Funded Grants

Mechanisms and evolution of complex life history traits in bacterial viruses

Bacterial viruses (aka "bacteriophages" or "phages") are the most abundant organisms on the planet. There are more phages in a handful of soil than there are humans on Earth. In the process of exclusively infecting bacteria, phages modify the dynamics of global biogeochemical cycles, affect the time course of human infectious diseases, and are responsible for the shuttling of novel genes throughout the microbial world. Yet, it is only in the past 10 years that scientists have begun to pay attention to what phages do in the environment in addition to how they can used as tools of molecular biology in the lab. Like human viruses, phages need not always kill the host they infect. When phages infect a bacterial cell, they redirect their bacterial host to produce viral proteins. These viral proteins determine the fate of the host cell: whether the cell lives with viral genetic material integrated into it, or whether it dies and viruses burst out ready to infect again.

The decision of whether to kill a host cell and produce progeny or enter a latent period is the most prominent example of a viral life history trait, and one that is shared by phages and human pathogens such as herpes simplex viruses. Phages exhibit a diverse range of strategies, some will never enter latency, whereas other will preferentially do so. Although phages possess no native metabolism, their choice of how to exploit a cell is seemingly reactive. Upon infection, certain phages manage to "choose" whether to kill a cell or enter latency depending on the state of the host cell. One of the factors that influences this choice is how many other phages have already infected a cell, implying that phages can somehow count or sense other phages. The idea that viruses can communicate and act in a collective manner has never been seriously considered. However, we recently demonstrated the first mechanistic principle by which phages can make collective decisions inside host cells. These decisions are central to the unfolding of a phage's life history.

How then do phages make collective decisions? Importantly, the viral proteins produced by a host cell are communal, diffusing and interacting regardless of which virus encoded the message to produce them. Thus when multiple phages infect the same cell, they can "talk" to each other via the interactions of viral proteins and viral genomes. As the number of viruses increases, greater cross-talk allows a group of viruses to alter a cell's fate in a dramatic and nonlinear fashion. For example, infecting a cell with one or two phages might trigger the production of proteins leading to cell death and phage release. However, infecting the same cell with three or more phages would cause one of them to integrate its genome into that of the host.

The finding that multiple infections can change behavior within a cell indicates that viral infections are not static, but rather may react to changes in population level dynamics. This response is, in principle, an evolvable life history trait of bacterial viruses conferring some selective benefit to strains which adopt this strategy. Hence, phages are likely to have a large variety of strategic responses to the question: "Should we kill our host or integrate into it?" Such strategic responses are the viral analogue of the complex life history traits possessed by higher organisms such as the age of reproductive maturation, number of progeny, and energy invested in offspring. However, phage adaptive responses to coinfection can also be antisocial, as may arise when phages of different strains infect the same host cell.

We have only scratched the surface of a fundamental understanding of the mechanisms and evolution of complex life history traits in phages. It is inconceivable that all phages behave like the organisms cultured in laboratories for which detailed numerical models can be built. But what our research suggests is that whenever phages multiply infect host cells, the number of viral genes changes, and this change in viral gene copy number can have dramatic effects on precisely how a group of viruses exploits a given cell. This finding is complementary to previous research which demonstrated that phage exploitation of bacteria depends upon the physiological state of the infected cell.

The choice of whether to burst from a cell or to remain/enter a latent state is a key feature of viruses from phages to human pathogens. This choice is just one viral decision process for which viruses may respond reactively to their own numbers and the physiological state of their host. Viruses may produce a few progeny or many. They may invest more cell resources to each viral progeny ensuring that they can survive longer outside the cell. They may take a highly variable time to burst from a cell. Ecologists have long advocated a systems perspective though they often lacked the data to support quantitative testing of dynamic models. Bacterial viruses are an ideal model system to integrate the new science of systems biology with the unifying perspectives of ecology.

Our principle aim is to develop a theoretical framework to predict how viral decisions vary with environmental context. We will work on modeling phages which have been extensively studied in the laboratory, as well as collaborate with environmental microbiologists to analyze the patterns of life history traits observed in naturally occurring phages. In so doing, we will address the following questions: (1) How do the exploitation strategies of viruses depend on the mechanisms of gene regulation and biophysical constraints? (2) How do the life history traits associated with viral exploitation evolve in distinct ecological contexts? (3) What is the empirical variability of life history traits in naturally occurring phages? We will accomplish this body of research in three stages.

First, we will extend gene regulatory models of viral life history decision making to include greater realism in the link between ecological dynamics and within-cell exploitation. What happens when different strains of viruses infect the same cell and they differ in terms of viral proteins produced and sensed? In essence, we will begin to address the questions that emerge when groups are comprised of mixed autonomous agents. The types of collective behaviors favored when organisms are allowed to vary their strategies is a hallmark of many game theoretic scenarios in which social and antisocial behaviors can emerge. In the process, we will also aim to elucidate the role and limits of random effects in viral reproductive strategies.

Next, we will integrate within-cell models of the systems biology of viral exploitation with ecological models of between-cell dynamics. We have worked extensively in the past on the evolutionary and population dynamics of bacterial viruses, demonstrating how traits involved in the interaction of viruses and hosts respond to changing selection pressures. Here, we will use a multi-scale framework to assess how ecological regimes select for complex viral life history traits. These traits then influence the number and diversity of their microbial hosts and other viruses, which then feeds-back into a new selective environment for both hosts and phages. Key to this component of research is a recognition that the evolution of strategies in diverse populations must be answered using the tools of game theory not of optimization. The central concept in game theory is that optimal strategies depend on the strategies used by other players. In this case, the emergent strategy or coalition of life history strategies depends on the diversity and population abundances of viruses and available hosts in the environment.

Finally, we will collaborate with microbiologists to assess the diversity of complex life history traits of naturally occurring phages. The use of high-throughput genomic screening methods have revealed a vast genetic diversity among phages. Yet, we still know very little about what all these phages are doing to the bacterial communities they infect. Building upon large-scale empirical studies of viral genetic diversity, we will aim to assess the functional diversity of phages, focusing on the variability in life history traits and their trade-offs. We will develop methods to extract estimates of the variation of essential life history traits in viral communities based on high-throughput assays. The challenge will be to estimate this variation for viruses whose bacterial host cannot even be cultured. This is not an easy task, but already we have developed a promising series of methods which shows how strain level information can be extracted from community level observations. We envision that evolutionary models will play a crucial role in analyzing observed patterns of life history variation and their relationship to environmental context.

Ultimately, this research program will take a multi-scale approach to understanding the diverse, often collective, mechanisms by which viruses exploit bacterial cells. In the process, we aim to provide deeper insight into the dynamics and evolution of a central, yet poorly understood, component of the Earth's biosphere.
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