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Detecting virulence and drug-resistance mycobacterial phenotypes in vivo

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Bacterial phenotypes are predominantly studied in culture because detection of their specific metabolic pathways in the host is challenging. Development of stable-isotope breath tests, allowing in situ phenotype analyses, may endow diagnostics with new modalities based upon direct monitoring of in vivo microbial metabolism and host–pathogen phenotypic interactions.

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Bacterial phenotypes in the host

Mycobacterium tuberculosis is a successful human pathogen because of two key attributes: (i) it uses its wide range of metabolic pathways to grow, survive, or persist in greatly differing cellular and anatomic sites of infection, and (ii) it is able to produce a plethora of molecules that defend against, and selectively control, the host's immune response. These mycobacterial phenotypes determine the key host–pathogen interactions and also control drug resistance. Strong associations between

Stable-isotope tracers for investigating in situ phenotypes

The idea is simple: stable-isotope tracers can undergo specific bacterial metabolism, and the labeled products (e.g., in breath) are analyzed to indicate bacterial metabolic phenotypes. Their enzymatic nature enables rapid amplification of the signal to detectable levels. The archetype of this approach is the 13C-urea breath test for Helicobacter pylori in which a labeled urea drink is specifically delivered to the infection site (stomach) where H. pylori urease, a key virulence factor,

Concluding remarks

It is an exciting development that, by using stable-isotope breath tests, we can detect bacterial phenotypic properties, including critical drug sensitivity, in situ. The lessons learned (Box 1) will help to more generally apply this approach in order to broadly understand the complex and varied roles of bacterial metabolic phenotypes that control both host and bacterial homeostasis in asymptomatic states and overt infectious disease.

Disclaimer statement

I am co-founder and Chief Science Adviser of Avisa Pharma, a company that licenses UNM patents on products of which I am an inventor. Avisa Pharma is developing an inhaled 13C-urea breath test for diagnosing serious lung infections.

Acknowledgments

I would like to thank the many collaborators who made these studies possible and enjoyable, and the National Institutes of Health (NIH) for funding (AI063486, AI081015).

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