Important nitrogen acquisition system identified in M. tuberculosis

30 September 2013

Scientists from NIMR, Université de Toulouse, CNRS-IPBS and INSERM have identified for the first time a nitrogen acquisition system in M. tuberculosis that is required during infection. The research is published in Nature Chemical Biology.

Nutrient acquisition is central to bacterial growth and pathogenesis. Despite this, little is known about the dietary needs of M. tuberculosis inside macrophages. More specifically, until now it has been unclear what is the preferred nitrogen source used by M. tuberculosis within the host. The transport systems essential for its uptake also remain undefined. A better understanding of M. tuberculosis metabolic requirements during host colonization may help identify targets for novel antimicrobials.

Gérald Larrouy-Maumus working in the laboratory of Luiz Pedro Carvalho (pictured), in NIMR’s Division of Mycobacterial Research, collaborated with researchers in France to identify the function of a previously mis-annotated transporter (AnsP1) as an aspartate transporter, and to determine its role during infection. Based on its primary amino acid sequence, AnsP1 was previously annotated as a putative asparagine transporter. With classic microbiology experiments and stable isotope tracing coupled to metabolomics they showed that AnsP1 is an aspartate transporter, required for nitrogen uptake. Using the mouse model of infection, the researchers were able to study not only the in vitro function of the transporter, but also probe its function during infection.

The results clearly demonstrated that AnsP1 plays an important role during infection. Moreover, imaging mass spectrometry data of M. tuberculosis-infected macrophages indicates that the importance of this transporter is due to an increase in aspartate concentration in the compartments where M. tuberculosis is present. Together, these results indicate that aspartate is a primary nitrogen source used by M. tuberculosis for host colonization, and the first to be identified during infection. This systems infection approach allows a first glimpse of the elusive mycobacterial nitrogen metabolism in vivo and its close connection with survival and pathogenesis.

Most of the mechanistic studies carried out in vitro might not yield the same results in vivo. Therefore, studies such as this, where physiology is also tested in vivo, are of great importance to define metabolic pathways that are essential in the host, instead of only in the Petri dish.

This study provides the first evidence for how M. tuberculosis obtains nitrogen/aspartate from the host. The study also reveals that aspartate accumulates in compartments containing M. tuberculosis indicating that these compartments are not deprived of amino acids. Our results shed light on how M. tuberculosis survives and thrives within human cells. We also envisage that this knowledge may be used for rational development of novel therapeutics against human tuberculosis.

Luiz Pedro Carvalho

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Legend for the figure: Schematic representation of nitrogen acquisition via AnsP1, and metabolism in Mycobacterium tuberculosis.

Original article

Alexandre Gouzy, Gérald Larrouy-Maumus, Ting-Di Wu, Antonio Peixoto, Florence Levillain, Geanncarlo Lugo-Villarino, Jean-Luc Gerquin-Kern, Luiz Pedro Sório de Carvalho, Yannick Poquet & Olivier Neyrolles (2013)

Mycobacterium tuberculosis nitrogen assimilation and host colonization require aspartate

Nature Chemical Biology Epub ahead of print. Publisher abstract

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