Evolving cell death in the virus- infected nervous system

In a recent article1xAltruistic cell suicide and the specialized case of the virus-infected nervous system. Allsopp, T.E and Fazakerley, J.H. Trends Neurosci. 2000; 23: 284–290Abstract | Full Text | Full Text PDF | PubMed | Scopus (37)See all References, Allsopp and Fazakerley presented evidence supporting the view that the death of nerve cells upon infection with virus might be viewed as an adaptation by the host to minimize the spread of infection throughout the nervous system. Such ‘altruistic’ cell suicide will presumably have evolved through kin selection2xThe genetical evolution of social behaviour. Hamilton, W.D. J. Theor. Biol. 1964; 7: 17–52Crossref | PubMedSee all References among clonal cell lineages, whereby infected cells not contributing directly to the germ line undergo apoptosis, and thereby reduce the impact of infection on the fitness of the organism as a whole. This assumes that the loss of a few infected cells outweighs the potential cost of a more sweeping infection. Allsopp and Fazakerley highlight the intriguing state-dependent sensitivity of cells to undergo cell death, where immature neurones are more susceptible to apoptosis than mature neurones.Given such an evolutionary conflict of interest between a parasite and its host, it is often useful to characterize in formal terms the parametric dependencies of the interaction. In an earlier paper3xThe evolution of virus induced apoptosis. Krakauer, D.C and Payne, R.J.H. Proc. R. Soc. London Ser. B. 1997; 264: 1757–1762Crossref | PubMed | Scopus (16)See all References, Robert Payne and I sought to derive mathematical conditions for the induction of apoptosis by either a virus or the infected cell. It is often uncertain which party initiates cell death, and hence one cannot always assume that apoptosis is in the host's best interest. Apoptosis could be undesirable for both the virus and the host, or even benefit the virus to the detriment of the host. The mathematical model seeks to classify the outcomes of the infection into host-induced, versus virus-induced cell death, and relates these outcomes to the productivity of infection, the average life span of the cell and the leakage of virions during apoptosis.The mathematical model considers uninfected cells, free virus and infected cells. Upon infection, the host cells and the virus both have access to pathways culminating in expression of pro-apoptotic genes. Infected cells have a natural (non-apoptotic) death rate described by the rate parameter μ. Virions are released from infected cells at a rate α. Upon programmed death of the cell, a quantity k virions are released. With these three parameters one can derive the expression:The right-hand side of this equation can be interpreted as the average number of virions produced by the infected cell without the induction of cell death (or lysis) minus the average number of virions produced upon cell death alone. The sign and magnitude of Δ provides a measure of the contribution to virus fitness of each of these modes of replication. When Δ > 0, increasing the rate of apoptosis is directly beneficial to the host, as the total viral load will be diminished. When Δ 0. This lends theoretical support to the arguments and evidence of Allsopp and Fazakerley.These models have assumed a well mixed population in which virions have access to the entire population of susceptible nerve cells. The topology of connections among cells is expected to have an impact on the benefits of apoptosis. Michael Stumpf and I have explored the effects of apoptosis on the propagation of prion infection through the central nervous system4xMapping the parameters of prion-induced neuropathology. Stumpf, M and Krakauer, D.C. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 10573–10577Crossref | PubMedSee all References. While current evidence suggests that prions are very different to viruses – in that they replicate through some form of autocatalytic polymerization – the dynamics of infection can be shown to follow very similar rules to viruses5xPrion infection dynamics. Nowak, M et al. Integr. Biol. 1998; 1: 3–15CrossrefSee all References. By developing models in which the connectivity among cells can be varied systematically, we find that the pathology varies according to whether the prion directly induces apoptosis, or whether the host cell dies through some vital loss of function. Small increases in the density of connections among cells, lead to large increases in the rate at which cells become infected. And increases in the rates of apoptosis, reduce the rate of infection most effectively in more sparsely connected networks. These topology-dependent sensitivities might help to explain the regional variability in cell death propensity in the brain.In summary, the degree to which nerve cell apoptosis should be viewed as a case of ‘altruistic suicide’ in response to virus infection must be related to the productivity of infection, the lifespan of infected cells and the density of connections among cells. Subtle variations in these parameters can transform apoptosis from an adaptation of benefit to the host to one where the infecting virus gains and the host only suffers.