Of Brain and Toxoplasma

Posted by Kasra

Comic Latest Page

This  wonderful comic had stayed in my drafts folder for a very long time and I had decided finally not to post since Calamaties of Nature had stopped publishing comics. But then again, a recent PLOS ONE paper reminded me of it again.  Toxoplasma gondii is one of my favorite parasites. It is one of the most common parasites of humans and in majority of cases lays dormant throughout life, making it one of the most successful parasites in Nature. After infection (eating poorly cooked infected meat or contact with feces of an infected cat), T. gondii escapes the gut and migrates to the brain. At first glance, it does not seem to do much over there, at least nothing drastic. But studies including current work by Ingram et al. have shown that T. gondii infection can permanently alter animal behavior, permanently meaning the behavioral change stays even after infection has been cleared.  This recent study is another example demonstrating this ability of the parasite:

Ingram et al. checked how the behavior of an infected or uninfected mouse differ when exposed to predators, in this case Bobcat urine. As you can see in the figure below (Part A), they set up a field, one part of which was spotted with Bobcat urine or Rabbit urine (controlling for effect of just urine versus predator urine). Infected, uninfected and infected with a attenuated parasite (which could successfully clear the infection) mice were let in the area to see which spots they spend more or less time at, translated to which areas they avoid and which areas they do not. As you can see in sections Bi and Bii, the mouse partly avoided the section with rabbit urine (hence the importance of controls!) but this avoidance was way stronger when exposed to Bobcat urine. Surprisingly this behavior almost vanishes in infected mice, regardless of the strain, in other words, regardless of presence or absence of parasites in the brain.

From Ingram et al. PLOS ONE, 2013

From Ingram et al. PLOS ONE, 2013

There is a body of research on possible effects of T. gondii infection on human brain and behavior and correlations to increased suicide and schizophrenia have been suggested, although not confirmed. Still we all keep in mind that correlation does not mean causation.

Could this alteration of animal behavior also have an evolutionary explanation/impact on Toxoplasma’s life cycle? In other words, is there more to this phenomenon than just parasite infects brain, brain acts strange?

There is a difference between cats (big and small, domestic and wild) and the rest of the animals when it comes to Toxoplasma. In other animals, as I mentioned above, Toxoplasma escapes the gut after ingestion and moves  to muscle  and brain tissue and just stays there. So basically the infection is kind of a dead-end. It cannot be transferred to the next host until the current host dies and gets eaten up by another one. However,cats are the main hosts for Toxoplasma. That is where the parasite goes through the sexual stage of its life cycle. Also, Toxoplasma cysts are constantly shed from an infected cat through its feces. Not a dead-end infection. Now the loss of predator in Toxo-infected mice makes sense! It helps the parasite get back to its main host where it can complete the cycle! This is a trait that would have been highly favored by natural selection whenever it evolved. Because it would strongly increase the chance of the parasite being passed around to the next host.

At the end, what the comic made me think of was, could those parasites also have parasites that would alter their behavior in their own benefit? Is this is a classic example of the Extended Phenotype idea introduced by Richard Dawkins?

Reference:

Ingram WM, Goodrich LM, Robey EA, & Eisen MB (2013). Mice Infected with Low-Virulence Strains of Toxoplasma gondii Lose Their Innate Aversion to Cat Urine, Even after Extensive Parasite Clearance. PloS one, 8 (9) PMID: 24058668

ResearchBlogging.org

Did fungi help mammals dominate Earth?

Image

From SMBC-Comics

 

Posted by Kasra

 

The Cretaceous mass extinction is one of the most exciting topics in evolutionary biology. There are always discussions on what caused the mass extinction, what happened during the extinction, what happened to all the dinosaurs, why did the mammals and birds survive, and so on. A recent article in PLoS Pathogens by Arturo Casadevall brings forward an interesting hypothesis: Fungi might have given mammals an evolutionary advantage during this period of time.

Casadevall mentions that humans and other mammals are generally resistant to fungal infections and most pathogenic fungi are in fact only opportunistic pathogens. He suggests that this is due to the mammalian control of body temperature – higher than optimal growth temperature of fungi – and evolution of powerful adaptive immunity. On the other hand, he brings forward examples of amphibians, being ectothermic, and primitive mammals, having lower body temperature, are more susceptible to fungal infections.

He next states that the Cretaceous-Tertiary (K-T) boundary included a cooling period with plenty of dust in the atmosphere and lack of sufficient sunlight. This led to a fungal bloom on the Earth and possible growth of pathogenic fungi. The hypothesis states that this higher than normal presence of fungi selected against surviving ectothermic reptiles and in favour of endothermic mammals. Thus, fungi might have indirectly helped mammals and possibly warm-blooded birds by killing off their competitors for the limited food resources.

Like any other scientific hypothesis, this one also needs to be tested. Unfortunately fossil records cannot tell us much of how common fungal infections were at the time. However, one can first look more closely if warm-bloodedness or higher body temperature does indeed aid in protection from fungal infection, given similar immune systems. Comparing today’s amphibians, reptiles and mammals can be tricky as the host-pathogen interactions may greatly differ among the groups. This could lead to conclusions that are confounded by differences in pathogenicity of fungi or power of the host immune system. Pooling data together from larger numbers host-pathogen pairs can lead to more robust conclusions. Application of heat-resistant fungi can also be beneficial for performing more controlled experiments rather than comparing natural histories. Casadevall himself suggests that climate change can promote evolution of fungi that can better survive in elevated temperatures and be threats as emerging pathogens. In this case, we would be a step in advance knowing what to expect, should these new pathogens emerge.

Casadevall A (2012). Fungi and the rise of mammals. PLoS pathogens, 8 (8) PMID: 22916007

ResearchBlogging.org

Persistence of parasites in the host: co-evolution of parasitism and immunity

Posted by: Kasra Hassani

Many pathogens are unable to live outside the host. Therefore, before killing or completely using up their host, they should ensure that they will be successfully transfered to another one, or one may say, those who did not never made it through evolution. Depending on their life-cycle and type, strategies to ensure transmission diffes among pathogens. In a comment for Nature Reviews in Immunology Sacks and Yazdanbakhsh comparatively discuss these strategies among air-borne pathogens, protozoan vector borne pathogens and also multicellular pathogens. Air-borne bacteria and viruses can easily spread after an acute infection and do not necessarily need to modulate immune response to avoid the up-coming sterilizing immunity. On the other hand, vector-borne parasites such as Plasmodium or the Trypanosomes require more time for efficient transmission. Therefore, parasites have developed strategies to delay life-long immunity. For instance, in African Trypanosomes (T. brucei) continuous variation of the surface glycoprotein (correctly named the variable surface glycoprotein or VSG) hiders development of a protective immune response and allows the parasite to reside in the blood for a long time. Alternatively, Leishmania infections co-inside with presence of regulatory T cells and considerable amounts of IL-10 which down-regulates the protective Th1 response. In larger parasites such as helminths rapid movement from immune-sensitive areas such as the skin or acquiring and presentation of host antigens are among the strategies that are used for delaying the immune response and buying time for transmission.

What I find more interesting among all of this is the evolution of the host in the same direction. In many parasitic infections, the immune response does not lead to complete parasite clearance, rather to a residual infection with minimum or no pathology yet still transmissibility.  Read et al. have argued in a Primer in PLoS Biology that this ‘tolerance’ is a type of immunity that can arise in the host-parasite co-evolution as an alternative to ‘resistance’ where complete of the pathogen clearance occurs. Firstly, complete clearance of the pathogen can be too costly compared to its control. Secondly, In the dynamic co-evolution of the host and the parasite, genes who confer tolerance against a pathogen could be favored to those who confer resistance. Evolution of tolerance does not harm or might even favor parasite existence since tolerant host are reservoirs of the parasites within the population. Therefore, they do not prompt counter-adaptation by the parasites.

Sacks and Yazdanbakhsh conclude their comment by mentioning that these immune strategies should be taken into consideration when designing vaccines for parasitic diseases. They suggest that instead of trying to override this desire of the immune system for tolerance rather than resistance, vaccines could induce tolerance where minimal pathology is caused by a controlled persistence of the parasites. A classic example of a vaccination strategy in this line is Leishmanization wherein live Leishmania parasites used to be inoculated in soldiers or children in risk of infection and would confer immunity to further infections. With regard to development of immunological tolerance to leishmaniasis, not resistance, these types of vaccines need reconsideration.

Can KTIM be a regulatory site widely used by cytosolic kinases?

Identification of Key Cytosolic Kinases Containing Evolutionarily Conserved Kinase Tyrosine-based Inhibitory Motifs (KTIMs).

Posted by: Issa Abu-Dayyeh

I have posted an earlier article to talk about our PLoS NTD paper where we have described a novel strategy by which Leishmania was able to inhibit TLR-mediated macrophage activation through its ability to inhibit IRAK-1 kinase activity by activating the protein tyrosine phosphatase  (PTP) SHP-1.

We have identified the site of binding between SHP-1 and IRAK-1 to be an evolutionarily conserved ITIM-like motif, which we called a kinase tyrosine-based inhibitory motif (KTIM). In this newly-published paper in Developmental and Comparative Immunology, Abu-Dayyeh et al. present evolutinary as well as experimental data that propose that KTIMs could potentially represent a novel regulatory site involved in the control of the kinase activity of many key kinases involved in siganlling pathways of immune cells. Although this work awaits to be further explored by other researches, I believe this work could open various doors towards many important discoveries in the field of immunology.

Here is the abstract of the paper:

We previously reported that SHP-1 regulates IRAK-1 activity by binding to an ITIM-like motif found within its kinase domain, which we named Kinase Tyrosine-based Inhibitory Motif (KTIM). Herein, we further investigated the presence, number, location, and evolutionary time of emergence of potential KTIMs in many cytosolic kinases, all known to play important roles in the signalling and function of immune cells. We unveil that several kinases contain potential KTIMs, mostly located within their kinase domain and appearing predominantly at the level of early vertebrates becoming highly conserved thereafter. Regarding the KTIMs that were found conserved in both vertebrates and invertebrates, we provide experimental data suggesting that such motifs may have constituted readily-available sites that performed new regulatory functions as soon as their binding partners (e.g. SHP-1) appeared in vertebrates. We thus propose KTIMs as novel regulatory motifs in kinases that function through binding to SH2 domain-containing proteins such as SHP-1. Copyright © 2009. Published by Elsevier Ltd.

PMID: 20043942

doi:10.1016/j.dci.2009.12.012

Dawkin’s “extended phenotype”, an extension or a revolution?

Posted by: Issa Abu-Dayyeh

The extended phenotype, a relatively longer and a more difficult reading than Dawkin’s “The selfish gene”, is in my opinion a book worth the reading effort for several reasons:

1-Although a big portion of the book was dedicated to rebuttal critics that showered Dawkins with accusations of being a genetic determinist and a reductionist (Based on his views in the Selfish gene), Dawkin’s replies to those criticisms are pretty logical and organised. In fact, Dawkins almost did not have to retract any of the claims he made 6 years before “the extended phenotype” was written.

2-The rest of the book sets to establish a new vision on the extent to which a gene can act.

Many of us would agree that an organisms’ behaviour is selected to maximize the success of the replication of the genes residing inside this organism. As tempting as this statement might be, this vision definitely pictures the body as the gene’s prison. It is the boundary, the wall,the farthest limit upon which a gene can act.

Dawkins suggests in “the extended phenotype” that the action of genes goes way beyond their ability to produce proteins for the bodies they reside in. In fact, genes can have effects on inaminate objects (such as the type of house an animal would build) or on other living beings. An example given by Dawkins is a trematode that lives in snails. This trematode codes for proteins that drive the snail to produce thicker shells than ususal. This provides greater protection for the trematode while diverting the snail’s energy from practices that could benefit the snail but not the trematode such as: reproduction. The author goes on and on giving examples of how genes can act at a distance!

But how influential is this extended phenotype argument? After reading the book, my initial thought was that it is really no revolution! This is simply an extension of our vision of how far genes should be seen to go. On a deeper thought, I believe this book is revolutionary from a different perspective. First, it places more emphasis on the interactions of genes (regardless of the organism that carries them) on the overall evolution of complex traits and the natural selection they undergo. The principle also explains how a parasite can alter the host’s behaviour to its advantage (therefore suggesting what was formerly thought as mal-adaptation of a host gene as good adaptation of the parasite gene), and how some parasites can end up as symbionts and ultimately interested in increasing the reproductive success of the host and, soon, very difficult to even be seen as  parasites (ex: the mitochondria and chloroplast endosymbiont theory).

This book simply modifies a vision: from behaviour maximizing the success of the genes inside the organism to behaviour maximizing the success of genes that code for that specific behaviour, no matter in whose body those genes are found. This definition reorganizes the genetic vision in a way highly compatible with dawkins’ selfish gene view of evolution and natural selection. Is he right about the extended phenotype or is he wrong? I think most of us would agree it is a logical extension of what we perceive as a direct effect of a gene, but what really matters is that it is different… and a different view is sometimes what we need to reevaluate our current vision and devise new experiments to expand our knowledge. Not to mention the importance of such a vision on the mathematics of genetic contributions to phenotypes. In a nutshell, this is a book worth reading!

Model for parasitism: invasive/evase vs. pathoantigenic molecules

Posted by Kasra Hassani

A very interesting conceptual model for parasitic virulence was proposed by Chang et al. (2003) a few years ago and has been recently discussed in Leishmania and Leishmaniasis by Banuls et al. (2007). It has long been established that parasitic organisms, bacteria, protozoa, helminths etc. benefit from certain molecules that enable them establish infection within the host and cause pathogenicity. It can be said that the parasites are at the same time ‘visible’ and ‘invisible’ to the host.

Here I briefly introduce the model with Leishmania as the model organism. The idea is to define twp groups of effective molecules named invasive/evasive and pathoantigenic. The invasive/evasive molecules help the parasite to evade from the innate immune system and its microbicidal mechanisms to establish its infection. These molecules usually stay ‘invisible’ to the immune system and their expression might end after the establishment of infection. Good examples in the case for Leishmania are gp63 surface protease and the surface molecule lypophosphoglycan (LPG). Both of these molecules have crucial roles in evasion from the complement system, facilitation of phagocytosis and subversion of macrophage signalling to the parasite’s benefit. Their expression is slowed down and LPG is almost totally absent in Leishmania amastigotes. As expected, they also do not elicit an immune response.

On the other hand, another rank of molecules, which are generally intracellular in Leishmania are pathoantigenic and cause immunopathologic responses. Interestingly, the majority of Leishmania’s immunogenic proteins are intracellular rather surface proteins and are being produced as a result of parasite’s multiplication within the host. They are believed to be exposed to the immune system during cytolysis and cause the virulence phenotype. A proper example is the amastigote-specific protein A2 which is an intracellular protein and is highly immunogenic. This protein being expressed in high levels in visceral species induces visceralization of Leishmaniasis.

Chang et al. have discussed their model extensively with Leishmania infection but have described how it could beautifully fit with other types of acute and chronic diseases. For instance in schistosomiasis, the adult worm stays in the blood vessel ‘invisible’ to the immune system while releaseing highly antigenic eggs that cause immunopathology. This model can present convergent evolution of parasitic strategies in very divergent parasites.

Perhaps each parasitologist could at least conceptually fit and expand this model for their own parasite of interest to have a better overall understanding of its parasitic strategies.

Parasites lead to evolution of robustness against gene loss in host signaling networks

Posted by Hamed Shateri Najafabadi

A new study by Marcel Salathé and Orkun Soyer reveals exciting evolutionary consequences of host-parasite interactions on the architecture of biological networks of the host. Their paper, which was published a few days ago in Molecular Systems Biology, is one of those that you read and wonder why no one had thought of it before! The approach that they use is elegant and the findings are very significant.

Marcel is now a postdoc fellow at Stanford and very soon is going to start working on “questions about the non-genetic (e.g. cultural) effects on disease dynamics” (I got it from his web page). I asked him to write a synopsis of his paper for The Parasite Diary, and here it is:

“Many molecular pathways are robust against removal of parts, but why such robustness is evolutionary maintained is a question that has not been answered yet. Another, seemingly unrelated finding in recent years is the process by which parasites attack their hosts and evade an immune response from the host. Evidence is accumulating that the most frequent evasion strategy of parasites is to interfere with the protein machinery of hosts, for example by suppressing important genes that are necessary to recognize a parasite and/or mount an immune response – we cite various key papers in the study.
Our idea was to bring these two observations together: if parasites interfere with host pathways, they create selective pressure on the host to avoid such interference. One obvious solution to this problem is that hosts would evolve pathways that are robust to the suppression of a protein – if a parasite suppresses the protein, the host would still be able to respond in the appropriate fashion. We believe that part of what we see in knockout studies – which are usually performed in the lab in the absence of parasites – could be explained by this phenomenon.
To see whether our idea made sense we used a mathematical model of pathway dynamics and ran evolutionary simulations in the computer. Our findings confirmed that our proposal is plausible, and in principle it is also testable. The evolved robustness resulted either from redundancy or from specific network architecture, and was more stable when it resulted from the latter; robustness based on redundancy alone was quickly lost under subsequent stabilizing evolution (without parasite interference).
Altogether, we hope that this type of research invites biologists to look closer at the ecological aspects of systems biology properties.
Parasites are an extremely strong and continuous source of selection on any species (with maybe the notable exception of viruses), and such strong selection pressures should not be ignored when we try to understand evolutionary processes.”

Thank you Marcel for your enjoyable paper. We are looking forward to your future works.