Transcriptional Reprogramming in Nonhuman Primate (Rhesus Macaque) Tuberculosis Granulomas

Abstract

BackgroundIn response to Mtb infection, the host remodels the infection foci into a dense mass of cells known as the granuloma. The key objective of the granuloma is to contain the spread of Mtb into uninfected regions of the lung. However, it appears that Mtb has evolved mechanisms to resist killing in the granuloma. Profiling granuloma transcriptome will identify key immune signaling pathways active during TB infection. Such studies are not possible in human granulomas, due to various confounding factors. Nonhuman Primates (NHPs) infected with Mtb accurately reflect human TB in clinical and pathological contexts.Methodology/Principal FindingsWe studied transcriptomics of granuloma lesions in the lungs of NHPs exhibiting active TB, during early and late stages of infection. Early TB lesions were characterized by a highly pro-inflammatory environment, expressing high levels of immune signaling pathways involving IFNγ, TNFα, JAK, STAT and C-C/C-X-C chemokines. Late TB lesions, while morphologically similar to the early ones, exhibited an overwhelming silencing of the inflammatory response. Reprogramming of the granuloma transcriptome was highly significant. The expression of ∼ two-thirds of all genes induced in early lesions was later repressed.Conclusions/SignificanceThe transcriptional characteristics of TB granulomas undergo drastic changes during the course of infection. The overwhelming reprogramming of the initial pro-inflammatory surge in late lesions may be a host strategy to limit immunopathology. We propose that these host profiles can predict changes in bacterial replication and physiology, perhaps serving as markers for latency and reactivation.

Doxycycline and HIV Infection Suppress Tuberculosis-induced Matrix Metalloproteinases

“…We did not demonstrate increased MMP gene expression in Mtb-infected guinea pigs, unlike in human TB infection (42). This may reflect a delayed global reprogramming of granuloma gene expression that has recently been identified in the primate model of TB (43). In addition, because no MMP-1 up-regulation was demonstrated in infected animals, and guinea pigs very rarely cavitate when infected with TB, this model may not be optimal to study MMP-modulating effects of doxycycline.…”

MMP-1 drives immunopathology in human tuberculosis and transgenic mice

“…More recently, gene expression profiling of macrophages demonstrated that MMP1 was the most potently upregulated gene in patients who developed pulmonary TB compared with those with latent disease (22). Similarly, microarray profiling of human TB granulomas has shown a 606-fold upregulation of MMP-1 expression compared with that in uninfected lung (23), and profiling of macaque lung tissue has demonstrated that MMP1 is one of the most upregulated genes of the 1,584 induced by TB (24). In the zebrafish model, host transcriptome analysis comparing virulent and attenuated strains of Mycobacterium marinum found that although most genes were equally modulated by infection, the virulent bacterial strain upregulated 2 collagenases more potently than the attenuated strain (25).…”

CD4 + T-cell–independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection

“…Thirty-seven specific pathogen-free, retrovirus-free, mycobacteria-naive, adult rhesus macaques that were bred and housed at the Tulane National Primate Research Center (TNPRC) and that ranged from 3 to 12 y of age were assigned to two groups, based on power calculations to detect, with sufficient power, statistically significant differences between the reactivating and nonreactivating groups following coinfection with SIV. All macaques were aerosol-exposed, as described previously (14,22,26,44), to a low dose (∼25 CFU implanted) of Mtb CDC1551. A subset of the macaques was also exposed approximately 9 wk later to 300 TCID50 (50% tissue culture infectious dose) of SIVmac239 administered intravenously in 1 mL saline, as described previously (22).…”