Abstract
The fate of Leishmania infection can be strongly influenced by the host genetic background. In this work, we describe gene expression modulation of the immune system based on dual global transcriptome profiles of bone marrow-derived macrophages (BMDMs) from BALB/c and C57BL/6 mice infected with Leishmania amazonensis. A total of 12,641 host transcripts were identified according to the alignment to the Mus musculus genome. Differentially expressed genes (DEGs) profiling revealed a differential modulation of the basal genetic background between the two hosts independent of L. amazonensis infection. In addition, in response to early L. amazonensis infection, 10 genes were modulated in infected BALB/c vs. non-infected BALB/c macrophages; and 127 genes were modulated in infected C57BL/6 vs. non-infected C57BL/6 macrophages. These modulated genes appeared to be related to the main immune response processes, such as recognition, antigen presentation, costimulation and proliferation. The distinct gene expression was correlated with the susceptibility and resistance to infection of each host. Furthermore, upon comparing the DEGs in BMDMs vs. peritoneal macrophages, we observed no differences in the gene expression patterns of Jun, Fcgr1 and Il1b, suggesting a similar activation trends of transcription factor binding, recognition and phagocytosis, as well as the proinflammatory cytokine production in response to early L. amazonensis infection. Analysis of the DEG profile of the parasite revealed only one DEG among the 8,282 transcripts, indicating that parasite gene expression in early infection does not depend on the host genetic background.
Highlights
The fate of Leishmania infection can be strongly influenced by the host genetic background
bone marrow-derived macrophages (BMDMs) from the BALB/c and C57BL/6 mouse strains were infected with L. amazonensis (MOI 5:1), and the infection index was analyzed at 4 h after infection
Transcriptomic analyses were performed on five independent biological replicates per analysis of BMDMs from BALB/c and C57BL/6 mice infected or not infected with L. amazonensis for 4 h, using Illumina NovaSeq. 6000 sequencing, which generated millions of reads
Summary
The fate of Leishmania infection can be strongly influenced by the host genetic background. Neutrophils and monocytes are first recruited to the site of the insect bite, which leads to the differentiation of macrophages; this differentiation is followed by the recognition and phagocytosis of the parasite, as well as the induction of a range of inflammatory signals Other phagocytes, such as dendritic cells, play important roles since they induce the response in other inflammatory tissues. Regulation of the host immune response to Leishmania has been well defined in L. major model in which the BALB/c mouse strain is susceptible to infection due to early bursts of IL4 that lead to disease progression. L. amazonensis induces severe lesions upon cutaneous inoculation in susceptible BALB/c mice, while the same parasite causes only moderate lesions in resistant C57BL/6 mice[21,27] Such variations in infection have been observed as differences in the lesion size, parasite burden, cellular activation and Th1/Th2 ratio between the different infected strains[21,25,28]. In Tlr4- and MyD88- deficient mice, L. amazonensis shows increased in vitro infectivity; in contrast Tlr2-deficient mice exhibited a decreased parasite loads, indicating that this receptor is required for disease progression[32]
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