Malaria. Plasmablasts are the real parasites.
Contributed by Jeremy F Brooks Ph.D.
My blogs are about understanding antibody responses to infectious diseases. Last month, I wrote about new biology in HIV. This time I will focus on Malaria.
General biology of malaria infections
Malaria is the disease caused by infection with Plasmodium parasites. In most cases, the parasites are transmitted by female Anopheles mosquitoes. The life-cycle of Plasmodium can be simplified as the following (also see graphic)– First, during blood-feeding, an infected mosquito (definitive host) carrying parasites in their salivary glands transmits infective cells (sporozoites) to humans (secondary host). Second, sporozoites travel through blood vessels and infect liver cells (hepatocytes) and begin to reproduce (asexually) generating merozoites. Third, merozoites are released and infect red blood cells and then continue to reproduce. Fourth, merozoites mature into gametocytes which are taken up by another mosquito during blood-feeding. In the infected mosquito, male and female gametes fuse to form a fertilized cell, which subsequently develops into a sporozoite, ready to repeat the process over again.
Recently, Plasmodium infections have caused >200 million cases of malaria each year, with almost 500,000 deaths from infection reported in 2017. Elimination of malaria by 2030 is a key public health goal in malaria-endemic countries including the Asia-Pacific region and the Americas. Malaria thrives in warmer places, typically tropical and subtropical countries. The species of malaria parasite can also vary by geography and is a determinant of disease severity. For example, Plasmodium falciparum is the dominant species in Africa and causes more lethal disease in humans than other related parasites such as Plasmodium vivax or Plasmodium ovale.
There is no current vaccine strategy that induces protective immunity for Plasmodium infection. Additionally, some strains of Plasmodium falciparum and Plasmodium vivax have evolved resistance to antimalarial drugs. Not all infections are the same – for example some can be asymptomatic and difficult to detect. Others can remain in the liver stage of infection for extended periods before relapsing disease occurs due to reactivation of the parasite life-cycle. Together these issues sustain malaria transmission and disease morbidity.
Understanding immunity to malaria
The immune response to malaria infection is fascinating. It is a prime example of an atypical immune response in that it is capable of clearing the infection but incapable of preventing re-infection in most people. Normally, our immune system will resist a pathogen and develop a memory of that pathogen, so as to efficiently dispose of it upon re-encounter. There are a few known reasons for why this is not the case in malaria, and this is the subject of the paper I’m writing about in this post. Without understanding how malaria is special in this regard, we will be unable to develop therapeutics tailored for enhancing immune responses against malaria infections.
The Butler lab at the University of Iowa seeks to understand why immunity to malaria is sub-optimal. A few years ago, they noticed an immune cell called a plasmablast – a short-lived cell that rapidly produces antibodies against the parasite early after infection – was unexpectedly associated with poorer control of malaria infection. Because antibodies and the cells that produce them are critical to resisting malaria infection by humans, it has been unclear why these cells are related with worse outcomes. Their current work published this month in the leading journal Nature Immunology establishes how this can be the case.
The researchers start by showing that mice infected with non-lethal malaria (here using Plasmodium falciparum) harbour a large number of plasmablasts early after infection, and their timing of appearance and magnitude seem to be associated with clearance of parasites. However, by using a series of genetic tools to remove these cells from the immune response, the researchers show that immunity against malaria infection is actually better when they’re missing. Not only are protective antibodies produced in greater abundance, but also the concert of cells required for producing long-term immunity against malaria are also bolstered. Indeed, when these plasmablasts are not around, the immune cells responsible for memory against malaria are heightened and are capable of protecting from a second round of infection with malaria, including a lethal species of the parasite.
By comparing the genes that are actively being expressed in these plasmablasts to other cells important in the immune response, it becomes obvious to the researchers that these plasmablasts have a hyperactive metabolism. They hypothesise that the increased uptake of metabolites in the local environment by plasmablasts is starving other immune cells of their vital needs. Without sufficient metabolism, the immune cells required for long-term protective immunity against malaria cannot function. The researchers go on to show that supplementation with an amino acid L-glutamine in the drinking water of mice infected with Plasmodium can lower parasite burden and enhance immune memory against malaria. Of high interest, they also show that there is a ‘therapeutic window’ – i.e. after a certain period, the addition of L-glutamine is no longer effective on the immune response. After the plasmablasts have reached their peak expansion, there was no advantage to treatment anymore.
At the very end of the paper, the researchers also show in 40 individuals that are voluntarily infected with malaria (and promptly cured with medicine), there is also an accumulation of plasmablasts, suggesting that this phenomenon may also be applicable to human malaria infection. The Butler lab is continuing to follow up this story. “We’re using combinations of human data, experimental models, single-cell technologies and functional genomic approaches to explore how this malaria-associated nutrient sink may short-circuit the epigenetic ‘programming and wiring’ of parasite-specific immune cells” Associate Professor Dr Noah Butler said. He also commented that there are “some preliminary data that the cascade of events that we describe in the paper may not be limited to malaria”, hinting that this biology in malaria may be relevant to other diseases as well.
These findings importantly help us to refine our therapeutic approaches for malaria. It would appear that Plasmodium is not the only ‘parasite’ here.
Dr Jeremy Brooks is a postdoctoral fellow in the Zikherman laboratory at UCSF. Jeremy’s work focuses on antibodies and the immune cells that produce them. Contact Jeremy with questions and feedback jeremy.brooks@ucsf.edu.
Primary article here.
Malaria life cycle beginning with the mosquito bite, moving through the human liver and red blood cells back to another mosquito. Source: BioRender (2020). Malaria Transmission Cycle. Retrieved from https://app.biorender.com/biorender-templates/t-5e629f969501410088a0156b-malaria-transmission-cycle