Suppression of Plasmodium MIF-CD74 Signaling Protects Against Severe Malaria

Alvaro Baeza Garcia, Edwin Siu, Xin Du, Lin Leng, Blandine Franke-Fayard, Chris J Janse, Shanshan W Howland, Laurent Rénia, Elias Lolis, Richard Bucala

Posted on: 27 February 2021

Preprint posted on 14 February 2021

Article now published in The FASEB Journal at http://dx.doi.org/10.1096/fj.202101072R

The Plasmodium protein PMIF has an anti-apoptotic effect on infected hepatic cells but also a pro-inflammatory effect on endothelial cells during malaria pathogenesis.

Selected by Joao Mello-Vieira

Categories: cell biology, immunology, microbiology

Background

Plasmodium parasites, the causative agents of the disease malaria, have a complex life cycle. They are transmitted to mammals by infected mosquitos, which deposit the hepatotropic form of the parasite, the sporozoite. These sporozoites migrate to the liver, where they infect hepatocytes. There, they replicate and differentiate into thousands of new parasites that are now able to infect erythrocytes. This blood stage of the infection is when the parasites cause harm to the infected individual. The infected erythrocytes accumulate in the microvasculature of tissues generating an intense immune response, which also occludes and destroys the microvasculature. If the infection is untreated and the inflammation is kept active, it leads to death.

Importantly, the hepatic stage of the disease, essential for the parasite’s progression through the life cycle, is not symptomatic. The hepatocyte senses the invading pathogens and activates cell-autonomous mechanisms to kill the parasite, most notably by inducing apoptosis. Essentially, by killing itself, the cell kills the parasite developing inside it. However, hepatocytes infected with Plasmodium sporozoites are resistant to apoptosis by a mechanism not completely understood (Leirião et al., 2005; Van De Sand et al., 2005), possibly through p53 downregulation (Kaushansky et al., 2013).

One factor that has generated interest is the parasite orthologue of an endogenous cytokine called MIF (Macrophage Migration Inhibitory Factor). Host MIF down-regulates p53 promoting cell survival and proliferation (Mitchell et al., 2002). Interestingly, all Plasmodium species express a protein that mimics mammalian MIF, called PMIF (Plasmodium Macrophage Migration Inhibitory Factor). PMIF strengthens the immune response created during the blood stage of the infection, thus accelerating pathogenic mechanisms that might lead to the death of infected individuals (Baeza Garcia et al., 2018). In this preprint, Baeza Garcia and colleagues (Baeza Garcia et al., 2021) discovered that PMIF has the ability to prevent activation of apoptosis in hepatocytes. Moreover, by acting through its cognate receptor (CD74) in the endothelium, PMIF promotes antigen cross-presentation, accelerating pathogenic mechanisms of Experimental Cerebral Malaria.

Key findings

HepG2 cells infected with rodent Plasmodium berghei parasites in which PMIF was knocked-out (PbAmif-) show increased ability to undergo apoptosis, leading to a higher resistance to infection. This happens because PbAmif- parasites ‘fail’ to control the Akt-p53 signalling axis of the hepatocyte they are infecting, leading to decreased expression of anti-apoptotic genes and increased expression of pro-apoptotic genes.
Plasmodium MIF exerts its effect by binding to the host protein CD74, the cognate receptor for host and parasite MIF. Both, CD74 deficient HepG2 cells and mice infected with Plasmodium show normal capacity to activate apoptosis, reducing the load of Plasmodium parasites in the liver (Figure 1).

Figure 1 – Lack of host CD74 impairs Plasmodium parasite development in the liver.

WT or CD74 knock-out mice were infected with Luciferase-expressing Plasmodium sporozoites, and liver infection was measured at 48 hours after infection. CD74^-/- mice show no luciferase signal in the liver, indicating an undetectable parasite burden, when compared to infected WT mice.

Surprisingly, CD74 does not only seem to have an impact during the liver stage of infection. In fact, during the symptomatic blood stage of infection, CD74 knockout mice are protected from a severe and fatal form of malaria called experimental cerebral malaria.
Curiously, the loss of CD74 in mice lead to a decreased immune response, manifested by a reduction in activated immune cells rather than a decrease in the total number of immune cells. The loss of CD74 specifically in the brain endothelium results in sub-optimal presentation of Plasmodium antigens to the immune system leading to less brain-activated CD8+ T cells, thereby protecting mice from cerebral malaria.

What I like about this work:

This work provides a description of the parasite protein PMIF and shows that it has two roles, depending on the life cycle stage of the parasite. When parasites are in the liver stage, this protein is important to silence apoptosis in hepatocytes, leading to a higher infection load. When parasites are in the blood stage, this protein activates the endothelial and immune cells, inducing a stronger immune response against the parasite. This response might be pathogenic to the infected individual leading to a more severe manifestation of malaria. As such, this protein presents an interesting drug target both to prevent infection but also to prevent pathophysiological mechanisms that lead to severe syndromes of malaria.

A possible use of this work is in malaria vaccination strategies as described before by the same authors (Baeza Garcia et al., 2018). Malaria vaccine research has recently focused on the use of attenuated living Plasmodium sporozoites delivered to the liver as a way of creating a natural immune response. This strategy has shown to provide sterile immunity to the vaccinated individuals in small clinical trials. A possible avenue for this strategy would be to combine doses of attenuated parasites with compounds that help cells dispose of the parasite inside them. This could potentially increase the exposure of antigens during the liver stage, thus enhancing the immune response and accelerating sterile immunity.

Questions for the future:

Can MIF inhibitors be used to prevent malaria complications in a clinical setting?

The authors address this by using MIF inhibitors against PMIF and show that liver burden and Experimental Cerebral Malaria is decreased in mice. Can these results be replicated in a hospital setting with people already mounting a pathogenic immune response?

Can MIF inhibitors be used as an adjuvant for whole sporozoite Plasmodium vaccination strategies?

Malaria vaccine research has focused on the use of attenuated Plasmodium parasites that deliver living sporozoites to the liver as a way of creating an immune response that would provide sterile immunity to the vaccinated individual. What if this strategy is coupled with compounds that help cells dispose of the parasite inside them? Would this increase the exposure of antigens, enhancing a protective immune response?

Questions for the authors:

How can PMIF exert its effect in infected hepatocytes? Since PMIF is present at the membrane of the parasite and the receptor CD74 is on the membrane of the infected cells, how do these two proteins interact? Is PMIF released from the membrane of the parasite? Does it interact with host CD74 (at the membrane of the hepatocyte) during the invasion step?
If PMIF is an immunogenic protein important for the establishment of Cerebral Malaria, how can PbAmif– parasites have the ability to induce this pathology, when they are passaged as blood forms (Figure S1F)?
The authors used a parasite line (PbA) that leads to the development of experimental cerebral malaria. Can these results be replicated with other parasite lines that lead to different disease outcomes, such as malaria-associated acute respiratory distress? Can MIF inhibition also prevent other malaria-associated syndromes?

Tags: apoptosis, hepatocytes, malaria, p53, plasmodium

doi: https://doi.org/10.1242/prelights.27537

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Author's response

Alvaro Baeza Garcia shared

I was fortunate to have a Zoom Meeting with the first author of the preprint, Dr. Alvaro Baeza Garcia, who replied to my questions and explained to me the future directions of the project.

Here is a summary of our meeting:

“João Mello-Vieira: How can PMIF exert its effect in infected hepatocytes?

Alvaro Baeza García: We have two hypothesis for PMIF::CD74 interaction:

On the one hand, MIF molecules are secreted, so we think that PMIF can be secreted by the sporozoites before infecting the host cells, binding with CD74 at the membrane and triggering survival signals (a known effect for CD74-MIF axis, Leng et al., 2001).

On the other hand, PMIF molecules are expressed at the Parasitophorous Vacuole Membrane during the liver stage of infection [a membrane that separates the parasite from the host cell cytosol]. The parasite also diverts endosomes to itself. So, it is possible that the PMIF::CD74 interaction happens in the cytosol of the hepatocyte, at the parasite interface.

JMV: You used a parasite line (PbA) that leads to the development of experimental cerebral malaria. Can these results be replicated with other parasite lines that lead to different disease outcomes, such as malaria-associated acute respiratory distress? Can MIF inhibition also prevent other malaria-associated syndromes?

ABG: That is probably the case because the endothelial cross-presentation in the lung has been demonstrated by Laurent Rénia (Claser, et al., 2019) and CD74 is known to be expressed by the lung endothelium (Sauler, et al., 2015). If the other malaria associated syndromes rely in CD74-PMIF axis, the inhibitor could block these syndromes.

JMV: Do you have plans to use PMIF as a target to prevent pathologies?

ABG: We used inhibitors of PMIF, such as 26k, to treat Experimental Cerebral Malaria in mice. However, we were only able to prevent this syndrome in 50% of the infected mice. One possibility is to vaccinate against PMIF, which we already performed (Baeza Garcia, et al., 2018). We want to further potentiate this by targeting this vaccine to the brain.“

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Suppression of Plasmodium MIF-CD74 Signaling Protects Against Severe Malaria

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