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Comparative Study
. 2019 Apr 24:9:111.
doi: 10.3389/fcimb.2019.00111. eCollection 2019.

Human Macrophages Clear the Biovar Microtus Strain of Yersinia pestis More Efficiently Than Murine Macrophages

Qingwen Zhang  1 , Youquan Xin  1 , Haihong Zhao  1 , Rongjiao Liu  2 , Xiaoqing Xu  1 , Yanfeng Yan  2 , Zhipeng Kong  1 , Tong Wang  2 , Zhizhen Qi  1 , Qi Zhang  1 , Yang You  2 , Yajun Song  2 , Yujun Cui  2 , Ruifu Yang  2 , Xuefei Zhang  1 , Zongmin Du  2
Affiliations
Comparative Study

Human Macrophages Clear the Biovar Microtus Strain of Yersinia pestis More Efficiently Than Murine Macrophages

Qingwen Zhang et al. Front Cell Infect Microbiol. .

Abstract

Yersinia pestis is the etiological agent of the notorious plague that has claimed millions of deaths in history. Of the four known Y. pestis biovars (Antiqua, Medievalis, Orientalis, and Microtus), Microtus strains are unique for being highly virulent in mice but avirulent in humans. Here, human peripheral lymphocytes were infected with the fully virulent 141 strain or the Microtus strain 201, and their transcriptomes were determined and compared. The most notable finding was that robust responses in the pathways for cytokine-cytokine receptor interaction, chemokine signaling pathway, Toll-like receptor signaling and Jak-STAT signaling were induced at 2 h post infection (hpi) in the 201- but not the 141-infected lymphocytes, suggesting that human lymphocytes might be able to constrain infections caused by strain 201 but not 141. Consistent with the transcriptome results, much higher IFN-γ and IL-1β were present in the supernatants from the 201-infected lymphocytes, while inflammatory inhibitory IL-10 levels were higher in the 141-infected lymphocytes. The expressions of CSTD and SLC11A1, both of which are functional components of the lysosome, increased in the 201-infected human macrophage-like U937 cells. Further assessment of the survival rate of the 201 bacilli in the U937 cells and murine macrophage RAW 264.7 cells revealed no viable bacteria in the U937 cells at 32 hpi.; however, about 5-10% of the bacteria were still alive in the RAW264.7 cells. Our results indicate that human macrophages can clear the intracellular Y. pestis 201 bacilli more efficiently than murine macrophages, probably by interfering with critical host immune responses, and this could partially account for the host-specific pathogenicity of Y. pestis Microtus strains.

Keywords: Yersinia pestis; biovar microtus; host-specific pathogenicity; human lymphocyte; transcriptomes.

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Figures

Figure 1
Figure 1
Differentially expressed genes in human peripheral lymphocytes infected with Y. pestis 201 or 141 strains. Numbers of genes that were differentially expressed at 2, 4, and 8 hpi in 201-infected (A) or 141-infected lymphocytes (B) in comparison with the uninfected lymphocytes and between the 201-infected and 141-infected lymphocytes (C) are shown here.
Figure 2
Figure 2
Gene expression patterns of the pathways that showing the significant differences between the Y. pestis 201- and 141-infected human peripheral lymphocytes. Some of the critical cellular pathways that were significantly enriched in the genes differentially expressed at 2, 4, or 8 hpi in 201- and 141-infected lymphocytes are shown (p < 0.05, Fisher's exact test followed by the Benjamini multiple testing correction). Changes of the differentially expressed genes are presented in different colors as shown in the color key.
Figure 3
Figure 3
Human peripheral lymphocytes infected with the Y. pestis 201 strain secreted more abundant IFN-γ and IL-1β, and less immunosuppressive IL-10 than those infected with the 141 strain. Culture supernatants from the infected lymphocytes were collected at 2, 4, and 8 hpi and analyzed for the different cytokines using BDTM CBA Kits. Significantly higher IFN-γ and IL-1β levels were present in the supernatant from the 201-infected lymphocytes, while inflammatory inhibitory IL-10 was higher in the 141-infected lymphocytes at 8 hpi. Figures were drawn using Graphpad Prism 5.0, and the statistical significance of the differences in the cytokine levels between the different groups of samples were analyzed by two-way ANOVA analysis followed by Bonferroni post-tests.
Figure 4
Figure 4
Immunoblotting detection of several proteins involved in lysosome activation in U937 and RAW264.7 cells infected with the Y. pestis 201 strain. Human macrophage-like U937 cells primed with PMA and murine macrophage RAW264.7 cells were infected with Y. pestis strain 201, and the cells were collected at 2, 4, 8 hpi and lysed for the immunoblotting detection of SLC11A1, CTSD, and CTSZ using specific antibodies. At least three independent experiments were performed and a representative result was shown here. The arrow indicates the position of CTSD bands.
Figure 5
Figure 5
Y. pestis strain 201 survival rates were significantly lower in U937 than in RAW264.7 cells. PMA primed U937 and RAW264.7 cells were infected with Y. pestis 201 strain at an MOI of 1 or 5, and the living bacteria inside the cells at 2, 4, 8, 20, and 32 hpi were counted by plating the cell lysates onto the agar plates. Experiments were performed in triplicates for three independent times and the similar results were obtained. The survival percentages of the bacteria, as based on a representative result, are shown in average and standard deviation.
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