Science answers WHY questions: programmed cell death in unicellular parasites

Posted by Kasra

Famous geneticist Josh Haldane once famously said “I would lay down my life for two brothers or eight cousins”.

Programmed cell death, otherwise known as apoptosis is a well justified procedure in multicellular organisms. All cells within a multicellular organism are originated from a single zygote and are genetically identical (except for some sets of immune cells that go through somatic mutation and genomic rearrangements, but that is different story). The purpose of the organism is to pass on the genetic material to the next generation and to maximize this genetic transfer. Therefore, if programmed death of some cells within the organism would help this purpose (i.e. increase the organism’s fitness), its evolution is logical. After all, often only a handful of cells (the gametes) get to pass their genetic material to the next generation and rest die eventually anyway.

This said, occurrence programmed cell death in unicellular organisms brings up an evolutionary dilemma. Scientists have found markers of apoptosis in unicellular organisms as wide as Plasmodium, Trypanosoma, Giardia and Saccharomyceses. Unicellular organisms within an ecosystem are usually competing with one another for resources, the same way animals and plants do in a larger scale. Therefore, evolution of a trait as strong and costly as altruistic death is worth a closer look, both mechanistically and rationally.

Reece et al. have discussed this matter in a recent review article published in PLoS Pathogens. Mainly focusing on Plasmodium, this review addresses hard questions such as why would altruism evolve in unicellular organisms? What could be the benefits of it? What are the factors that control its occurrence?

Discussing the ideas and hypotheses presented in the review here would be spoilers for those who are eager to read it. In that case you may stop right now and download the open access article right here. If not, you can continue reading as I bring up a few highlights of the paper that I found most interesting.

Hamilton’s rule in evolutionary biology states that cooperation can evolve under these circumstances:

rb – c > 0

Where <r> is relatedness, (for instance the ratio of relatedness between siblings is 0.5 because they share 50% of their genome), <b> is the benefit the receiver gets, and <c> is the cost of the giver. So if benefit x relatedness is larger than cost, then cooperation or sacrifice can be actually be worth it. It is with reference to this rule that Josh Haldane was willing to give away his life for two brothers or eight cousins.

Within multicellular organisms, r = 1 because all cells have been deriven from a single clone. Therefore, wherever, b > c, cell death can evolve. But in unicellular organisms, the story is different. For instance, the population of Plasmodium or Leishmania parasites in the mosquito can be genetically very close or very diverse. Now the evolutionary theory would predict that if occurrence of apoptosis is for altruism and cooperation, it is favourable if the parasites within the population are genetically close to one another. This is a theory that can be tested in a lab: both genetic diversity of different parasite populations and occurence of apoptosis within those populations are measurable with today’s techniques.

Going further from the evolutionary strategy behind evolution of programmed cell death in unicellular organisms, we should also think about what could be possibly the benefits of the receivers that would favor death of the others. One of the theories is that overgrowth of parasites can result in limitation of resources and/or harm to the vector (in this case the Phlebotomine mosquito). If the vector gets overwhelmed by the parasites, it cannot transfer them to the next stage in the life cycle. Thus as Reece et al. suggest, death can be density dependent to control the parasite popultion, another hypothesis which is also readily testable.

And finally, we get to (in my opinion) the difficult part, which is to discover the mechanism underneath these strategies. How can parasites detect relatedness or density? It is possible that sophisticated strategies and mechanisms simply do not exist in certain populations because infecting populations have always been clonal and measurement of relatedness has not been needed. But it cannot always be case. Reece et al. point out to some studies which show evidence of detection of genetic diversity by parasites and existence of mechanisms similar to bacterial quorum sensing.

There is still a lot more to learn and be amazed with.

Reece SE, Pollitt LC, Colegrave N, & Gardner A (2011). The meaning of death: evolution and ecology of apoptosis in protozoan parasites. PLoS pathogens, 7 (12) PMID: 22174671

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Altruism in Leishmania: apoptotic parasites are required for infectivity of metacyclic promastigotes

Posted by Kasra Hassani

Suppression of the innate immune response and inhibition of activation of phagocytes that would otherwise kill the parasites has long been established as mechanisms of immune evasion and persistence among Leishmania parasites.

In their paper, van Zandbergen et al. have indicated presence of a high ratio (more than 40%) of apoptotic cells in the metacyclic/stationary phage parasites. They have characterized these cells by occurrence of phosphatidyl serine (PS) in the outer leaflet of plasma membrane as well as PS-binding protein Anexin A5(AnxA5). The majority of AnxA5+ cells have been shown to be apoptotic and different in morphology to infective parasites and they have shown that depletion of these apoptotic cells from the infective population substantially abrogates infectivity.

Apoptotic cells induce production of TGF-beta and IL-10 which are anti-inflammatory cytokines; these cytokines are produced as well by neutrophils when they phagocyte apoptotic Leishmania. Apoptotic parasites also hamper secretion of TNF-alpha, all of which results in inactivation of neutrophils and later macrophages and their inability to kill the phagocytosed parasites.

This is an interesting example of altruism among single-cell populations; the authors have suggested that apoptosis is probably triggered in late log phase and stationary phase promastigotes in the sandfly midgut due to nutrient depletion prior to their entry into the mammalian host.