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Metapopulation structure selects for IFN shutdown MEFs in a 96-well format were inoculated with a limiting dilution of an approximately 1:1 mix of the WT and a NmAb-resistant Δ51 virus. Titres produced by each variant in each well were determined by the plaque assay. Left, Box plots of the WT and Δ51 titres in wells showing only one variant (pure; n = 20 for WT and n = 35 for Δ51) or a mixture of the two variants (mixed; n = 16). The lower and upper limits of the box indicate the twenty-fifth and seventy-fifth percentiles and the middle line shows the median. Whiskers show the tenth and ninetieth percentiles and outlying points are plotted individually. Middle, titres produced in each individual well. Right, overall WT and Δ51 yield in the metapopulation (sum of all wells).
Source publication
Antiviral immunity has been studied extensively from the perspective of virus−cell interactions, yet the role of virus−virus interactions remains poorly addressed. Here, we demonstrate that viral escape from interferon (IFN)-based innate immunity is a social process in which IFN-stimulating viruses determine the fitness of neighbouring viruses. We...
Similar publications
IFN is the most potent antiviral cytokine required for the innate and adaptive immune responses, and its expression can help the host defend against viral infection. Arteriviruses have evolved strategies to antagonize the host cell’s innate immune responses, interfering with IFN expression by interfering with RIG, blocking PRR, obstructing IRF-3/7,...
Citations
... These findings suggest that viral evolution is driven by multiple complex mechanisms rather than a single process. It is a non-linear dynamics influenced by successive selection challenges specific to different stages of infection or epidemic spread [15], involving mechanisms common across various life forms [16,15]. ...
... Some studies have linked this phenomenon to cross-immunoreactivity, explaining prolonged stasis in immune escape and the coexistence of intra-host variant clusters [19,20]. More recent studies propose that specific cooperative interactions among viral variants [21,22,16,15] allow viral populations to adapt as quasi-social systems [16]. ...
... Some studies have linked this phenomenon to cross-immunoreactivity, explaining prolonged stasis in immune escape and the coexistence of intra-host variant clusters [19,20]. More recent studies propose that specific cooperative interactions among viral variants [21,22,16,15] allow viral populations to adapt as quasi-social systems [16]. ...
The paper continues the study of the phenomenon of local immunodeficiency (LI) in viral cross-immunoreactivity networks, with a focus on the roles and interactions between altruistic and persistent viral variants. As always, only the state of stable (i.e. observable) LI is analysed. First, we show that a single altruistic viral variant has an upper limit for the number of persistent viral variants that it can support. Our findings reveal that in viral cross-immunoreactivity networks, altruistic viruses act essentially autonomously from each other. Namely, connections between altruistic viruses do not change neither their qualitative roles, nor the quantitative values of the strengths of their connections in the CRNs. In other words, each altruistic virus does exactly the same actions and with the same strengths with or without presence of other altruistic viruses. However, having more altruistic viruses allows to keep sizes of populations of persistent viruses at the higher levels. Likewise, the strength of the immune response against any altruistic virus remains at the same constant level regardless of how many persistent viruses this altruistic virus supports, i.e. shields from the immune response of the host's immune system. It is also shown that viruses strongly compete with each other in order to become persistent in the state of stable LI. We also present an example for a CRN with stable LI that only consists of persistent viral variants.
... Error threshold in real is exploring the limits of variant possibilities until the end. However, surprisingly, the end does not exist because, unless the mutational input becomes unbearably high due to externally introduced mutagenic agents, quasispecies cooperation and competition always succeed (Domingo-Calap et al. 2019). This is important for virus-host co-evolution because, principally, it opens new ways of adaptation to whatever will happen in the real-life world. ...
The quasispecies theory is a helpful concept in the explanation of RNA virus evolution and behaviour, with a relevant impact on methods used to fight viral diseases. It has undergone some adaptations to integrate new empirical data, especially the non-deterministic nature of mutagenesis, and the variety of behavioural motifs in cooperation, competition, communication, innovation, integration, and exaptation. Also, the consortial structure of quasispecies with complementary roles of memory genomes of minority populations better fits the empirical data than did the original concept of a master sequence and its mutant spectra. The high productivity of quasispecies variants generates unique sequences that never existed before and will never exist again. In the present essay, we underline that such sequences represent really new ontological entities, not just error copies of previous ones. Their primary unique property, the incredible variant production, is suggested here as quasispecies productivity, which replaces the error-replication narrative to better fit into a new relationship between mankind and living nature in the twenty-first century.
... Yet, it has provided the impetus that has driven the study of social behavior since Charles Darwin. Altruism has been widely studied in eukaryotes [15][16][17][18][19][20], prokaryotes [21][22][23][24] and viruses [25], and is thought to underlie the biological success of highly social organisms such as social bees, ants, termites and social wasps, which together account for 75% of the world's total insect biomass [26]. Despite its ubiquitous observations, little is understood about altruism in the context of cancer cells [27,28], where its occurrence can be even more puzzling. ...
Background
Social behaviors such as altruism, where one self-sacrifices for collective benefits, critically influence an organism’s survival and responses to the environment. Such behaviors are widely exemplified in nature but have been underexplored in cancer cells which are conventionally seen as selfish competitive players. This multidisciplinary study explores altruism and its mechanism in breast cancer cells and its contribution to chemoresistance.
Methods
MicroRNA profiling was performed on circulating tumor cells collected from the blood of treated breast cancer patients. Cancer cell lines ectopically expressing candidate miRNA were used in co-culture experiments and treated with docetaxel. Ecological parameters like relative survival and relative fitness were assessed using flow cytometry. Functional studies and characterization performed in vitro and in vivo include proliferation, iTRAQ-mass spectrometry, RNA sequencing, inhibition by small molecules and antibodies, siRNA knockdown, CRISPR/dCas9 inhibition and fluorescence imaging of promoter reporter-expressing cells. Mathematical modeling based on evolutionary game theory was performed to simulate spatial organization of cancer cells.
Results
Opposing cancer processes underlie altruism: an oncogenic process involving secretion of IGFBP2 and CCL28 by the altruists to induce survival benefits in neighboring cells under taxane exposure, and a self-sacrificial tumor suppressive process impeding proliferation of altruists via cell cycle arrest. Both processes are regulated concurrently in the altruists by miR-125b, via differential NF-κB signaling specifically through IKKβ. Altruistic cells persist in the tumor despite their self-sacrifice, as they can regenerate epigenetically from non-altruists via a KLF2/PCAF-mediated mechanism. The altruists maintain a sparse spatial organization by inhibiting surrounding cells from adopting the altruistic fate via a lateral inhibition mechanism involving a GAB1-PI3K-AKT-miR-125b signaling circuit.
Conclusions
Our data reveal molecular mechanisms underlying manifestation, persistence and spatial spread of cancer cell altruism. A minor population behave altruistically at a cost to itself producing a collective benefit for the tumor, suggesting tumors to be dynamic social systems governed by the same rules of cooperation in social organisms. Understanding cancer cell altruism may lead to more holistic models of tumor evolution and drug response, as well as therapeutic paradigms that account for social interactions. Cancer cells constitute tractable experimental models for fields beyond oncology, like evolutionary ecology and game theory.
... In recent years, researchers have made noteworthy observations about cooperative traits in viruses: the collective escape from interferon-based innate immunity (Domingo-Calap et al., 2019) These findings have sparked an interest in studying viral populations from a social perspective, leading to the coining of the term "Sociovirology" (Díaz-Muñoz et al., 2017;Leeks et al., 2021, in press;Sanjuán, 2017Sanjuán, , 2021. In their review, Leeks et al. (2023) Interestingly, quasispecies theory and classical population genetics are essentially equivalent, although they differ in their assumptions about mutation rates and mutational effects (Wilke, 2005). ...
... evasion of cellular interferon-based innate immunity. Interferon-stimulating viruses will assess the status of neighboring viruses to determine whether interferon pathways should be blocked [147]. This decision matrix can yield a loss of viral progeny production which has been termed 'altruistic' in an evolutionary sense [147,148]. ...
... Interferon-stimulating viruses will assess the status of neighboring viruses to determine whether interferon pathways should be blocked [147]. This decision matrix can yield a loss of viral progeny production which has been termed 'altruistic' in an evolutionary sense [147,148]. ...
... Recent research supports this conclusion. Viral escape from interferon-based innate immunity has been demonstrated to be a social process [147]. Domingo-Calap et al. [147] conclude that fundamental viral social rules exist, including cooperation, communication, conflict, and cheating. ...
Neo-Darwinism conceptualizes evolution as the continuous succession of predominately random genetic variations disciplined by natural selection. In that frame, the primary interaction between cells and the virome is relegated to host-parasite dynamics governed by selective influences. Cognition- Based Evolution regards biological and evolutionary development as a reciprocating cognition-based informational interactome for the protection of self-referential cells. To sustain cellular homeorhesis, cognitive cells collaborate to assess the validity of ambiguous biological information. That collective interaction involves coordinate measurement, communication, and active deployment of resources as Natural Cellular Engineering. These coordinated activities drive multicellularity, biological develop-ment, and evolutionary change. The virome participates as the vital intercessory among the cellular domains to ensure their shared permanent perpetuation. The interactions between the virome and the cellular domains represent active virocellular cross-communications for the continual exchange of resources. Modular genetic transfers between viruses and cells carry bioactive potentials. Those exchanges are deployed as nonrandom flexible tools among the domains in their continuous confrontation with environmental stresses. This alternative framework fundamentally shifts our perspective on viral-cellular interactions, strengthening established principles of viral symbiogenesis. Pathogenesis can now be properly appraised as one expression of a range of outcomes between cells and viruses within a larger conceptual framework of Natural Viral Engineering as a co-engineering participant with cells. It is proposed that Natural Viral Engineering should be viewed as a co-existent facet of Natural Cellular Engineering within Cognition-Based Evolution.
... Considering infected type II cells and macrophages to be the primary IFN producers in the lung is supported by Swiecki and Colonna (2011) and Wang et al. (2009). Interferons trigger the following protection mechanisms proportional to interferon concentration: an infected type II cell occupying a lattice site has a probability of being eliminated by macrophages; virions are eliminated at a rate ; type II cells are immunized (Domingo-Calap et al., 2019;Michael Lavigne et al., 2021;Segredo-Otero and Sanjuán, 2020;Sa Ribero et al., 2020;Voigt et al., 2016) using a Poisson probability density at a rate (Segredo-Otero and Sanjuán, 2020) and stay immunized for a certain time (Iyer et al., 2017;Michael Lavigne et al., 2021) before becoming infectable again (called paracrine protection); once a type II site becomes infected, interference of cellular assembly and replication processes imposes a reduced rate of shed virions during the shedding phase by introducing a pre-factor (1 − ( )), where ( ) = + (called autocrine protection). ...
We develop a lattice-based, hybrid discrete-continuum modeling framework for SARS-CoV-2 exposure and infection in the human lung alveolar region, or parenchyma, the massive surface area for gas exchange. COVID-19 pneumonia is alveolar infection by the SARS-CoV-2 virus significant enough to compromise gas exchange. The modeling framework orchestrates the onset and progression of alveolar infection, spatially and temporally, beginning with a pre-immunity baseline, upon which we superimpose multiple mechanisms of immune protection conveyed by interferons and antibodies. The modeling framework is tunable to individual profiles, focusing here on degrees of innate immunity, and to the evolving infection-replication properties of SARS-CoV-2 variant strains. The model employs partial differential equations for virion, interferon, and antibody concentrations governed by diffusion in the thin fluid coating of alveolar cells, species and lattice interactions corresponding to sources and sinks for each species, and multiple immune protections signaled by interferons. The spatial domain is a two-dimensional, rectangular lattice of alveolar type I (non-infectable) and type II (infectable) cells with a stochastic, species-concentration-governed, switching dynamics of type II lattice sites from healthy to infected. Once infected, type II cells evolve through three phases: an eclipse phase during which RNA copies (virions) are assembled; a shedding phase during which virions and interferons are released; and then cell death. Model simulations yield the dynamic spread of, and immune protection against, alveolar infection and viral load from initial sites of exposure. We focus in this paper on model illustrations of the diversity of outcomes possible from alveolar infection, first absent of immune protection, and then with varying degrees of four known mechanisms of interferon-induced innate immune protection. We defer model illustrations of antibody protection to future studies. Results presented reinforce previous recognition that interferons produced solely by infected cells are insufficient to maintain a high efficacy level of immune protection, compelling additional mechanisms to clear alveolar infection, such as interferon production by immune cells and adaptive immunity (e.g., T cells). This manuscript was submitted as part of a theme issue on “Modelling COVID-19 and Preparedness for Future Pandemics”.
... For instance, human immunodeficiency virus (HIV) is able to increase human cytomegalovirus (HCMV) replication in various tissues as a result of lymphocyte activation [21], and humans infected with herpes simplex virus (HSV) are more susceptible to HIV infections and more contagious due to an increased expression of the receptor CCR5 [22,23]. Innate immunity can also promote negative interaction between viruses [24,25]. Cooperative and competitive interactions mediated by cross-reactive innate immunity appear to be particularly frequent among respiratory viruses [26]. ...
... Less attention was traditionally paid to cases of interactions between viruses of the same species (with the exception of genetic complementation), in which the ability of a viral particle to achieve a successful infection is promoted or hampered by the presence of other viral particles. However, several research lines have emerged in recent years showing this kind of viral interactions in various processes including evasion of host immunity [24] and regulation of virulence [27]. Inclusive fitness theory is a wellestablished theoretical framework for studying these interactions, which was initially developed to explain the evolution of altruism in higher organisms but allows viral interactions to be formally analyzed in terms of fitness costs and benefits. ...
... benefit of this trait correlates with genetic relatedness which, in viruses, depends essentially on the spatial structure of the population [24]. In structured infections where VSV virus spread took place in foci, the wildtype IFN blocking virus was vastly superior to a mutant defective for this trait, whereas this advantage was lost in unstructured infections in which the two virus variants were spatially mixed. ...
Despite extensive evidence of virus-virus interactions, not much is known about their biological significance. Importantly, virus-virus interactions could have evolved as a form of cooperation or simply be a by-product of other processes. Here, we review and discuss different types of virus-virus interactions from the point of view of social evolution, which provides a well-established framework for interpreting the fitness costs and benefits of such traits. We also classify interactions according to their mechanisms of action and speculate on their evolutionary implications. As in any other biological system, the evolutionary stability of viral cooperation critically requires cheaters to be excluded from cooperative interactions. We discuss how cheater viruses exploit cooperative traits and how viral populations are able to counteract this maladaptive process.
... IFN-mediated innate immune responses are crucial in protecting the host from viral infections and activating adaptive immunity [30,31]. In response to viral infection, host cells activate multiple signaling cascades to disrupt viral replication when specific molecular components of viruses are recognized [32,33]. ...
Pseudorabies virus (PRV) has evolved various strategies to escape host antiviral immune responses. However, it remains unclear whether and how PRV-encoded proteins modulate the RIG-I-like receptor (RLR)-mediated signals for immune evasion. Here, we show that the PRV tegument protein UL13 functions as an antagonist of RLR-mediated antiviral responses via suppression of the transcription of RIG-I and MDA5, but not LGP2. UL13 overexpression significantly inhibits both the mRNA and protein levels of RIG-I and MDA5, along with RIG-I- or MDA5-mediated antiviral immune responses, whereas overexpression of RIG-I or MDA5 counteracts such UL13-induced suppression. Mechanistically, UL13 suppresses the expression of RIG-I and MDA5 by inhibiting activation of the transcription factor NF-κB. Consequently, overexpression of p65 promotes the activation of RIG-I and MDA5 promoters. Moreover, deletion of the p65-binding sites in the promoters of RIG-I or MDA5 abolishes the suppression role of UL13. As a result, mutant PRV lacking UL13 elicits stronger host antiviral immune responses than PRV-WT. Hence, our results provide a novel functional role of UL13-induced suppression of host antiviral immunity through modulating receptors’ transcription.
... Besides a general theoretical interest of these results they also attracted interest of experimentalists. For example, the recent paper [12] studied a social structure of population of viruses in an experimental framework. ...
... However, their results showed a different type of altruism, which is like a more selfish altruism. Indeed, true altruists should sacrifice themselves for others (as [1] demonstrated) but the viruses called altruistic in [12] help themselves and also they help some other viruses, but not more than they help themselves. It is not quite altruism as it is usually understood, and which was observed in [1]. ...
We analyze three aspects of the phenomenon of local immunodeficiency. In all cases only a stable (i.e. observable) state of local immunodeficiency is considered. At first, we show that the appearance of a new virus may result in a change in the roles played by previously existed viruses in the in-host cross-immunoreactivity network. Particularly a persistent virus may become neutral and vice versa. Then we study what happens if two cross-immunoreactivity networks with stable local immunodeficiency get connected. It is shown that already for minimal (just three-viruses) networks, various transformations of viruses functions may occur. Namely, the resulting network will carry the state of stable local immunodeficiency, and indeed functions of different viruses may change. But, on top of that, some viruses may become inactive or organize their own cross-immunoreactivity network. The results of these two parts of the paper are rigorous. We also study numerically time evolution (dynamics) of cross-immunoreactivity networks after the addition of a new virus. It allows to see how the processes uncovered in the first part evolve in time, i.e. how, for instance, a new virus becomes persistent. Clearly, it does not happen instantly but involves some complicated processes of competition and cooperation. One of the most interesting findings is that appearance of a new virus in a network, which did not have a state of stable local immunodeficiency, may actually create such state.
... The interaction between coinfecting viruses ranges from synergy to antagonism depending on the virus pairs and the host (25)(26)(27)(28)(29)(30)(31). Functional complementation occurs when one virus provides a function that is absent or less efficient in the other virus. ...
Highly pathogenic avian influenza viruses (HPAIV) emerge from low pathogenic avian influenza viruses (LPAIV) through the introduction of basic amino acids at the hemagglutinin (HA) cleavage site. Following viral evolution, the newly formed HPAIV likely represents a minority variant within the index host, predominantly infected with the LPAIV precursor. Using reverse-genetics engineered H5N8 viruses differing solely at the HA cleavage, we tested the hypothesis that the interaction between the minority HPAIV and the majority LPAIV could modulate the risk of HPAIV emergence and that the nature of the interaction could depend on the host species. In chickens, we observed that the H5N8 LP increased H5N8 HP replication and pathogenesis. By contrast, the H5N8 LP antagonized H5N8 HP replication and pathogenesis in ducks. Ducks mounted a more potent antiviral innate immune response than chickens against the H5N8 LP , which correlated with H5N8 HP inhibition. These data provide experimental evidence that HPAIV may be more likely to emerge in chickens than in ducks and underscore the importance of within-host viral variants interactions in viral evolution.
IMPORTANCE
Highly pathogenic avian influenza viruses represent a threat to poultry production systems and to human health because of their impact on food security and because of their zoonotic potential. It is therefore crucial to better understand how these viruses emerge. Using a within-host competition model between highly and low pathogenic avian influenza viruses, we provide evidence that highly pathogenic avian influenza viruses could be more likely to emerge in chickens than in ducks. These results have important implications for highly pathogenic avian influenza virus emergence prevention and they underscore the importance of within-host viral variants interactions in virus evolution.
