Co-evolution: Immune to defeat
Organisms that grow in close contact with one another often co-evolve. This is particularly evident in pathogens and their hosts, with each always needing to stay one small step ahead of the other in order to survive. This evolutionary competition has given rise to the systems of immune molecules that hosts use to recognize and neutralize invading pathogens, and also to the effector molecules that pathogens use to survive attack by the immune system. A prime example of this can be seen in the interactions between a class of enzymes called the immune-related GTPases (IRG proteins) and the pathogens that they recognize and destroy (Kim et al., 2012). It is known that IRG proteins work by assembling on the surface of the vacuoles within which the pathogens replicate, but the details of this mechanism are poorly understood.
Now, in eLife, Jonathan Howard of the University of Cologne and colleagues present striking evidence that the co-evolution of IRG proteins with Toxoplasma gondii—the parasite that causes toxoplasmosis—has been an important driving force in the functional evolution of the IRG system (Lilue et al., 2013). Howard and colleagues—including Jingtao Lilue as first author, Urs Muller and Tobias Steinfeldt—found that mice derived from wild mice were resistant to strains of the parasite that were lethal to laboratory mice. Remarkably, they demonstrated that this resistance was due to genetic variation in one particular form of IRG protein, named Irgb2-b1: they found that certain alleles of Irgb2-b1 appeared to inhibit the activity of the effector molecules secreted by the parasite, which themselves have evolved to inactivate the IRG system.
As it enters a new host cell, Toxoplasma secretes an active kinase called ROP18 and a diverse family of pseudokinases, called ROP5. The ROP5 pseudokinases appear to sequester the IRG proteins and then present them for phosphorylation by ROP18 (Fleckenstein et al., 2012). The process of phosphorylation inactivates the IRG proteins, which prevents them from assembling on the surface of the vacuole. This, in turn, allows the parasites to replicate (Figure 1; Steinfeldt et al., 2010; Fentress et al., 2010). There are considerable differences in the virulence (to mice) of the major strains of Toxoplasma, and genetic variations in ROP5 and ROP18 can explain almost all of these differences (Saeij et al., 2006; Taylor et al., 2006; Behnke et al., 2011; Reese et al., 2011). This highlights the importance of the IRG system in the control of Toxoplasma infection in mice, and the pressure that competition with this system has placed on the parasite.
As is typical of genes under strong selective pressure, the IRG genes differ both in copy number and in coding sequence in closely related species and even, as described by Lilue et al., among individuals within the same species. Previously the different forms of an IRG protein have been grouped into two distinct functional classes: effector IRG proteins that destroy the vacuoles inside which the pathogens replicate, and regulatory IRGs that are thought to inhibit premature activation of the system (Hunn et al., 2011). However, Irgb2-b1—the form of the protein identified by Lilue et al.—appears to belong to a third class of IRG proteins that recognize a particular pathogen effector rather than the pathogen itself. They found that Irgb2-b1 only attached itself to Toxoplasma vacuoles that were already coated with ROP5. Moreover, Irgb2-b1 loading appeared to block the activity of the ROP5 and ROP18 proteins. This left the effector IRG proteins free to assemble on the surface of the vacuole, thus leading to the destruction of the parasite (Figure 1). Strikingly, mice that carried the protective allele of Irgb2-b1 were able to survive acute infection with a highly virulent strain of the parasite, whereas infection by just one parasite of the same strain would kill a laboratory mouse.
Toxoplasma is also a survivor—as the acute infection ends, the parasite switches to a slow-growing form that becomes enclosed within cysts in the brain and muscle of the host, as was the case with the wild mice studied by Lilue et al. When a host is killed and eaten by a carnivore, the parasite switches back to a fast growing stage to infect its new host. Because strains of the parasite that secrete the virulent versions of both ROP5 and ROP18 are able to completely defeat the IRG system in laboratory mice, it was thought that these strains could not have co-evolved with mice, because the death of the host can be an evolutionary dead-end for a pathogen. The fact that Irgb2-b1 derived from wild mice represents a specific countermeasure to the parasite effectors provides a strong argument for co-evolution. The work of Lilue, Muller, Steinfeldt and Howard thus reminds us to look beyond lab-adapted organisms and examine biology in the wild to discover its full diversity.
Virulence differences in Toxoplasma mediated by amplification of a family of polymorphic pseudokinasesProc Natl Acad Sci USA 108:9631–9636.https://doi.org/10.1073/pnas.1015338108
IFN-inducible GTPases in host cell defenseCell Host Microbe 12:432–444.https://doi.org/10.1016/j.chom.2012.09.007
Polymorphic family of injected pseudokinases is paramount in Toxoplasma virulenceProc Natl Acad Sci USA 108:9625–9630.https://doi.org/10.1073/pnas.1015980108
Article and author information
- Version of Record published: October 29, 2013 (version 1)
© 2013, Reese
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
- Page views
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
- Evolutionary Biology
- Microbiology and Infectious Disease
Many bacterial genomes carry prophages whose induction can eliminate competitors. In response, bacteria may become resistant by modifying surface receptors, by lysogenization, or by other poorly known processes. All these mechanisms affect bacterial fitness and population dynamics. To understand the evolution of phage resistance, we co-cultivated a phage-sensitive strain (BJ1) and a poly-lysogenic Klebsiella pneumoniae strain (ST14) under different phage pressures. The population yield remained stable after 30 days. Surprisingly, the initially sensitive strain remained in all populations and its frequency was highest when phage pressure was strongest. Resistance to phages in these populations emerged initially through mutations preventing capsule biosynthesis. Protection through lysogeny was rarely observed because the lysogens have increased death rates due to prophage induction. Unexpectedly, the adaptation process changed at longer time scales the frequency of capsulated cells in BJ1 populations increased again, because the production of capsule was fine-tuned, reducing the ability of phage to absorb. Contrary to the lysogens, these capsulated resistant clones are pan-resistant to a large panel of phages. Intriguingly, some clones exhibited transient non-genetic resistance to phages, suggesting an important role of phenotypic resistance in coevolving populations. Our results show that interactions between lysogens and sensitive strains are shaped by antagonistic co-evolution between phages and bacteria. These processes may involve key physiological traits, such as the capsule, and depend on the time frame of the evolutionary process. At short time scales, simple and costly inactivating mutations are adaptive, but in the long-term, changes drawing more favorable trade-offs between resistance to phages and cell fitness become prevalent.
- Immunology and Inflammation
- Microbiology and Infectious Disease
Hantaviruses are high-priority emerging pathogens carried by rodents and transmitted to humans by aerosolized excreta or, in rare cases, person-to-person contact. While infections in humans are relatively rare, mortality rates range from 1 to 40% depending on the hantavirus species. There are currently no FDA-approved vaccines or therapeutics for hantaviruses, and the only treatment for infection is supportive care for respiratory or kidney failure. Additionally, the human humoral immune response to hantavirus infection is incompletely understood, especially the location of major antigenic sites on the viral glycoproteins and conserved neutralizing epitopes. Here, we report antigenic mapping and functional characterization for four neutralizing hantavirus antibodies. The broadly neutralizing antibody SNV-53 targets an interface between Gn/Gc, neutralizes through fusion inhibition and cross-protects against the Old World hantavirus species Hantaan virus when administered pre- or post-exposure. Another broad antibody, SNV-24, also neutralizes through fusion inhibition but targets domain I of Gc and demonstrates weak neutralizing activity to authentic hantaviruses. ANDV-specific, neutralizing antibodies (ANDV-5 and ANDV-34) neutralize through attachment blocking and protect against hantavirus cardiopulmonary syndrome (HCPS) in animals but target two different antigenic faces on the head domain of Gn. Determining the antigenic sites for neutralizing antibodies will contribute to further therapeutic development for hantavirus-related diseases and inform the design of new broadly protective hantavirus vaccines.