Abstract
Tuberculous meningitis (TBM), caused by Mycobacterium tuberculosis (Mtb), is the deadliest form of tuberculosis in humans, particularly in children and the geriatric population. However, the host-pathogen interactions underlying TBM is not well understood. Rabbits are a valuable model system to study TB in humans. The rabbit model of TB recapitulates several pathophysiological characteristics, including heterogeneity, architecture, and development of granulomas at the site of infection as observed in Mtb-infected human organs. Previously, our group has established a rabbit model of TBM that has been used to understand the host immune response to Mtb infection and to evaluate novel intervention therapies for TBM. In this model, rabbits infected intracisternally with Mtb showed histopathologic manifestations in the brain and meninges that are hallmarks of TBM in humans, including inflammatory cell accumulation and thickening of the leptomeninges. However, in this model, a helmet made of dental acrylic was attached to rabbit's skull with screws under anesthesia. At 24 h post-procedure, the animals were injected intracisternally with Mtb using a spinal needle. The rabbits were necropsied at various experimental time points up to 2 weeks post-infection. Although this method has been successful in establishing TBM, placement of the dental acrylic helmet on rabbit skull with screws that stays until the experimental endpoint poses stress to the animals and increases the chances of secondary infection. To alleviate these issues, we have developed an improved protocol, in which sedated rabbits are placed on specialised stereotaxic equipment and injected with Mtb intracisternally. This method is less cumbersome, faster, and more efficient in delivering the bacteria. Besides, the animals are not stressed by this method, compared to the previous one.
Highlights
Tuberculous meningitis (TBM) constitutes approximately 5%–10% of extra-pulmonary TB cases and about 1% of all active TB cases, but it is the deadliest form of TB as the death rate is alarmingly high (>50%) among all extra-pulmonary TB cases [1,2]
The incidence and prevalence of TBM is higher in children aged below four years and in older people, especially those suffering from severe pulmonary TB and immune-compromised individuals [2,3,4]
A recent study shows that about 40% of TBM cases with a deteriorating disease would die within six months of diagnosis [1,5]
Summary
Tuberculous meningitis (TBM) constitutes approximately 5%–10% of extra-pulmonary TB cases and about 1% of all active TB cases, but it is the deadliest form of TB as the death rate is alarmingly high (>50%) among all extra-pulmonary TB cases [1,2]. At 6–15 days post-inoculation, tubercles were produced in the meninges accompanied by signs of TBM, such as paralysis, followed by death This early study demonstrated the resemblance of disease progression and the immunopathology between human TBM and the rabbit model. A rabbit model of TBM derived from the original publication by Dacey and Sande was used [10,11,12] In this model, on day-1, the rabbit skull was fit with four aluminum screws of 0.5 × 2 inches under anesthesia with an intramuscular injection of ketamine (0.5 ml/kg) and xylazine (3.5 ml/kg) before bacterial inoculation. The critical modification made in the new procedure is the usage of an adapter that fits well with the stereotactic frame and holds the rabbits firmly in place for intracisternal injection This method avoids multiple sedation treatment, and the animals would be less stressed.
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