Early innate immunity determines outcome of Mycobacterium tuberculosis pulmonary infection in rabbits.

Abstract

BACKGROUND:

Pulmonary infection of humans by Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), results in active disease in 5-10% of individuals, while asymptomatic latent Mtb infection (LTBI) is established in the remainder. The host immune responses that determine this differential outcome following Mtb infection are not fully understood. Using a rabbit model of pulmonary TB, we have shown that infection with the Mtb clinical isolate HN878 (a hyper-virulent W-Beijing lineage strain) leads to progressive cavitary disease similar to what is seen in humans with active TB. In contrast, infection with Mtb CDC1551 (a hyper-immunogenic clinical isolate) is efficiently controlled in rabbit lungs, with establishment of LTBI, which can be reactivated upon treatment with immune-suppressive drugs. We hypothesize that the initial interaction of Mtb with the cells of the host response in the lungs determine later outcome of infection.

RESULTS:

To test this hypothesis, we used our rabbit model of pulmonary TB and infected the animals with Mtb HN878 or CDC1551. At 3 hours, with similar lung bacillary loads, HN878 infection caused greater accumulation of mononuclear and polymorphonuclear leukocytes (PMN) in the lungs, compared to animals infected with CDC1551. Using whole-genome microarray gene expression analysis, we delineated the early transcriptional changes in the lungs of HN878- or CDC1551-infected rabbits at this time and compared them to the differential response at 4 weeks of Mtb-infection. Our gene network and pathway analysis showed that the most significantly differentially expressed genes involved in the host response to HN878, compared to CDC1551, at 3 hours of infection, were components of the inflammatory response and STAT1 activation, recruitment and activation of macrophages, PMN, and fMLP (N-formyl-Methionyl-Leucyl-Phenylalanine)-stimulation. At 4 weeks, the CDC1551 bacillary load was significantly lower and the granulomatous response reduced compared to HN878 infection. Moreover, although inflammation was dampened in both Mtb infections at 4 weeks, the majority of the differentially expressed gene networks were similar to those seen at 3 hours.

CONCLUSIONS:

We propose that differential regulation of the inflammation-associated innate immune response and related gene expression changes seen at 3 hours determine the long term outcome of Mtb infection in rabbit lungs.

• Authors: Selvakumar Subbian, Nirmalya Bandyopadhyay, Liana Tsenova, Paul O'Brien, Viraj Khetani, Nicole L Kushner, Blas Peixoto, Patricia Soteropoulos, Joel S Bader, Petros C Karakousis, Dorothy Fallows, Gilla Kaplan
• Journal: Cell communication and signaling : CCS (Cell Commun Signal) Vol. 11 Pg. 60 (Aug 19 2013) ISSN: 1478-811X [Electronic] England
• PMID: 23958185 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• STAT1 Transcription Factor

Topics

• Animals
• Immunity, Innate
• Inflammation (immunology)
• Leukocytes, Mononuclear (metabolism)
• Macrophages (metabolism)
• Mycobacterium tuberculosis
• Neutrophils (metabolism)
• Rabbits
• STAT1 Transcription Factor (metabolism)
• Time Factors
• Transcriptome
• Tuberculosis, Pulmonary (immunology, microbiology)