Molecular constraints to interspecies transmission of viral pathogens

Abstract

The successful replication of a viral pathogen in a host is a complex process involving many interactions. These interactions develop from the coevolution of pathogen and host and often lead to a species specificity of the virus that can make interspecies transmissions difficult. Nevertheless, viruses do sporadically cross species barriers into other host populations, including humans. In zoonotic infections, many of these interspecies transfer events are dead end, where transmission is confined only to the animal-to-human route but sometimes viruses adapt to enable spread from human to human. A pathogen must overcome many hurdles to replicate successfully in a foreign host. The viral pathogen must enter the host cell, replicate with the assistance of host factors, evade inhibitory host products, exit the first cell and move on to the next, and possibly leave the initial host and transmit to another. Each of these stages may require adaptive changes in the pathogen. Although the factors that influence each stage of the replication and transmission of most agents have not been resolved, the genomics of both hosts and pathogens are now at hand and we have begun to understand some of the molecular changes that enable some viruses to adapt to a new host.

Figure 1. Receptor specificities of influenza A viruses affect host range.

Although the primary reservoir of influenza A viruses is the aquatic birds of the world, stable lineages are present in other hosts such as humans. Analysis of the receptor-binding preferences of viruses from each of these hosts has shown that human and avian viruses have preferences for different conformations of the cellular receptor, sialic acid. Because of this, viruses adapted to humans replicate in and transmit well to other humans, but poorly to aquatic birds. Conversely, viruses adapted to aquatic birds replicate in and transmit well to other aquatic birds, but poorly to humans. Swine seem to be unique in terms of influenza A ecology and show an intermediate susceptibility to both human and avian viruses.

Figure 2. Distinct cellular tropism of influenza viruses in differentiated cultures of human tracheobronchial epithelial cells.

The cultures were infected with either human virus (left) or duck virus (right), fixed 7 h after infection, and immunostained for both virus antigen (brown) and cilia of ciliated cells (gray). Whereas the human virus preferentially infects nonciliated cells, the duck virus infects ciliated cells.

Figure 3. Molecular mechanisms for generating viral diversity.

Viruses have evolved three main mechanisms for generating diversity on replication. (a) During replication, single point mutations are incorporated into one or more genomic positions as a result of a lack of proofreading activity of the viral polymerase. (b) During recombination, foreign genetic material is incorporated into the viral genome through mechanisms such as template switching during replication. (c) During reassortment, which occurs on dual infection of a cell with segmented genome viruses, whole gene segments can be swapped. All three mechanisms, which are not exclusive, may result in viruses that have new biological properties, such as new host range and pathogenic potential.