This Week in TB R&D – 30 March 2010

29 Mar 2010
by Working Group

APOPO rat TB screen
Rat TB testing apparatus

The use of animal models for drug discovery is a key step in the process. Rodents, in particular mice, have been indispensible for understanding the pharmacodynamics (what the drug does to the body) and pharmacokinetics (the time-course of how the body handles the drug) of drugs because they are easy to handle, require small doses of drug, and cost less than larger animals. However, the use of animal models as viable diagnostic tools is still relatively novel, especially for TB detection.

On World TB Day, posted a blog entitled ‘A Nose Knows: Heroic Rats Sniff Out Tuberculosis’, and earlier last year Global Health Magazine posted a similar blog focusing on the efforts of HeroRATs. We did some review of our own to learn more about this organization and its benefit to TB R&D. HeroRATs is a project established by APOPO, an organization dedicated to training African giant pouched rats to detect landmines and in recent years pulmonary M. tb infection. APOPO utilizes the exquisite olfactory system of the rat as a technology to support what they believe will positively impact human lives (i.e., landmine clearance and disease identification). Through exposure to chemicals that make up explosives or volatile organic compounds released by M. tb in combination with a series of behavioral conditioning assays, rats are rewarded with a food treat when they accurately identify a positive sample.

In early 2009, APOPO published their research on the effectiveness of condition trained African pouched rats to detect M. tb positive human sputum samples in The International Journal of Tuberculosis and Lung Disease. Using a long narrow cage, cassette-carriers containing 10 individual sputum samples were inserted under sniffing holes engineered in the floor of the cage. Each sniffing hole is covered by a metal plate which is uncovered as a rat proceeds across the floor of the cage sniffing. If the rat does not smell anything, it continues to walk along the floor of the cage. However, when the rat smells what is believed to be chemicals emitted by the bacteria in infected sputum samples, the rat will remain at the hole for many seconds and scratch the hole. After identifying a positive sample, the rat is rewarded with a food treat (watch a training session).

In this published study, human sputum samples (3 per patient) with complete sample data including patient information, history, and acid-fast bacilli result were collected from selected DOTS centers in Tanzania. Samples were then used to prepare cultures and smear preparations. Of the 20 rats tested, 18 were able to detect positive M. tb sputum samples with >70% accuracy compared to either culture- or Ziehl-Neelsen smear-confirmed sputum samples with false positive rate of

Moreover, these rats were able to assess on average 3.5 sputum samples/minute – a rate that is significantly faster than a lab technician having to view smear samples under a microscope. The results suggest that in resource-limited settings, the use of TB-trained detection rats may be a viable, low cost diagnostic tool worth further investigation (and funding). The authors concede that additional research needs to be done to verify intra-animal reproducibility and examine testing of HIV-TB patient sputum samples. HIV-TB co-infected individuals tend to have more smear-negative samples due to the difficulties in producing large enough sputum samples to enable M. tb detection.

If the rats used to detect M. tb are exposed to M. tb, can they also be infected?

Weetjens et al. report that the rats they used were not susceptible to TB infection when exposed to M. tb in a specialized cage. While debate has existed on whether rats can contract TB infection, a recent report suggests using rats as a model for TB infection (.pdf – 1,200kb) by aerosol exposure. Why the discrepancy? One possible explanation may be the immune system of rats (.pdf – 664kb), specifically neutrophils, which may function to protect some rat strains against TB better than others. Another explanation may be that the rats are exposed to sputum samples and not concentrated amounts of M. tb freely flowing in the air.

Other Questions for discussion:

If African pouch rats are indeed resistant to TB, can be used effectively in resource-limited settings, increase the rate and accuracy of detection, and at a low cost, should they be used? Should African pouched rats or other rat species be considered as viable and reliable diagnostic tools in place of current diagnostic tools, why or why not? What are your thoughts?

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