Ascorbate-Dependent Peroxidase (APX) from Leishmania amazonensis Is a Reactive Oxygen Species-Induced Essential Enzyme That Regulates Virulence
| Autor: | Lucia Xiang, Fernando Y. Maeda, Jason Hauzel, Maria Fernanda Laranjeira-Silva, Norma W. Andrews, Bidyottam Mittra |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Immunology Leishmania mexicana Virulence Leishmaniasis Cutaneous Mitochondrion Microbiology 03 medical and health sciences Mice Ascorbate Peroxidases Animals Amastigote Cells Cultured Leishmania major chemistry.chemical_classification Infectivity Reactive oxygen species 030102 biochemistry & molecular biology biology Macrophages food and beverages Leishmania biology.organism_classification APX Mice Inbred C57BL Oxidative Stress 030104 developmental biology Infectious Diseases chemistry Parasitology Fungal and Parasitic Infections Reactive Oxygen Species Intracellular |
| Zdroj: | Infect Immun |
| Popis: | The molecular mechanisms underlying biological differences between two Leishmania species that cause cutaneous disease, L. major and L. amazonensis, are poorly understood. In L. amazonensis, reactive oxygen species (ROS) signaling drives differentiation of nonvirulent promastigotes into forms capable of infecting host macrophages. Tight spatial and temporal regulation of H(2)O(2) is key to this signaling mechanism, suggesting a role for ascorbate-dependent peroxidase (APX), which degrades mitochondrial H(2)O(2). Earlier studies showed that APX-null L. major parasites are viable, accumulate higher levels of H(2)O(2), generate a greater yield of infective metacyclic promastigotes, and have increased virulence. In contrast, we found that in L. amazonensis, the ROS-inducible APX is essential for survival of all life cycle stages. APX-null promastigotes could not be generated, and parasites carrying a single APX allele were impaired in their ability to infect macrophages and induce cutaneous lesions in mice. Similar to what was reported for L. major, APX depletion in L. amazonensis enhanced differentiation of metacyclic promastigotes and amastigotes, but the parasites failed to replicate after infecting macrophages. APX expression restored APX single-knockout infectivity, while expression of catalytically inactive APX drastically reduced virulence. APX overexpression in wild-type promastigotes reduced metacyclogenesis, but enhanced intracellular survival following macrophage infection or inoculation into mice. Collectively, our data support a role for APX-regulated mitochondrial H(2)O(2) in promoting differentiation of virulent forms in both L. major and L. amazonensis. Our results also uncover a unique requirement for APX-mediated control of ROS levels for survival and successful intracellular replication of L. amazonensis. |
| Databáze: | OpenAIRE |
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