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

Selvakumar Subbian,Joel S Bader,Gilla Kaplan,Viraj Khetani,Dorothy Fallows,Petros C Karakousis,Blas Peixoto,Liana Tsenova,Nirmalya Bandyopadhyay,Paul O’Brien,Nicole L Kushner,Patricia Soteropoulos

doi:10.1186/1478-811x-11-60

Abstract

BackgroundPulmonary 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.ResultsTo 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.ConclusionsWe 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.

Highlights

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
Pulmonary infection of rabbits with Mtb HN878, a hyper-virulent W-Beijing strain, results in progressive cavitary disease; infection with CDC1551 is effectively cleared over time, establishing LTBI that can be reactivated upon immune suppression
We observed activation of cellular networks involved in the inflammatory response, STAT1 activation, recruitment and activation of macrophages and polymorphonuclear leukocytes (PMN), and fMLP-stimulation in the lungs of HN878infected rabbits

Summary

Introduction

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. Infection with CDC1551 results in early transient limited bacillary growth, followed by spontaneous clearance of organisms, as manifested by an absence of detectable colony forming units (CFU) in the lungs, liver and spleen by 12 to 16 weeks post-infection, depending on the initial inoculum [13]. This phenomenon represents true LTBI rather than tissue sterilization, since reactivation of the infection is achieved with immune suppression of rabbits with triamcinolone, a synthetic corticosteroid. HN878 infection is associated with lung inflammation, followed by a slow and sub-optimal activation of the host innate and adaptive immune responses and the sustained presence of activated CD4+ and CD8+ T cells throughout the course of infection, which seems to be driven by the bacillary load in the lungs [12]

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