Transcriptional reprogramming in nonhuman primate (rhesus macaque) tuberculosis granulomas.
BACKGROUND
In 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.


RESULTS
We 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 IFNgamma, TNFalpha, 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 approximately two-thirds of all genes induced in early lesions was later repressed.


CONCLUSIONS
The 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.
Mehra
Smriti
S
Divisions of Bacteriology and Parasitology, Tulane National Primate Research Center, Covington, Louisiana, United States of America.
Pahar
Bapi
B
Dutta
Noton K
NK
Conerly
Cecily N
CN
Philippi-Falkenstein
Kathrine
K
Alvarez
Xavier
X
Kaushal
Deepak
D
D000818:Animals; D020869:Gene Expression Profiling; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008171:Lung Diseases / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology; D008253:Macaca mulatta; D009169:Mycobacterium tuberculosis / Q000502:physiology; D013997:Time Factors; D014375:Tuberculoma / Q000235:genetics* / Q000276:immunology
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