Related Experiment Video
Updated: May 8, 2026
Intranasal Immunization and Milk Collection in Studies of Maternal Immunization in New Zealand White Rabbits (Oryctolagus cuniculus)
Published on: July 31, 2021
Early innate immunity determines outcome of Mycobacterium tuberculosis pulmonary infection in rabbits
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.
Insights
Early immune responses in the lungs significantly influence tuberculosis (TB) outcomes. Differential regulation of inflammation and gene expression at 3 hours post-infection predicts long-term TB progression or latency.
Area of Science:
- Immunology
- Microbiology
- Genomics
Background:
- Tuberculosis (TB) results from Mycobacterium tuberculosis (Mtb) infection, with outcomes ranging from latent infection (LTBI) to active disease.
- Host immune responses dictate TB outcomes, but the precise mechanisms remain unclear.
- A rabbit model demonstrated that Mtb strains HN878 and CDC1551 induce distinct disease progressions, mimicking human TB and LTBI, respectively.
Purpose of the Study:
- To investigate how initial host-Mtb interactions in the lungs influence long-term infection outcomes.
- To identify early immune response markers that predict TB disease progression or latency.
Main Methods:
- Infection of rabbits with Mtb strains HN878 (hyper-virulent) and CDC1551 (hyper-immunogenic).
- Analysis of lung immune cell accumulation (mononuclear and polymorphonuclear leukocytes) at 3 hours post-infection.
- Whole-genome microarray analysis to assess early (3 hours) and later (4 weeks) host gene expression changes.
Main Results:
- At 3 hours post-infection, HN878 induced greater leukocyte accumulation compared to CDC1551, despite similar bacillary loads.
- Early gene expression analysis revealed significant differences in inflammatory response and STAT1 activation pathways between HN878 and CDC1551 infections.
- At 4 weeks, HN878 infection showed higher bacillary loads and granulomatous response; gene expression patterns at 4 weeks largely mirrored those at 3 hours.
Conclusions:
- Differential regulation of the innate immune response and associated gene expression at 3 hours post-Mtb infection is critical.
- These early inflammatory and transcriptional events predict the long-term outcome of Mtb infection in the lungs.
