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. 2019 Dec 4;14(12):e0225272.
doi: 10.1371/journal.pone.0225272. eCollection 2019.

Gene expression is associated with virulence in murine macrophages infected with Leptospira spp

Erivelto Corrêa de Araújo Junior  1 , Leandro Encarnação Garcia  1 , Matheus Janeck Araújo  1 , Itamar Souza Oliveira-Junior  2 , Daniel Robert Arnold  1 , Flavia Lombardi Lopes  1 , Márcia Marinho  1
Affiliations

Gene expression is associated with virulence in murine macrophages infected with Leptospira spp

Erivelto Corrêa de Araújo Junior et al. PLoS One. .

Abstract

Leptospira genus contains species that affect human health with varying degrees of pathogenicity. In this context, we aimed to evaluate the differences in the modulation of host gene expression by strains of Leptospira varying in virulence. Our data showed a high number of differentially expressed transcripts in murine macrophages following 6h of infection. Leptospira infection modulated a set of genes independently of their degree of virulence. However, pathway analysis indicated that Apoptosis, ATM Signaling, and Cell Cycle: G2/M DNA Damage Checkpoint Regulation were exclusively regulated following infection with the virulent strain. Taken together, results demonstrated that species and virulence play a role during host response to Leptospira spp in murine macrophages, which could contribute to understanding the pathogenesis of leptospirosis.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Differentially expressed genes after 6 hours of infection in murine macrophages J774A.1 with saprophytic, attenuated and virulent strains of Leptospira spp.
The colored bars show the up-regulated (red) or down-regulated (green) genes and grey a total of genes. (n = 3 / assay, FDR-adjusted p<0.05, fold change ± 2).
Fig 2
Fig 2. Venn diagram for differentially expressed genes after 6 hours of infection in murine macrophages J774A.1 with saprophytic, attenuated and virulent strains of Leptospira spp.
Total number of canonical pathways (n = 3/treatment; FDR<0.05, fold change ± 2) in the contrasts Infected (Saprophyte; Attenuated and Virulent) vs. Non-infected Control.
Fig 3
Fig 3. Heatmap of differentially expressed genes shows the average signal by macrophages at 6 hours of infection in different strains of Leptospira spp.
The red color indicate increased expression, green color indicates the decreased expression as compared to control (n = 3/treatment; p-value<0.01; FDR<0.05; linear fold change ± 2).
Fig 4
Fig 4. Venn diagram for pathways of modulated macrophages at 6 hours of infection with different strains of Leptospira spp.
Total number of canonical pathways (n = 3/treatment; FDR<0.05, fold change ± 2) in the contrasts Infected (Saprophyte; Attenuated and Virulent) vs. Non-infected Control.
Fig 5
Fig 5. Canonical signaling pathway obtained by the IPA (Ingenuity Pathway Analysis software.
Red and green indicate upregulated and down-regulated genes, respectively, compared to control group, and belongs to datasets of DEGs virulent vs. control assays. Color intensity corresponds to the degree of up or downregulation (fold-change). White represents the known genes of the pathway without identification in the transcriptomic analysis. Panel A) Canonical signaling pathway of Apoptosis of in vitro macrophages. Panel B) Canonical signaling of ATM of in vitro macrophages. Panel C) Canonical signaling pathway of Cell Cycle: G2 / M DNA Damage Checkpoint Regulation of in vitro macrophages.
Fig 6
Fig 6. qRT-PCR of mRNA expression levels in infected macrophages with different strains of Leptospira compared to non-infected controls.
Panel A) Relative expression of TNF-α in saprophyte, culture-attenuated and virulent compared to control. Panel B) Relative expression of IL-1β in saprophyte, culture-attenuated and virulent compared to control. Panel C) Relative expression of NOS2 in saprophyte, culture-attenuated and virulent compared to control (p <0.05). Different superscript letters differs significantly (p <0.05).
Fig 7
Fig 7. Heatmap of Canonical pathways predicted through z-score to be inhibited or activated in macrophages, at six hours of infection by different strains of Leptospira spp.
Activated pathways are plotted in red color and inhibited pathways in blue. (n = 3/treatment; p-value < 0.01).
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