Discover how a deficiency in the PBGD enzyme confers resistance to certain malaria species while leaving others unaffected
8 min read
For centuries, malaria has shaped human history and evolution, leaving its mark on our very DNA. The deadly dance between parasite and host has driven protective mutations in erythrocyte (red blood cell) proteins—from sickle cell trait to thalassemia—that persist because they offer survival advantages in malaria-endemic regions. Now, a groundbreaking study reveals a new player in this ancient arms race: porphobilinogen deaminase (PBGD), a crucial enzyme in heme production. Intriguingly, deficiency in this enzyme confers resistance to certain malaria species while leaving others unaffected—a discovery that could open new pathways for antimalarial therapies 1 2 .
This article explores how scientists uncovered this phenomenon through elegant experiments involving mouse models, human blood cells, and genetic manipulation of parasites. The findings, published in Frontiers in Cellular and Infection Microbiology, reveal not only a previously unknown host defense mechanism but also highlight the complex interplay between parasite biology and host biochemistry 3 .
PBGD deficiency provides resistance to some malaria species but not others, revealing the complex host-parasite relationship.
Heme is an essential iron-containing molecule that serves as a cofactor for numerous proteins, most notably hemoglobin, which carries oxygen in our red blood cells. The production of heme occurs through an eight-step enzymatic pathway that begins with simple molecules—glycine and succinyl-CoA—and ends with protoporphyrin IX combining with iron to form heme.
Each step in this pathway is catalyzed by a specific enzyme, and deficiencies in these enzymes lead to a group of disorders called porphyrias. These conditions are characterized by the buildup of toxic precursors that can cause symptoms ranging from photosensitivity to neurological problems 2 .
Malaria parasites, during their blood-stage infection, have an insatiable appetite for heme. They require it for their own energy production and detoxification processes. However, Plasmodium parasites exhibit a fascinating dichotomy: while they possess their own complete heme biosynthesis pathway, research has shown that during the blood stages of infection, they largely dispense with their own enzymes and instead scavenge heme from the host red blood cell or exploit host enzymes 2 3 .
This dependency makes the host's heme production machinery a potential Achilles' heel—and indeed, previous studies have shown that deficiencies in other heme pathway enzymes (like ferrochelatase) can impair parasite growth 2 .
An eight-step process where each step is catalyzed by a specific enzyme, with PBGD playing a crucial role in the third step
Researchers employed a powerful genetic technique called ENU mutagenesis to identify novel malaria resistance genes. ENU (N-ethyl-N-nitrosourea) is a chemical that induces random mutations in mouse DNA, allowing scientists to screen for interesting phenotypes—in this case, resistance to malaria infection 2 4 .
Through this large-scale screen, they identified a mouse (dubbed MRI58155) with a distinctive microcytic anemia (small red blood cells) accompanied by moderately elevated reticulocyte (immature red blood cell) counts. Genetic mapping and whole-exome sequencing revealed a single base substitution (A to G) in the gene encoding porphobilinogen deaminase (PBGD), designated as PbgdMRI58155 2 .
The mutation was located in a splicing site and predicted to disrupt normal protein function, resulting in a truncated, non-functional enzyme. Heterozygous mice (with one copy of the mutation) showed:
| Parameter | Wild-Type Mice | Heterozygous Mutant Mice | Significance |
|---|---|---|---|
| PBGD activity in erythrocytes (nkat/L) | 6.53 ± 2.14 | 3.38 ± 1.80 | p = 0.048 |
| PBGD activity in reticulocytes (nkat/L) | 60.0 ± 36.3 | 22.1 ± 14.3 | p = 0.08 |
| Spleen weight | Normal | Moderately increased | Significant |
| Erythrocyte lifespan | Normal | Normal | Not significant |
| Embryonic viability | Normal | Lethal in homozygotes | N/A |
Table 1: Characteristics of PBGD-Deficient Mice Compared to Wild-Type
When researchers infected PBGD-deficient mice with Plasmodium chabaudi (a species that preferentially infects mature erythrocytes), they observed a modest but significant resistance to infection. The mutant mice showed:
This suggested that the host's PBGD deficiency wasn't preventing entry but was instead creating a hostile intracellular environment for the parasite once inside the red blood cell.
| Parasite Species | Host Cell Preference | Growth in PBGD-Deficient Cells | Potential Reasons |
|---|---|---|---|
| P. chabaudi | Mature erythrocytes | Significantly reduced | Limited heme availability in mature RBCs |
| P. berghei | Reticulocytes | No difference | Higher PBGD activity in reticulocytes |
| P. falciparum | Mature erythrocytes (human) | No difference | Alternative heme acquisition strategies |
Table 2: Parasite Growth in PBGD-Deficient Host Cells
To further investigate, researchers created PBGD-null mutants of both P. berghei and P. falciparum. These genetically modified parasites lacked their own PBGD enzyme but:
This demonstrated that the parasites' own PBGD is dispensable during blood-stage growth—they rely primarily on the host's enzyme or alternative heme sources.
| Parasite Type | Growth in Wild-Type Host Cells | Growth in PBGD-Deficient Host Cells |
|---|---|---|
| P. chabaudi wild-type | Normal | Reduced |
| P. berghei wild-type | Normal | Normal |
| P. berghei PBGD-null | Normal | Normal |
| P. falciparum wild-type | Normal | Normal |
| P. falciparum PBGD-null | Normal | Normal |
Table 3: Comparative Growth of Wild-Type vs. PBGD-Null Parasites
Understanding how host genetics influence malaria resistance requires sophisticated tools and experimental models. Here are some key research reagents and their applications:
| Research Tool | Function/Description | Application in This Study |
|---|---|---|
| ENU mutagenesis | Chemical mutagen that creates random mutations in mouse DNA | Identification of novel malaria resistance genes |
| PbgdMRI58155 mouse model | Mice with specific mutation in PBGD gene | In vivo testing of malaria resistance mechanisms |
| Acute Intermittent Porphyria (AIP) patient erythrocytes | Human red blood cells with 20-50% reduced PBGD activity | In vitro culture studies with P. falciparum |
| PBGD-null transgenic parasites | Genetically modified parasites lacking PBGD gene | Testing parasite dependency on own vs. host enzyme |
| PBGD activity assay | Sensitive measurement of enzyme activity | Quantifying PBGD levels in erythrocytes and reticulocytes |
Table 4: Essential Research Reagents and Their Applications
ENU mutagenesis and transgenic models enabled discovery of the PBGD mutation
PBGD activity measurements confirmed enzyme deficiency in mutant mice
In vitro studies with human AIP erythrocytes revealed species-specific effects
The discovery that PBGD deficiency confers resistance to P. chabaudi but not other malaria species highlights the complex evolutionary relationship between hosts and pathogens. Unlike mutations such as sickle cell trait that provide broad protection against severe malaria, the protective effect of PBGD deficiency appears to be species-specific 1 3 .
This specificity may explain why no strong population-level signature of PBGD deficiency has been observed in human populations endemic for malaria—its benefits might be too restricted to confer a significant evolutionary advantage against the diverse Plasmodium species that infect humans.
The findings suggest that targeting host enzymes rather than parasite proteins might be a viable strategy for antimalarial drug development. Such approaches could potentially avoid the rapid development of drug resistance that plagues current antimalarials, since host enzymes don't evolve as quickly as parasite targets 2 .
However, the species-specific effects mean that any therapeutic approach targeting PBGD would need to be carefully evaluated for effectiveness against different malaria parasites. Additionally, since complete PBGD deficiency is embryonic lethal in mice, any pharmacological inhibition would need to be partial and carefully controlled 2 .
The research provides fascinating insights into the metabolic flexibility of malaria parasites. The fact that P. falciparum can grow normally in PBGD-deficient human erythrocytes suggests it has alternative pathways for obtaining heme—possibly by directly scavenging heme from hemoglobin degradation or by using other host enzymes in the pathway 3 .
Similarly, P. berghei's preference for reticulocytes (which have much higher PBGD activity) may explain its indifference to host PBGD deficiency—it simply has access to more abundant enzyme reserves in these immature cells 1 2 .
The discovery that PBGD deficiency confers resistance to P. chabaudi but not to P. berghei or P. falciparum represents both a breakthrough and a puzzle. It reveals the incredible specificity of host-parasite interactions while raising new questions about the metabolic dependencies of different Plasmodium species 1 3 .
As our understanding of the complex relationship between host genetics and parasite biology deepens, we move closer to innovative approaches for combating one of humanity's oldest and deadliest diseases 2 4 .
This article was based on the research study "Host Porphobilinogen Deaminase Deficiency Confers Malaria Resistance in Plasmodium chabaudi but Not in Plasmodium berghei or Plasmodium falciparum During Intraerythrocytic Growth" published in Frontiers in Cellular and Infection Microbiology (2020).