Abstract
Leishmaniasis is caused by intracellular parasites transmitted to vertebrates by sandfly bites. Clinical manifestations include cutaneous, mucosal or visceral involvement depending upon the host immune response and the parasite species. To assure their survival inside macrophages, these parasites developed a plethora of highly successful strategies to manipulate various immune system pathways. Considering that inflammasome activation is critical for the establishment of a protective immune response in many parasite infections, in this study we determined the transcriptome of THP-1 cells after infection with L. infantum, with a particular focus on the inflammasome components. To this end, the human cell line THP-1, previously differentiated into macrophages by PMA treatment, was infected with L. infantum promastigotes. Differentiated THP-1 cells were also stimulated with LPS to be used as a comparative parameter. The gene expression signature was determined 8 hours after by RNA-seq technique. Infected or uninfected THP-1 cells were stimulated with nigericin (NIG) to measure active caspase-1 and TNF-α, IL-6 and IL-1β levels in culture supernatants after 8, 24 and 48 hours. L. infantum triggered a gene expression pattern more similar to non-infected THP-1 cells and very distinct from LPS-stimulated cells. Some of the most up-regulated genes in L. infantum-infected cells were CDC20, CSF1, RPS6KA1, CD36, DUSP2, DUSP5, DUSP7 and TNFAIP3. Some up-regulated GO terms in infected cells included cell coagulation, regulation of MAPK cascade, response to peptide hormone stimulus, negative regulation of transcription from RNA polymerase II promoter and nerve growth factor receptor signaling pathway. Infection was not able to induce the expression of genes associated with the inflammasome signaling pathway. This finding was confirmed by the absence of caspase-1 activation and IL-1β production after 8, 24 and 48 hours of infection. Our results indicate that L. infantum was unable to activate the inflammasomes during the initial interaction with THP-1 cells.
Highlights
Leishmaniasis are a group of increasingly prevalent diseases transmitted to humans by sandflies, mainly Phlebotomus and Lutzomya [1]
To investigate the parasite-host interaction is fundamental to understand the immunopathogenesis of visceral leishmaniasis and to allow the development of new therapeutic strategies
We used RNA-seq, a tool that allowed to investigate the global gene expression of THP-1 cells, which is a macrophage-like human cell line, infected with L. infantum. This approach allowed us to evaluate the expression of genes that compose the inflammasomes pathway and other gene networks and signaling pathways triggered after infection. This analysis indicated that, unlike species causing cutaneous leishmaniasis, L. infantum did not induce the expression of genes of inflammasome pathways, nor caspase-1 activation or IL-1β production, possibly reflecting a parasite strategy to manipulate immune system and to allow its survival inside the cells
Summary
Leishmaniasis are a group of increasingly prevalent diseases transmitted to humans by sandflies, mainly Phlebotomus and Lutzomya [1]. Very distinct outcomes as cutaneous lesions, mucosal lesions and visceral involvement can occur depending upon the parasite specie and the immune condition of the vertebrate host [2]. 0.2 to 0.4 million visceral cases and 0.7 to 1.2 million cases of cutaneous leishmaniasis occur each year. Macrophages play a pivotal role in these diseases; they are the primary resident cells and they are permissive for parasite proliferation [4]. They are considered the most relevant effector cells being responsible for Leishmania elimination through activation of inflammatory signaling pathways and oxidative burst [5,6,7]. The establishment of the infection depends on the efficiency of the host to induce effector immune response and the parasite’s efficiency to subvert the immune response of the host [11]
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