- Open Access
Host-hijacking and planktonic piracy: how phages command the microbial high seas
© The Author(s). 2019
- Received: 20 April 2018
- Accepted: 17 January 2019
- Published: 1 February 2019
Microbial communities living in the oceans are major drivers of global biogeochemical cycles. With nutrients limited across vast swathes of the ocean, marine microbes eke out a living under constant assault from predatory viruses. Viral concentrations exceed those of their bacterial prey by an order of magnitude in surface water, making these obligate parasites the most abundant biological entities in the ocean. Like the pirates of the 17th and 18th centuries that hounded ships plying major trade and exploration routes, viruses have evolved mechanisms to hijack microbial cells and repurpose their cargo and indeed the vessels themselves to maximise viral propagation. Phenotypic reconfiguration of the host is often achieved through Auxiliary Metabolic Genes – genes originally derived from host genomes but maintained and adapted in viral genomes to redirect energy and substrates towards viral synthesis. In this review, we critically evaluate the literature describing the mechanisms used by bacteriophages to reconfigure host metabolism and to plunder intracellular resources to optimise viral production. We also highlight the mechanisms used when, in challenging environments, a ‘batten down the hatches’ strategy supersedes that of ‘plunder and pillage’. Here, the infecting virus increases host fitness through phenotypic augmentation in order to ride out the metaphorical storm, with a concomitant impact on host substrate uptake and metabolism, and ultimately, their interactions with their wider microbial community. Thus, the traditional view of the virus-host relationship as predator and prey does not fully characterise the variety or significance of the interactions observed. Recent advances in viral metagenomics have provided a tantalising glimpse of novel mechanisms of viral metabolic reprogramming in global oceans. Incorporation of these new findings into global biogeochemical models requires experimental evidence from model systems and major improvements in our ability to accurately predict protein function from sequence data.
- AMGs, marine
- Nucleotide scavenging
- Biogeochemical cycling
- Host-virus interactions
Based on their extraordinary abundance and diversity, J.B.S. Haldane once quipped that ‘The Creator would appear as endowed with a passion for stars, on the one hand, and for beetles on the other’ . In comparison, the Creator’s zeal for viruses would make stars and beetles appear to be a side-project performed with perfunctory indifference. It is estimated that there are a million viruses in the ocean for every star in the universe . Assuming an average size of 100 nm in length, placed end-to-end marine viruses would stretch to our nearest neighbour star (Proxima Centauri, 4.22 light years away) and back. The vast majority of these viruses are obligate parasites of marine bacteria - the primary drivers of global carbon biogeochemistry . With 1028 infections occurring per day in the oceans , these bacteriophages are responsible for up to 50% of bacterial mortality  and the daily release of 12.4 μg of organic carbon per litre of seawater, or an estimated 10 billion tons globally per day [5, 6]. Release of cellular substrates through lysis have been shown to stimulate surviving members of the community and increase microbial productivity through nutrient recycling [7–9]. Thus, marine viruses are a major component of global carbon cycling.
Lysis and release of cellular material as dissolved organic matter is only the final step of a complex host-virus interaction where the invading pathogen can manipulate host metabolism and alter its phenotype to favour viral replication at the expense of host function. Once a virus has overcome host defences, lytic viral infection typically involves a shut-down of host metabolism, followed by degradation of macromolecules and scavenging of intracellular resources. Virally encoded ‘Auxiliary Metabolic Genes’ (AMGs) are expressed during infection to augment and redirect energy and resources towards viral production [10–13]. These AMGs are often repurposed versions of host-genes picked up during ancestral infections, evolving separately to improve viral fitness [14, 15]. Conservation of AMGs across phage lineages suggests that not only are such genes critical for viral success, but that viral modulation of marine nutrient cycling via metabolic hijacking is an important, but understudied component of biogeochemical cycles. Furthermore, viral replication through lysis is only beneficial to the virus if upon release, its progeny can infect other susceptible cells. This process is governed by host availability and density-dependent selection. In resource-limited or otherwise challenging environments viral fitness may be better served by maximising host fitness until such time as the conditions are met for a lytic approach to be favourable. Single amplified genomes of bacterial cells from marine environments have shown that ~ 1/3 contain viral sequences [16, 17]. Between 28 and 71% of marine bacterial isolates contain inducible prophage, with greater occurrence of lysogeny associated with low-nutrient environments [18–21]. In extreme environments such as hot-springs, nearly all cells contained a viral signature . In lysogenic cells, the viruses are not passive passengers, but actively promote the host fitness through expression of viral genes increasing metabolic flexibility, enabling antibiotic resistance, toxin production and immunity to similar viruses  (reviewed in ). The aim of this review is to illustrate the different ways in which bacteriophages alter the function of their hosts, emphasising how marine viruses modify the metabolism of environmentally relevant bacteria and in turn their impact on global carbon biogeochemistry. We also discuss how novel molecular methods are providing greater insight into the breadth and scale of viral hijacking in the global ocean.
In March 1723, the pirate Captain Low approached a Spanish merchant ship in the Bay of Honduras under the Spanish colors. Once they drew near the vessel, they:
‘hauled them down, hoisted up their black flag, fired a broadside and boarded her’ .
Indeed, it was commonplace for pirates to sail under false flags of different countries in order to prevent their targets from identifying them as a threat until it was too late. Similarly, viruses encode genetic tools to prevent a hijacked host from recognising an infection and taking appropriate action. As internal concentrations of cellular substrates decrease, cells can undergo a ‘stringent response’ where they down-regulate growth functions and, in some cases, initiate programmed cell death, regulated by the toxin-antitoxin pair MazEF. Nutrient limitation results in uncharged tRNAs, which triggers increasing concentrations of guanosine tetraphosphate (ppGpp). This in turn inhibits RNA transcription and promotes transcription of the global stress response regulator RpoS, shifting the cell into stationary phase . Increasing concentrations of ppGpp also increases production of MazF, a toxin that inhibits protein synthesis (resulting in cell dormancy). In some circumstances, MazF also initiates programmable cell death, with different mechanisms used under different stressors such as antibiotic treatment or DNA damage [79, 80]. Programmable cell death is thought to sacrifice a large proportion of a population, so that a small sub-population can survive by recycling released nutrients . Programmable cell death regulated by MazEF has been shown to play a role in the survival of a bacterial population against phage infection. Hazan and Engelberg-Kulka showed that 400 times more viral progeny were produced in ΔmazEF E. coli cells infected with phage P1 compared to wild-type cells. In addition, when lysogens were mixed with non-lysogens, the ΔmazEF cells were susceptible to infection and lysed, whereas the non-lysogen wild-type cells were not infected by the induced phage. They suggested that it is likely the wild-type lysogens were killed by MazEF, preventing viral replication to the benefit of the population . Similar observations of the role of toxin-antitoxin mechanisms for phage resistance were observed in Erwinia carotovora, where expression of the toxin-antitoxin system conferred resistance to a broad range of viruses .
Given its dual role as both a regulator of the stringent response and of MazEF-regulated resistance and cell death, increasing cellular levels of ppGpp pose a clear threat to viral replication. Many viruses are dependent on host RNA transcription for replication, and viral replication has been shown to be drastically reduced or suspended in infected E. coli cells that enter stationary phase . Cell death limits the spread of phages through a population by reducing host density and purges lysogens from the population. Thus, is of little surprise that in the arms-race between viruses and their hosts, the viruses have commandeered a ppGpp regulator to counter host defence mechanisms. MazG has been shown to decrease cellular concentrations of ppGpp in E. coli and thus repress production of MazF . Thus in the host MazG serves as a switch to recover from a starvation response upon return to nutrient replete conditions and to abort programmable cell death. mazG is common in viral genomes from marine environments and has been reported in viruses infecting both heterotrophs [84, 85] and phototrophs [14, 86]. The oligotrophic nature of vast areas of the ocean make it likely that a starvation state for host cells is the norm, resulting in high cellular concentrations of ppGpp and minimal transcription. It is likely that phages overcome this limitation by using virally-encoded MazG to deplete cellular ppGpp concentrations and thus force the infected cell to respond as if it were nutrient-replete, enabling transcription so that it may be hijacked for viral replication . In addition, suppression of programmable cell death may prevent the host population from sacrificing itself in order to limit viral infection. Recent work in has shown that phages can utilise host quorum sensing to coordinate a lytic-lysogenic switch using a phage-derived oligopeptide signal  . Given that programmable cell death has been shown to be orchestrated through quorum sensing , and that suppression of mazEF expression increases host resistance to phages, it is conceivable that infecting viruses can use MazG to manipulate ppGpp concentrations and thus maintain the susceptibility of hosts within a population to subsequent infection by viral progeny. In pirate terms, viruses have evolved the capacity to sail under a false flag, disabling host alarm systems until it is too late. Further experimental evidence of the use of MazG and its effects on marine populations is required to explore whether this phenomenon is observed in nature.
The current understanding of how viruses hijack host metabolism during infection is the result of both culturing experiments in model systems; and culture-independent techniques such as viral metagenomics. Culture-dependant techniques have significant advantages: Model systems enable us to study the relationship between host and viruses in controlled conditions; viral replication cycles and critical parameters (e.g. host range; burst size) can be defined, and the functionality of viral genes may be determined in vitro. In culture, predator-prey interactions can be isolated from those occurring in complex microbial communities. This reduction in complexity allows for investigation into how transcriptomes, proteomes and metabolites are altered during infection and thus enable a systems-biology approach to understanding complex metabolic cascades and regulation (e.g. [12, 13, 25, 45, 90]. However, many important marine taxa have, to date, resisted efforts to culture them . Consequently, our model systems of host-virus interactions in marine systems are limited to a handful of taxa, with a major focus on the cyanobacteria and a limited number of heterotrophic hosts.
For systems outside of cultured representatives, viral metagenomic studies to date have provided major insights into to viral taxonomic and functional distribution and diversity [30, 32, 47, 53]. Understanding the extent and mechanisms of metabolic hijacking by marine viruses using metagenomic data comes with its own challenges: Firstly, in any viral metagenome there is the possibility of contaminating cellular DNA or randomly packaged host DNA encapsulated in gene transfer agent particles [32, 92]. As viral genomes are assembled from short read data, there is the possibility of cellular functions being misassembled into viral contigs. In such circumstances, the function may be interpreted as a novel AMG acquired by the virus to improve fitness, rather than as an artefact of bioinformatic processing [93, 94], with a concomitant over-estimation in the degree of viral piracy that occurs in marine systems. Secondly, some of the most cosmopolitan and dominant viruses on Earth are challenging to assemble using short-read technology and are under-represented in marine viral metagenomes [95, 96]. Complementary approaches to construct viral genomes from environmental samples such as single cell genomics and the development of long-read viral sequencing can alleviate these problems to some degree. Assembly of short-read data from a genome amplified from a single cell or single virus cell vastly reduces the complexity of the De Bruijn Graph and captures taxa missing from shotgun metagenomic approaches.
This approach has successfully to identify new viruses and novel AMGs [16, 17, 96]. Long-read viral metagenomics  offers the potential to accurately identify putative AMGs as viral, rather than cellular contaminants, by capturing the gene neighbourhood of the AMG to reliably assess its viral origins. Capturing full length viral genomes on single reads is now technically feasible and will provide a powerful tool to explore how AMGs are distributed within viral populations and how their evolution is impacted by recombination, shown to be the dominant form of mutation in some phages . Long-read metagenomics from cellular fractions will better quantify the extent of lysogeny within a population by capturing integrated viral genomes on single reads.
It is worth noting however, that no matter how sophisticated sequencing methods become, perhaps the greatest barrier to understanding how marine viruses influence cellular metabolism during infection lies in our extremely limited capacity to identify the function of viral genes, in both cultured isolates and genomes constructed from environmental DNA. Whilst machine learning approaches are rising to meet this challenge [32, 99], one must consider that the scale of the ‘known unknowns’ is vast, with 63–93% of protein sequence space lacking functional or taxonomic annotations . < 1% of viral populations in the Pacific Ocean Virome had a closely related taxonomic representative in culture . Methods to identify viral host range through computational methods such as correlative abundance  or nucleotide composition [103, 104], are undergoing rapid development, but must be used cautiously for inferring ecological patterns . Despite these challenges, the last decade has seen a dramatic improvement in our capacity to generate and interpret viral metagenomic data, largely driven by efforts to understand marine systems (e.g. ). This improvement has revealed a growing body of evidence identifying viruses as important agents in global carbon biogeochemical cycles, through: 1) lysis-dependent nutrient cycling and increased community productivity [7–9]; 2) influences on host-substrate interactions through auxiliary metabolic genes, shaped through viral evolution (reviewed in ). Viral metagenomics allows microbial ecologists to directly ascribe such functions to viruses and provides relative quantitation of viral populations and genetic diversity in a way that is challenging from cellular metagenomic data. More recently, these methods have been applied to medical microbiology and have similarly established viruses as an equally important component of the human microbiome alongside their cellular counterparts (reviewed in ). Indeed, there is a growing consensus that our view of microbial ecology must put viruses centre stage as key players in shaping community structure and function. Increasing interest in the role of viruses in microbiomes will undoubtedly catalyse a feedback loop that energises the development of novel bioinformatic and culturing methods. Such tools will ultimately overcome the technical limitations previously outlined, revealing more of the metabolic capacity for cellular piracy encoded within viral sequence space.
The contemporary image of pirates is typically one of swashbuckling, romantic characters of Robert Louis Stevenson’s Treasure Island and J.M. Barrie’s Peter Pan. Piecemeal accounts and a lack of historical records has enabled myth and legend to supersede the violent and unpleasant reality written in Charles Johnson’s A General History of the Robberies and Murders of the Most Notorious Pyrates . Similarly, the relationships between marine viruses and their hosts have been considered through the paradigm of predator and prey, with much research focused on viruses as agents of top-down control. Our understanding of viral impact on host metabolism in marine systems is derived from a few model systems, or inferred from model systems of medically relevant pathogens that have evolved in nutrient-rich environments supporting high cellular densities. It is now clear however that lysogeny is common in marine systems and has the capacity for reconfiguration of host metabolism and increasing host fitness during frequent periods of nutrient limitation. Viral metagenomics continues to offer tantalising evidence of putative mechanisms for viral piracy, but even the most advanced machine learning approaches are limited by comparison to existing model systems. Thus, if we are to better understand the impact of viral metabolic hijacking on global biogeochemical cycles, advances in computational methods must be matched with recent efforts to improve the culturing important marine taxa [108, 109] and their associated viruses, followed by in vitro determination of mechanism and impacts on host and viral fitness. Our efforts will be repaid in full as data is fed back into computational approaches to facilitate the accurate translation of experimentally observed phenotypic changes into impacts on global biogeochemical cycling in our current models.
The authors would like to thank the anonymous reviewers for their critical and constructive comments. The authors would also like to thank Kema Malki (USF) for providing the artwork for Fig. 1.
This work was funded by the BIOS-SCOPE award from Simons Foundation International, and by Natural Environment Research Council (NERC) awards NE/R010935/1 and NE/P008534/1. JWD and HB were funded by NERC GW4+ Doctoral Training Partnerships.
JWD, HB and BT wrote the manuscript; MA provided direction and edits for the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
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