By: Brandon Invergo
Red blood cells infected with Plasmodium berghei gametocytes
It's a classic image that many people have seen in school: an egg cell lying in wait while numerous sperm cells race towards it. The sperm that reaches the egg first gets to fertilise it. When multiple males are competing, this race can lead to the evolution of, for example, faster-swimming sperm.
Now imagine a more difficult scenario: before its sperm can swim to the egg, the male would first need to race to make the sperm. This is similar to what malaria parasites must do when they are first passed to a mosquito, and they have evolved to do it extremely fast. We wanted to know what's happening inside the parasite to help it to so quickly prepare to reproduce and we found that maybe these species don't follow the usual rules.
First, the malaria parasite needs a way to say to itself, “Ok, I'm inside the mosquito now. It's time to get ready to reproduce!” One way that a cell can do this is by modifying its proteins – the cell recognises a change in its environment and some protein is modified as a result. This protein can then pass on the message by modifying other proteins, and so on in a chain, eventually leading to important cellular machinery being turned on. We performed an experiment that allowed us to watch how the parasites use one such protein modification, called phosphorylation, while they prepare to sexually reproduce.
What is the parasite doing at this point? Before the mosquito drinks the infected blood, some of the parasites are already separated into males and females. Once they're inside the mosquito midgut, they leap into action, with each male producing eight “microgametes” and each female becoming a “macrogamete.” Like sperm, the microgametes then have to race to find a macrogamete to fertilise.
In order to produce those eight microgametes, the male must copy its DNA and separate the copies three times, as well as building everything needed to make the gametes swim. In human embryonic cells, each cycle of copying and separation might take around 30 minutes each time, but the parasites can do all three cycles in only 10 minutes. We saw that even within the first 20 seconds, hundreds of proteins are being modified. We were sure that we would only see a few proteins affected in such a short period.
However, when we looked at which proteins were being modified, we had an even bigger surprise: not only did we see the proteins needed for copying DNA, we also saw ones related to separating the copies, as well as for the motors needed for swimming. In most species, these steps happen one after the other. Thanks to our results however, we are now starting to think that malaria parasites don't wait for one step to finish before beginning the next.
This is the first really dynamic, “big-picture” look at how the parasite works “under the hood” and it's shocking just how fast it is and just how much is happening in such a short period of time. This will be useful to other researchers because if we can figure out how the parasite goes about preparing for reproduction, we might be able to figure out new ways to block it from happening. Preventing this reproduction preparation could then help to stop the spread of the disease.
This was interdisciplinary research that required the collaboration of teams at the Sanger Institute and EMBL-EBI (https://www.ebi.ac.uk). The project was especially made possible thanks to the joint EMBL-EBI / Sanger Institute ESPOD postdoctoral fellowship, which gave me the opportunity to perform interdisciplinary research as a member of both institutes. The fellowship has been an excellent and unique experience, which I would enthusiastically recommend to anyone wanting to combine experimental and computational techniques in their research.
About the author:
Dr Brandon Invergo is an EBI–Sanger postdoctoral fellow (ESPOD) at EMBL-EBI and the Sanger Institute, working in the groups of Pedro Beltrao (EMBL-EBI), Oliver Billker (Sanger Institute), and Jyoti Choudhary (formerly Sanger Institute, now at the Institute of Cancer Research) on protein signalling in malaria parasites.
Invergo BM et al. (2017). Sub-minute Phosphoregulation of Cell Cycle Systems during Plasmodium Gamete Formation.Cell Reports Vol 21, issue 7, pages 2017-2029. DOI:10.1016/j.celrep.2017.10.071