Unique Chemokine Profiles of Lung Tissues Distinguish Post-chemotherapeutic Persistent and Chronic Tuberculosis in a Mouse Model

Abstract

There is a substantial need for biomarkers to distinguish latent stage from active Mycobacterium tuberculosis infections, for predicting disease progression. To induce the reactivation of tuberculosis, we present a new experimental animal model modified based on the previous model established by our group. In the new model, the reactivation of tuberculosis is induced without administration of immunosuppressive agents, which might disturb immune responses. To identify the immunological status of the persistent and chronic stages, we analyzed immunological genes in lung tissues from mice infected with M. tuberculosis. Gene expression was screened using cDNA microarray analysis and confirmed by quantitative RT-PCR. Based on the cDNA microarray results, 11 candidate cytokines genes, which were obviously up-regulated during the chronic stage compared with those during the persistent stage, were selected and clustered into three groups: (1) chemokine genes, except those of monocyte chemoattractant proteins (MCPs; CXCL9, CXCL10, CXCL11, CCL5, CCL19); (2) MCP genes (CCL2, CCL7, CCL8, CCL12); and (3) TNF and IFN-γ genes. Results from the cDNA microarray and quantitative RT-PCR analyses revealed that the mRNA expression of the selected cytokine genes was significantly higher in lung tissues of the chronic stage than of the persistent stage. Three chemokines (CCL5, CCL19, and CXCL9) and three MCPs (CCL7, CCL2, and CCL12) were noticeably increased in the chronic stage compared with the persistent stage by cDNA microarray (p < 0.01, except CCL12) or RT-PCR (p < 0.01). Therefore, these six significantly increased cytokines in lung tissue from the mouse tuberculosis model might be candidates for biomarkers to distinguish the two disease stages. This information can be combined with already reported potential biomarkers to construct a network of more efficient tuberculosis markers.

Mucosal delivery of ESX-1–expressing BCG strains provides superior immunity against tuberculosis in murine type 2 diabetes

“…S11), essential coreceptors for the TDM-induced immune response which have been associated with impaired innate recognition of Mtb in T2D mice (47). Furthermore, CCL12, intracellular NOD2, and lysosomal cathepcin C, all of which have been implicated in immunity to Mtb (22,48,49), were also found to be significantly down-regulated in T2D mice. Major transcriptomic changes were observed following Mtb infection.…”

“…Among those, 312 genes were mutually differentially regulated in TB/T2D and TB mice. These include genes previously found in blood and lung transcriptome profiles from TB patients and Mtbinfected mice, respectively (21,22). In addition, 124 DEGs were differentially expressed between T2D and naïve control mice.…”

Insight into the Molecular Characteristics of Langhans Giant Cell by Combination of Laser Capture Microdissection and RNA Sequencing

“…27 Previous studies have suggested that CCL7 was up-regulated in active tuberculosis patients and was down-regulated in post-chemotherapeutic treated mouse tuberculosis model. 28,29 Moreover, in Leishmania major infection, CCL7 was found to be an inflammatory regulator in different organs. 30 Therefore, CCL7 may be a potential target for the host-directed treatment of infectious granulomatous disease.…”