Host Porphobilinogen Deaminase Deficiency Confers Malaria Resistance in Plasmodium chabaudi but Not in Plasmodium berghei or Plasmodium falciparum During Intraerythrocytic Growth
| Autor: | Denis C. Bauer, Giovanna Graziadei, Cilly Bernardette Schnider, Hao Yang, Kathryn Matthews, Gaetan Burgio, Elena Di Pierro, Anna Ehmann, Lora Starrs, Farid Rahimi, Simon J. Foote, Brendan J. McMorran, Tania F. de Koning-Ward |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Microbiology (medical) Plasmodium Porphobilinogen deaminase 030106 microbiology Immunology malaria lcsh:QR1-502 Microbiology host resistance lcsh:Microbiology Plasmodium chabaudi 03 medical and health sciences intraerythrocytic growth parasitic diseases medicine Plasmodium berghei porphobilinogen [deaminase] Acute intermittent porphyria biology Heterozygote advantage Plasmodium falciparum biology.organism_classification medicine.disease 3. Good health Red blood cell 030104 developmental biology Infectious Diseases medicine.anatomical_structure |
| Zdroj: | Frontiers in Cellular and Infection Microbiology, Vol 10 (2020) |
| ISSN: | 2235-2988 |
| Popis: | An important component in host resistance to malaria infection are inherited mutations that give rise to abnormalities and deficiencies in erythrocyte proteins and enzymes. Understanding how such mutations confer protection against the disease may be useful for developing new treatment strategies. A mouse ENU-induced mutagenesis screen for novel malaria resistance-conferring mutations identified a novel nonsense mutation in the gene encoding porphobilinogen deaminase (PBGD) in mice, denoted here as PbgdMRI58155. Heterozygote PbgdMRI58155 mice exhibited approximately 50% reduction in cellular PBGD activity in both mature erythrocytes and reticulocytes, although enzyme activity was approximately 10 times higher in reticulocytes than erythrocytes. When challenged with blood-stage P. chabaudi, which preferentially infects erythrocytes, heterozygote mice showed a modest but significant resistance to infection, including reduced parasite growth. A series of assays conducted to investigate the mechanism of resistance indicated that mutant erythrocyte invasion by P. chabaudi was normal, but that following intraerythrocytic establishment a significantly greater proportions of parasites died and therefore affected their ability to propagate. The Plasmodium resistance phenotype was not recapitulated in Pbgd-deficient mice infected with P. berghei, which prefers reticulocytes, or when P. falciparum was cultured in erythrocytes from patients with acute intermittent porphyria (AIP), which had modest (20-50%) reduced levels of PBGD. Furthermore, the growth of Pbgd-null P. falciparum and Pbgd-null P. berghei parasites, which grew at the same rate as their wild-type counterparts in normal cells, were not affected by the PBGD-deficient background of the AIP erythrocytes or Pbgd-deficient mice. Our results confirm the dispensability of parasite PBGD for P. berghei infection and intraerythrocytic growth of P. falciparum, but for the first time identify a requirement for host erythrocyte PBGD by P. chabaudi during in vivo blood stage infection. |
| Databáze: | OpenAIRE |
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