The Blood Transcriptome of Experimental Melioidosis Reflects Disease Severity and Shows Considerable Similarity with the Human Disease

Abstract

Melioidosis, a severe human disease caused by the bacterium Burkholderia pseudomallei, has a wide spectrum of clinical manifestations ranging from acute septicaemia to chronic localized illness or latent infection. Murine models have been widely used to study the pathogenesis of infection and to evaluate novel therapies or vaccines, but how faithfully they recapitulate the biology of human melioidosis at a molecular level is not known. Here, mice were intranasally infected with either high or low doses of B. pseudomallei to generate either acute, chronic or latent infection and host blood and tissue transcriptional profiles were generated. Acute infection was accompanied by a homogeneous signature associated with induction of multiple innate immune response pathways, such as IL10, TREM1 and IFN-signaling, largely found in both blood and tissue. The transcriptional profile in blood reflected the heterogeneity of chronic infection and quantitatively reflected the severity of disease. Genes associated with fibrosis and tissue remodelling, including MMPs and collagen, were upregulated in chronically infected mice with severe disease. Transcriptional signatures of both acute and chronic melioidosis revealed upregulation of iNOS in tissue, consistent with the expression of IFN-γ, but also Arginase-1, a functional antagonist of the iNOS pathway, and was confirmed by immunohistochemistry. Comparison of these mouse blood datasets by pathway and modular analysis with the blood transcriptional signature of patients with melioidosis showed that many genes were similarly perturbed, including Arginase-1, IL10, TREM1 and IFN-signaling, revealing the common immune response occurring in both mice and humans.

Common Host Responses in Murine Aerosol Models of Infection Caused by Highly Virulent Gram-Negative Bacteria from the Genera Burkholderia, Francisella and Yersinia

“…Further, even though infection was commonly found to induce a variety of transcripts for chemokines involved in cellular recruitment it is notable either here (Table S1) or through previous studies [9,12,15,32] that there is a demonstrable reduction in RANTES expression early in the time course of infection in the mouse consistent with previous research [35] (Figure 2). This is significant as the downregulation of RANTES has previously been suggested as an early indicator of sepsis in humans [36] suggesting a more active modulation of cellular recruitment to the lung by the bacteria at the protein rather than the transcript level.…”

“…The data arising from this RNAseq approach complement those gained from microarray/chip-based analyses of the transcriptome and the pathways triggered in response to infection with species from the Genera Burkholderia, Francisella and Yersinia [12,17,22,[26][27][28][29][30]. In particular, our data closely mirrors that previously published for a different clinical strain of B. pseudomallei within experimental murine (C57BL/6) models of infection and human blood responses [12]. The rapidity of the replication of B. pseudomallei from the primary site of infection is well known [9,10] and was observed here ( Figure S1).…”

“…Natural human infections occur percutaneously through skin abrasions and by the inhalation of aerosols from ground water. The disease exists in both acute and chronic forms, ranging from a localised infection to septicemia involving multiple organs, most commonly the spleen, liver and lung within humans and experimental mouse models [9][10][11][12]. The disease has the ability to become latent and reappears several years later possibly at the onset of an immunosuppressive condition such as late-onset diabetes.…”

Tissue and host species-specific transcriptional changes in models of experimental visceral leishmaniasis

“…The clinical value of this signature is however questionable, given the lack of similarity between whole blood transcriptomic responses observed in our study and that of humans with VL in Brazil 39 . In a similar study in acute melioidosis, 26.9% of genes were similarly regulated in murine and human infection 21 . The reasons for this lack of similarity in VL are likely to be multiple, including the chronicity of infection, difference in pathogen ( L. donovani vs. L. infantum ), specific characteristics of Brazilian VL 12 or differing analytical methods.…”

Dysregulation of TNF-α and IFN-γ expression is a common host immune response in a chronically infected mouse model of melioidosis when comparing multiple human strains of Burkholderia pseudomallei

“…Furthermore, we used flow-cytometry to identify the increase in specific inflammatory cells (macrophages, neutrophils, and NK cells) in chronically infected spleens, which was not used in the C57BL/6 study, although neutrophils had been identified earlier from the same group to be the major host cell response required for protection against B. pseudomallei in an acute infection model in C57BL/6 mice [62]. Conejero et al [2015] [63] have further reported on a transcriptome analysis of experimental melioidosis and were able to identify different markers that were associated with acute and chronic infection. There was an upregulation of iNOS in tissue which was reported to be associated with the expression of IFN-γ, and also they found the upregulation of Arginase-1 that was confirmed by immunohistochemistry.…”