Molecular Determinants of Adaptation of Highly Pathogenic Avian Influenza H7N7 Viruses to Efficient Replication in the Human Host

Abstract

Two viruses isolated during the highly pathogenic avian influenza (HPAI) H7N7 virus outbreak in TheNetherlands in 2003, one isolated from a person with conjunctivitis and one from a person who died as the result of infection, were used for an in vitro study of influenza A virus pathogenicity factors. The two HPAI H7N7 viruses differed in 15 amino acid positions in five gene segments. Assays were designed to investigate the role of each of these substitutions in attachment and entry, transcription and genome replication, and virus production and release as determined by hemagglutinin (HA), polymerase proteins, nonstructural protein 1 (NS1), and neuraminidase (NA). These in vitro studies confirmed the roles of the E627K substitution in basic polymerase 2 (PB2) and the A143T substitution in HA in pathogenicity observed in a mouse model previously. However, the in vitro studies identified a contribution of acidic polymerase (PA) and NA to the efficient replication in human cells of the fatal case virus, despite the fact that these are rarely marked as determinants of pathogenicity in in vivo studies. With the exception of PB2 E627K, all substitutions contributing to enhanced replication of the fatal case virus in vitro were present in poultry viruses prior to transmission to the human fatal case, indicating that viruses with enhanced replication efficiency in the mammalian host can be generated in poultry. Thus, detailed in vitro analyses of mutations facilitating replication of avian influenza viruses in mammalian cells are important to assess the zoonotic risk posed by these viruses and, in addition, highlight the value of in vitro studies to complement animal models.

First field evidence of the evolution from a non-virulent HPR0 to a virulent HPR-deleted infectious salmon anaemia virus

“…Although the role of other proteins than HE and F in ISAV pathogenesis so far remains elusive, further mutations of other proteins are expected to increase virulence [11,22,42,43] as demonstrated in other members of the orthomyxovirus family, e.g. influenza viruses [44][45][46][47][48].…”

Structure and Receptor Complexes of the Hemagglutinin from a Highly Pathogenic H7N7 Influenza Virus

“…The Glu627Lys substitution in the PB2 of NL219 virus was reported previously as a main determinant of virus pathogenicity and tissue distribution in a mouse model, while a Ala125Thr substitution on the HA generated a consensus motif for N-linked glycosylation of Asn123. This change was correlated with increased replication efficiency and wider tissue distribution of NL219 virus (HA numbering used herein is based on the mature protein) (13,32).…”

Within-host competitive interactions as a mechanism for the maintenance of parasite diversity

“…These traits can be exclusive to the pathogen, such as a greater number of nutrient receptors or increased replication machinery (e.g. [6,7]). Alternatively, faster growth rate can be achieved by the release of compounds that enable degradation of host tissues or sequestration of nutrients [8,9].…”