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Quantification of Intracellular Growth Inside Macrophages is a Fast and Reliable Method for Assessing the Virulence of Leishmania Parasites
Published on: March 16, 2018
Infection with Leishmania major induces a cellular stress response in macrophages
Alessandra A Filardy1, Ana Caroline Costa-da-Silva1, Carolina M Koeller1
1Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Abstract:
We investigated early cellular responses induced by infection with Leishmania major in macrophages from resistant C57/BL6 mice. Infection increased production of reactive oxygen species by resident, but not inflammatory peritoneal macrophages. In addition, infection increased activation of stress-activated protein kinases/c-Jun N-terminal kinases (SAPK/JNK) in resident, but not in inflammatory peritoneal macrophages. Infection also increased expression of membrane and soluble FasL, but infected macrophages remained viable after 48 h. Infection increased secretion of cytokines/chemokines TNF-α, IL-6, TIMP-1, IL-1RA, G-CSF, TREM, KC, MIP-1α, MIP-1β, MCP-1, and MIP-2 in resident macrophages. Addition of antioxidants deferoxamine and N-acetylcysteine reduced ROS generation and JNK activation. Addition of antioxidants or JNK inhibitor SP600125 reduced secretion of KC. Furthermore, treatment with antioxidants or JNK inhibitor also reduced intracellular parasite replication. These results indicated that infection triggers a rapid cellular stress response in resident macrophages which induces proinflammatory signals, but is also involved in parasite survival and replication in host macrophages.
Insights
Leishmania major infection triggers cellular stress responses in resident macrophages, increasing reactive oxygen species and JNK activation. These pathways promote parasite survival and replication within host cells.
Area of Science:
- Immunology
- Cell Biology
- Parasitology
Background:
- Leishmania major infects macrophages, the primary host cells.
- Understanding early host-pathogen interactions is crucial for developing treatments.
Purpose of the Study:
- To investigate early cellular responses in macrophages infected with Leishmania major.
- To elucidate the role of reactive oxygen species (ROS) and stress-activated protein kinases/c-Jun N-terminal kinases (SAPK/JNK) pathways in Leishmania infection.
Main Methods:
- Infection of C57/BL6 mouse-derived resident and inflammatory peritoneal macrophages with Leishmania major.
- Measurement of ROS production, SAPK/JNK activation, FasL expression, and cytokine/chemokine secretion.
- Treatment with antioxidants (deferoxamine, N-acetylcysteine) and a JNK inhibitor (SP600125).
- Assessment of intracellular parasite replication.
Main Results:
- Leishmania major infection increased ROS production and SAPK/JNK activation in resident macrophages, but not inflammatory ones.
- Infected resident macrophages secreted various pro-inflammatory cytokines and chemokines.
- Antioxidants and JNK inhibition reduced ROS generation, JNK activation, KC secretion, and intracellular parasite replication.
Conclusions:
- Leishmania major infection induces a rapid cellular stress response in resident macrophages.
- The ROS and SAPK/JNK pathways are involved in promoting parasite survival and replication within macrophages.
- Targeting these pathways may offer therapeutic strategies against leishmaniasis.
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