Tuberculosis genes expressed during persistence and reactivation in the resistant rabbit model

Abstract

As previously published, after aerosol infection with Mycobacterium tuberculosis H37Rv, New Zealand white rabbits established infection with active bacillary replication, but later contained disease to a paucibacillary state through an effective adaptive response consistent with latency. Despite the heterogeneity among outbred rabbits, the resistant response was uniform. Immunosuppression resulted in reactivation with increased lung bacillary burden. Using this rabbit model, we isolated bacillary RNA from infected rabbit lungs and assessed transcriptional profiles of bacillary genes using RT-PCR to examine genes differentially regulated during active replication, persistence, steroid-induced reactivation, and post-steroid immune reconstitution. Genes involved in hypoxia response (fdxA), resuscitation promoting factors (rpfB), and DNA repair pathways (Rv2191) may be important in bacillary persistence. Further investigation into these gene pathways is warranted.

The multistage vaccine H56 boosts the effects of BCG to protect cynomolgus macaques against active tuberculosis and reactivation of latent Mycobacterium tuberculosis infection

“…Sherman, unpublished observations). Consistent with previous studies in mice and rabbits (14,25), Rv2660c showed high relative expression in each sample (Figure 1). ESAT-6 was also expressed, at levels similar to Rv2660c.…”

Latent Tuberculosis Infection: Myths, Models, and Molecular Mechanisms

“…On the other hand, rabbits are naturally resistant to M. tuberculosis infection, resulting in a paucibacillary population in the lungs of animals at 10 weeks, which can be reactivated with immune-modulating agents (92,93). Since prior sensitization can alter disease pathology in the rabbit and different strains of M. tuberculosis cause various spectrums of disease (94,95), these parameters may be manipulated to establish a model of latency.…”

Resuscitation-promoting factors are important determinants of the pathophysiology inMycobacterium tuberculosisinfection

“…The subsequent transition to chronic persistent infection is marked by the development of cell-mediated immunity which stabilizes bacillary replication (Hu et al, 2015;Munoz-Elias et al, 2005). Throughout this period, the expression of rpfA-rpfE can be detected (Kesavan et al, 2009;Tufariello et al, 2006). Although the precise role of Rpf is unclear, the study of rpf deletion mutants underscores the importance of Rpf in the initial stages of infection.…”