poor interferon systems (stem cells and oocytes) or in viral suppressors of RNAi (VSR) deficiency virus infections. Our research originally discovered that infecting macrophages with wild-type coronavirus (Infectious bronchitis virus, IBV) and influenza viruses (Avian influenza virus, AIV) can trigger RNAi antiviral immunity and produce a certain amount of virus-derived siRNA (vsiRNA). These vsiRNAs have an inhibitory effect on the virus and carry out targeted silencing along the Dicer-Ago2-vsiRNA axis. Notably, these vsiRNAs are distributed throughout of the virus’s entire genome, with a predilection for A/U at the 5’ and 3’ termini of vsiRNA. In addition, Dicer cleavage produces vsiRNA based on the RWM motif, where R represents A/G, W represents A/C, and M represents A/U. Additionally, we discovered that avian LGP2 and MDA5 proteins positively impact the expression of the Dicer protein and the Dicer subtype “DicerM”, which exhibits a potent antiviral activity compared to Dicer itself. Most importantly, the psilencer4.1-plasmid constructed based on vsiRNA combined with nanomaterial polyetherimide (PEI) showed excellent anti-virus activity in specific-pathogen-free (SPF) chickens. These findings show that RNA viruses trigger the production of the vsiRNA in avian somatic cells, which is of great significance for the application of therapeutic vaccines in poultry.
Project description:RNA interference (RNAi) is a key antiviral immune mechanism in eukaryotes. However, in vertebrates such as birds and mammals, antiviral RNAi has only been observed in cells with poor interferon systems (stem cells and oocytes) or in viral suppressors of RNAi (VSR) deficiency virus infections. Our research originally discovered that infecting macrophages with wild-type coronavirus (Infectious bronchitis virus, IBV) and influenza viruses (Avian influenza virus, AIV) can trigger RNAi antiviral immunity and produce a certain amount of virus-derived siRNA (vsiRNA). These vsiRNAs have an inhibitory effect on the virus and carry out targeted silencing along the Dicer-Ago2-vsiRNA axis. Notably, these vsiRNAs are distributed throughout of the virus’s entire genome, with a predilection for A/U at the 5’ and 3’ termini of vsiRNA. In addition, Dicer cleavage produces vsiRNA based on the RWM motif, where R represents A/G, W represents A/C, and M represents A/U. Additionally, we discovered that avian LGP2 and MDA5 proteins positively impact the expression of the Dicer protein and the Dicer subtype “DicerM”, which exhibits a potent antiviral activity compared to Dicer itself. Most importantly, the psilencer4.1-plasmid constructed based on vsiRNA combined with nanomaterial polyetherimide (PEI) showed excellent anti-virus activity in specific-pathogen-free (SPF) chickens. These findings show that RNA viruses trigger the production of the vsiRNA in avian somatic cells, which is of great significance for the application of therapeutic vaccines in poultry.
Project description:Influenza A viruses (IAVs) present major public health threats from annual seasonal epidemics and pandemics as well as from viruses adapted to a variety of animals including poultry, pigs, and horses. Vaccines that broadly protect against all such IAVs, so-called “universal” influenza vaccines, do not currently exist, but are urgently needed. Here, we demonstrated that an inactivated, multivalent whole virus vaccine, delivered intramuscularly or intranasally, was broadly protective against challenges with multiple IAV hemagglutinin and neuraminidase subtypes in both mice and ferrets. The vaccine is comprised of four beta-propiolactone-inactivated low pathogenicity avian influenza A virus subtypes of H1N9, H3N8, H5N1, or H7N3. Vaccinated mice and ferrets demonstrated substantial protection against a variety of IAVs, including the 1918 H1N1 strain, the highly pathogenic avian H5N8 strain, and H7N9. We also observed protection against challenge with antigenically variable and heterosubtypic avian, swine, and human viruses. Compared to mock vaccinated animals, vaccinated mice and ferrets demonstrated marked reductions in viral titers, lung pathology, and host inflammatory responses. This vaccine approach indicates the feasibility of eliciting broad, heterosubtypic IAV protection and identifies a promising candidate for influenza vaccine clinical development.
Project description:Influenza A viruses (IAVs) present major public health threats from annual seasonal epidemics and pandemics as well as from viruses adapted to a variety of animals including poultry, pigs, and horses. Vaccines that broadly protect against all such IAVs, so-called “universal” influenza vaccines, do not currently exist, but are urgently needed. Here, we demonstrated that an inactivated, multivalent whole virus vaccine, delivered intramuscularly or intranasally, was broadly protective against challenges with multiple IAV hemagglutinin and neuraminidase subtypes in both mice and ferrets. The vaccine is comprised of four beta-propiolactone-inactivated low pathogenicity avian influenza A virus subtypes of H1N9, H3N8, H5N1, or H7N3. Vaccinated mice and ferrets demonstrated substantial protection against a variety of IAVs, including the 1918 H1N1 strain, the highly pathogenic avian H5N8 strain, and H7N9. We also observed protection against challenge with antigenically variable and heterosubtypic avian, swine, and human viruses. Compared to mock vaccinated animals, vaccinated mice and ferrets demonstrated marked reductions in viral titers, lung pathology, and host inflammatory responses. This vaccine approach indicates the feasibility of eliciting broad, heterosubtypic IAV protection and identifies a promising candidate for influenza vaccine clinical development.
Project description:Ducks and wild aquatic birds are the natural reservoirs of avian influenza viruses. However, the host proteome response that causes disease in vivo during infection by the highly pathogenic avian influenza (HPAI) H5N1 virus is still not well understood. In the present study, we compared the proteome response in Muscovy duck lung tissue during 3 day of infection with either a highly virulent or an avirulent H5N1 virus. During infection, proteins involved in immune response of neutrophils and size of cells were increased markedly in the lung by the virulent strain, while the avirulent strain evoked a distinct response, characterized by an increase in proteins involved in cell movement, maturation of dendritic cells, adhesion of phagocytes, and immune response of macrophages.
Project description:Periodic outbreaks of highly pathogenic avian H5N1 influenza viruses and the current H1N1 pandemic highlight the need for a more detailed understanding of influenza virus pathogenesis. To investigate the host transcriptional response induced by pathogenic influenza viruses, we used a functional-genomics approach to compare gene expression profiles in lungs from wild-type 129S6/SvEv and interferon receptor (IFNR) knockout mice infected with either the fully reconstructed H1N1 1918 pandemic virus (1918) or the highly pathogenic avian H5N1 virus Vietnam/1203/04 (VN/1203).
Project description:Hanl Lee & Angelyn Lao. Transmission dynamics and control strategies assessment of avian influenza A (H5N6) in the Philippines. Infectious Disease Modelling 3 (2018).
Due to the outbreaks of Highly Pathogenic Avian Influenza A (HPAI) H5N6 in the Philippines (particularly in Pampanga and Nueva Ecija) in August 2017, there has been an increase in the need to cull the domestic birds to control the spread of the infection. However, this control method poses a negative impact on the poultry industry. In addition, the pathogenicity and transmissibility of the H5N6 in both the birds and the humans remain largely unknown which call for the necessity to develop more strategic control methods for the virus. In this study, we constructed a mathematical model for the bilinear and half-saturated incidence to compare their corresponding effect on transmission dynamics of H5N6. The simulations of half-saturated incidence model were similar to what occurred during the H5N6 outbreak (2017) in the Philippines. Instead of culling the birds, we implemented other control strategies such as non-medicinal (personal protection and poultry isolation) and medicinal (poultry vaccination) ways to prevent, reduce, and control the rate of the H5N6 virus transmission. Among the proposed control strategies, we have shown that the poultry isolation strategy is still the most effective in reducing the infected birds.
Project description:Hanl Lee & Angelyn Lao. Transmission dynamics and control strategies assessment of avian influenza A (H5N6) in the Philippines. Infectious Disease Modelling 3 (2018).
Due to the outbreaks of Highly Pathogenic Avian Influenza A (HPAI) H5N6 in the Philippines (particularly in Pampanga and Nueva Ecija) in August 2017, there has been an increase in the need to cull the domestic birds to control the spread of the infection. However, this control method poses a negative impact on the poultry industry. In addition, the pathogenicity and transmissibility of the H5N6 in both the birds and the humans remain largely unknown which call for the necessity to develop more strategic control methods for the virus. In this study, we constructed a mathematical model for the bilinear and half-saturated incidence to compare their corresponding effect on transmission dynamics of H5N6. The simulations of half-saturated incidence model were similar to what occurred during the H5N6 outbreak (2017) in the Philippines. Instead of culling the birds, we implemented other control strategies such as non-medicinal (personal protection and poultry isolation) and medicinal (poultry vaccination) ways to prevent, reduce, and control the rate of the H5N6 virus transmission. Among the proposed control strategies, we have shown that the poultry isolation strategy is still the most effective in reducing the infected birds.