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Transmission of Influenza Virus: What Is Keeping the Next Pandemic at Bay?: Crossing Species


Crossing Species

The distinct receptor specificity and sialic acid linkage expression generally prevent human and avian influenza viruses crossing between the 2 species. However, these restrictions are not insurmountable, and as shown both historically and currently, avian viruses can infect humans and other species.[2] The affinity of HA for its sialic acid ligand is quite low, in the millimolar range, and may rely heavily on the avidity of multiple HA-sialic acid interactions for successful binding and uptake by epithelial cells. A variety of experimental studies have shown that HA proteins can shift between alpha2,3 and alpha2,6 specificities with as few as 2 amino acid changes.[2,3,11] Moreover, avian influenza viruses have been isolated with dual (alpha2,3 and alpha2,6) specificities.[3]

Like the HA specificity, sialic acid linkage expression and distribution are also not absolute. Although alpha2,6-linked sialic acids predominate in the upper respiratory tract of humans, alpha2,3-linked sialic acids are found in abundance in the lower respiratory tract. Generally, influenza virus infection is initiated and restricted to the upper respiratory tract, but alpha2,3-linked sialic acid expression in the lower respiratory tract could allow for infection of humans with avian influenza viruses if they are exposed to sufficient amounts of the avian influenza virus. Avian influenza virus infection of the lower respiratory tract could thus result in serious disease, but may not result in efficient shedding or transmission because there may be minimal virus in aerosol droplets generated by sneezing and coughing without upper respiratory tract infection.[2]

Intermediary hosts provide another possible path for avian influenza viruses to enter humans. Swine have long been hypothesized as a path for avian influenza viruses to enter human populations. The epithelial cells in the swine respiratory tract express both alpha2,3- and alpha2,6-linked sialic acids, and swine are susceptible to infection by both human and avian influenza viruses.[2] This provides the opportunity for pigs to serve as "mixing vessels" by enabling reassortment if coinfected with human and avian influenza viruses. Also, when influenza viruses infect new species, constant mutation allows the virus to adapt to the receptors present, so that a virus with an alpha2,3 specificity could acquire an alpha2,6 specificity if both linkages are present.

Receptor specificity is not the only determinant of transmissibility or species specificity. Three proteins, acidic polymerase and basic polymerase 1 and 2 (PA, PB1, and PB2, respectively), form the influenza RNA-dependent, RNA polymerase complex. Investigations of the 1918 Spanish influenza and avian influenza viruses have suggested that changes in the polymerase complex are critical for replication in humans.[2-4] Mutations in the HA and NA of influenza virus can reduce the requirement for tissue-specific proteases for replication. This can allow virus dissemination and/or replication in more and different cell types and/or tissues, providing the opportunity for additional mutation, shedding, and transmission.[2-4]

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