Determinants of North American low pathogenic avian influenza virus tropism
Pickens, Jennifer Ann
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Avian influenza viruses are endemic in wild aquatic birds and were generally thought to be apathogenic in humans until the 1997 outbreak of an extremely virulent highly pathogenic avian influenza (HPAI) H5N1 virus that resulted from direct transmission of a solely avian virus to humans. Since then, much of the research has concentrated on a limited number of HPAI subtypes and little is known about the pandemic potential of low pathogenic avian influenza (LPAI) strains from the natural reservoir. Most LPAI require exogenous trypsin to replicate in cell culture and is often an indicator of potential pathogenicity. Here a collection of 419 North America LPAI isolates was examined for their ability to replicate independent of exogenous trypsin in cell culture. Approximately 10% of the isolates replicated to high viral titers in various mammalian cell lines independent of trypsin. Two LPAI isolates, RT/645 (H1N9) and RT/625 (H6N1) replicated and induced pulmonary lesions in the ferret and mouse model systems without prior adaptation. The objective of this research was to examine the genetic features that mediate tropism and replication capacity of selected LPAI isolates, as well as host features that contribute to trypsin independent phenotype and the transmission observed in mammals. A subset of twenty-three LPAI isolates that exhibited the trypsin independent phenotype were examined and all maintained the classical avian monobasic HA cleavage site and α2,3-linked sialic acid binding affinity. The trypsin independent phenotype did not appear to be mediated by the viral hemagglutinin or neuraminidase glycoproteins alone but was instead facilitated by virus infection. Using a protease inhibitor screen, the RT/645 and RT/625 isolates were shown to induce alternative proteases to mediate HA cleavage independent of serine proteases and exogenous trypsin. It is not clear why some LPAI isolates induce proteases while other viruses do not. It is certain that not all LPAI viruses adhere to the protease requirements described in the literature for proteolytic HA activation. These studies help to provide a better understanding of the genotypes and/or phenotypes associated with avian influenza viruses that infect, replicate, and transmit in mammalian cell culture, human airway cell cultures, and ferrets.