Potential for Low-Pathogenic Avian H7 Influenza A Viruses To Replicate and Cause Disease in a Mammalian Model

Abstract

H7 subtype influenza A viruses are widely distributed and have been responsible for human infections and numerous outbreaks in poultry with significant impact. Despite this, the disease-causing potential of the precursor low-pathogenic (LP) H7 viruses from the wild bird reservoir has not been investigated. Our objective was to assess the disease-causing potential of 30 LP H7 viruses isolated from wild avian species in the United States and Canada using the DBA/2J mouse model. Without prior mammalian adaptation, the majority of viruses, 27 (90%), caused mortality in mice. Of these, 17 (56.7%) caused 100% mortality and 24 were of pathogenicity similar to that of A/Anhui/1/2013 (H7N9), which is highly pathogenic in mice. Viruses of duck origin were more pathogenic than those of shorebird origin, as 13 of 18 (72.2%) duck origin viruses caused 100% mortality while 4 of 12 (33.3%) shorebird origin viruses caused 100% mortality, despite there being no difference in mean lung viral titers between the groups. Replication beyond the respiratory tract was also evident, particularly in the heart and brain. Of the 16 viruses studied for fecal shedding, 11 were detected in fecal samples. These viruses exhibited a strong preference for avian-type ␣2,3-linked sialic acids; however, binding to mammalian-type ␣2,6-linked sialic acids was also detected. These findings indicate that LP avian H7 influenza A viruses are able to infect and cause disease in mammals without prior adaptation and therefore pose a potential public health risk.IMPORTANCE Low-pathogenic (LP) avian H7 influenza A viruses are widely distributed in the avian reservoir and are the precursors of numerous outbreaks of highly pathogenic avian influenza viruses in commercial poultry farms. However, unlike highly pathogenic H7 viruses, the disease-causing potential of LP H7 viruses from the wild bird reservoir has not been investigated. To address this, we studied 30 LP avian H7 viruses isolated from wild avian species in the United States and Canada using the DBA/2J mouse model. Surprisingly, the majority of these viruses, 90%, caused mortality in mice without prior mammalian adaptation, and 56.7% caused 100% mortality. There was also evidence of spread beyond the respiratory tract and fecal shedding. Therefore, the disease-causing potential of LP avian H7 influenza A viruses in mammals may be underestimated, and these viruses therefore pose a potential public health risk.KEYWORDS H7, influenza, avian viruses, viral pathogenesis

Potent anti-influenza H7 human monoclonal antibody induces separation of hemagglutinin receptor binding head domains

“…Laboratory studies have shown only three amino acids are required to completely change receptor specificity from avian to human, allowing human-to-human transmission and increasing the chance of a new pandemic (8). In fact, an outbreak of H7N9 virus in China in 2013 has been linked to close contact of humans with poultry where chickens, ducks, and pigeons were identified as a reservoir for the virus (7,9). Since then, H7N9 has continued to circulate in poultry reservoirs causing a spike in human infections in recent years (7).…”

“…In fact, an outbreak of H7N9 virus in China in 2013 has been linked to close contact of humans with poultry where chickens, ducks, and pigeons were identified as a reservoir for the virus (7,9). Since then, H7N9 has continued to circulate in poultry reservoirs causing a spike in human infections in recent years (7). Several H7-specific mAbs have been described recently, including H7.137, H7.167, and H7.169, which target highly conserved regions of the HA head adjacent to the RBS (10).…”

The significance of avian influenza virus mouse-adaptation and its application in characterizing the efficacy of new vaccines and therapeutic agents

“…Although all of H7Nx subtypes have been isolated from wild birds, H7N1 [ 50 ], H7N3 [ 51 ], and H7N7 [ 52 ] subtypes have shown high pathogenicity to poultries. Recent studies demonstrated that many LPAI H7 viruses isolated from avian species in Eurasia and North America caused mortality in mice prior to adaptation [ 53 54 55 ], suggesting a potential public health risk. Furthermore, various avian H7 subtypes in combination with N2, N3, N7, and N9 have been introduced into humans through exposure to domestic poultry [ 7 ].…”

“…Like HPAI H5N1, many H7 viruses, including LPAIs, are lethal to mice prior to adaptation [ 53 ]; many studies have demonstrated the adaptation of both HPAI [ 57 58 ] and LPAI [ 59 60 ] H7 viruses in mice to identify genetic determinants of virulence in a mammalian host. Both HPAI and LPAI H7 viruses acquired high virulence in three to seven passages in mice lungs [ 57 59 60 ]; this is slower than HPAI H5N1, but faster than LPAI H5N2 viruses.…”

A DNA Vaccine That Targets Hemagglutinin to Antigen-Presenting Cells Protects Mice against H7 Influenza

“…Viruses isolated from human cases, perhaps including secondary cases of human transmissions, show only a few accumulated mutations in surface glycoproteins ( 2 ). Thus, it is difficult to predict the antigenic determinants of transmissibility that are needed to break the zoonotic barrier and also how these would influence the viral pathogenicity in humans ( 3 ). However, the human population is presently serologically naive toward H7 influenza; therefore, the potential acquisition of mutations enabling efficient human-to-human transmission could have a devastating effect.…”