Fig 1.
This essay focuses on the most extreme bottleneck in viral disease emergence: The replication of animal viruses in their first human host.
On the left is a typical representation of the zoonosis pyramid, modified from [1,3–5]. The concept here is that animal viruses become increasingly human-adapted through a series of evolutionary steps represented from bottom to top. In our view, these steps are best described as 1) random variants arise in the animal reservoir that are capable of replicating themselves in humans, 2) variants are then selected for the ability to transmit between people, and 3) sometimes, as in the case of HIV-1 group M [12], these viruses become stably maintained in humans and are divorced from their former animal reservoir. The pyramid shape properly demonstrates that increasingly fewer viruses progress through the different stages of zoonosis but is misleading in that it doesn’t represent the scale of probabilities in these events. Instead, based on the arguments laid out in the essay, the pyramid should more correctly be depicted as a pinhole. As shown on the right, our current understanding is that <0.1% of animal viruses have any ability to replicate in humans (step 1), and then fewer still are able to meet the relevant criteria as the process continues upwards. The bottlenecks leading to the latter two steps don’t seem to be as extreme. One study of zoonotic pathogens (those already at step 1) found that 33% are transmissible between humans (step 2), and 3% spread so effectively that they become permanently sustained in humans (step 3) [10]. Herein, we discuss how experimental virology and an understanding of host–virus interactions render clear the reasons for the most extreme bottleneck in this process (green arrow).
Table 1.
Animal models of human viruses as examples of attempted “reverse zoonoses.”
Table 2.
Some of the human proteins known to block replication of animal viruses.
Table 3.
Examples of animal viruses that are known to have infected humans.
Fig 2.
Receptors used by viruses are under positive selection at the host–virus interaction interface.
The cocrystal structures are shown for four human cellular receptors (green) in complex with the surface glycoproteins (blue) of four viruses that use these receptors to enter cells. In each case, we analyzed the evolution of the receptor gene throughout the speciation of the animals that have served as long-term reservoirs for each of these viruses (rodents, bats, and primates in these four cases). In those analyses, amino-acid positions in the receptors that are evolving under positive selection (dN/dS > 1; red spheres) were identified that mapped directly to the interaction interface with the indicated viruses [93–96]. These residue positions are rapidly evolving, which means that each species within these animal groups tends to encode unique amino acids at these positions. This explains why viruses often have to accumulate mutations in their surface glycoprotein that allow them to use the version of their receptor in a new species. Cocrystals shown are TfR1 (PBD: 3KAS [103]), ACE2 (PDB: 2AJF [104]), CD4 (PDB: 1RZJ [105]), and NPC1 (PDB: 5F1B [106]). The rendering of the CD4 cocrystal is from [92]. ACE2, angiotensin I converting enzyme 2; dN, rate of nonsynonymous substitution; dS, rate of synonymous substitution; NPC1, NPC intracellular cholesterol transporter 1; PDB, Protein Data Bank; SARS, severe acute respiratory syndrome; TfR1, transferrin receptor 1.
Fig 3.
The emergence of the 1918 flu during World War I.
This photo shows soldiers at Camp Funston in Fort Riley, Kansas, in late November of 1918. This camp is where some of the very first cases of the 1918 flu were reported, earlier in the year of 1918, and then again just around the time that this photo was taken [118]. Based on this, some of the soldiers shown are very likely infected with the 1918 influenza virus at the time the photo was taken. The soldiers are watching a Thanksgiving football game, and it is interesting to speculate that this dense human crowd may have set the 1918 flu, a respiratory virus, onto its disastrous course. Photo reproduced with permission from the National World War I Museum and Memorial, Kansas City, Missouri, U.S.A.