Abstract
Recombinant influenza viruses are promising viral platforms to be used as antigen delivery vectors. To this aim, one of the most promising approaches consists of generating recombinant viruses harboring partially truncated neuraminidase (NA) segments. To date, all studies have pointed to safety and usefulness of this viral platform. However, some aspects of the inflammatory and immune responses triggered by those recombinant viruses and their safety to immunocompromised hosts remained to be elucidated. In the present study, we generated a recombinant influenza virus harboring a truncated NA segment (vNA-Δ) and evaluated the innate and inflammatory responses and the safety of this recombinant virus in wild type or knock-out (KO) mice with impaired innate (Myd88 -/-) or acquired (RAG -/-) immune responses. Infection using truncated neuraminidase influenza virus was harmless regarding lung and systemic inflammatory response in wild type mice and was highly attenuated in KO mice. We also demonstrated that vNA-Δ infection does not induce unbalanced cytokine production that strongly contributes to lung damage in infected mice. In addition, the recombinant influenza virus was able to trigger both local and systemic virus-specific humoral and CD8+ T cellular immune responses which protected immunized mice against the challenge with a lethal dose of homologous A/PR8/34 influenza virus. Taken together, our findings suggest and reinforce the safety of using NA deleted influenza viruses as antigen delivery vectors against human or veterinary pathogens.
Highlights
Influenza A viruses (Orthomyxoviridae) have two glycoproteins anchored on the viral envelope: hemagglutinin (HA) and neuraminidase (NA)
To assert if the generated virus is able to trigger immune response in human epithelial cells we evaluated the induction of type I and III interferons in A549 cells infected with PR8 or recombinant virus harboring a truncated NA segment (vNA-D) virus in the presence of exogenous neuraminidase or incubated with the same media without virus (VcNA treated control)
The results depicted in figure 1C show that both PR8 and recombinant vNA-D viruses were able to induce type I and III interferons, which attained their maximal fold induction at 24 hours postinfection
Summary
Influenza A viruses (Orthomyxoviridae) have two glycoproteins anchored on the viral envelope: hemagglutinin (HA) and neuraminidase (NA). Recombinant influenza viruses have been proven to be very efficient as antigen delivery vectors [2,3]. Some strategies have already been developed to generate recombinant influenza viruses, most of them are hampered by retention of their original virulence [4,5]. Fuji and colleagues generated recombinant influenza viruses harboring a partially deleted neuraminidase segment, where its catalytic region was replaced by a foreign sequence [6,7]. Influenza viruses lacking functional neuraminidase have been found to be highly attenuated in wild type mice, the inflammatory response triggered by those viruses, as well as their safety in immunocompromised hosts remains to be evaluated. Influenza viruses lacking functional neuraminidase have been found to be highly attenuated in wild type mice, the inflammatory response triggered by those viruses, as well as their safety in immunocompromised hosts remains to be evaluated. [6,7,8]
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