M tuberculosis truncated hemoglobins in persistence

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant):
Recrudescence of latent tuberculous infection contributes significantly to
the pathogenesis of disease caused by Mycobacterium tuberculosis (Mtb). The
mechanisms by which the tubercle bacillus establishes latency and later
reactivates are, however, poorly understood. Two truncated hemoglobins
(trHb?s), HbN and HbO, encoded by the gene glbN and glbO, respectively, exist
in Mtb. Initial characterization of HbN and HbO in M. bovis BCG has shown
that: i) glbN and glbO are differentially expressed --the expression of HbN in
vitro is most prominent in the stationary phase of growth, while HbO is
invariably detected throughout the various growth phases; ii) both trHb?s have
high affinity for oxygen, albeit via different mechanisms; iii) HbN and HbO
can detoxify nitric oxide (NO) by conversion of the nitrogen oxide to nitrate;
significantly, a BCG deletion mutant of glbN is markedly attenuated for its
ability to consume NO; iv) the function of HbO may be essential. Based on
these findings, we propose to test the hypothesis that HbN and HbO are
required for the survival and/or persistence of Mtb within the host. This
survival/persistence-promoting attribute can be due to the ability of HbN and
HbO to detoxify the antimycobacterial NO. In addition, by virtue of their
ability to bind oxygen with high affinity, HbN and HbO can function as an
oxygen reservoir in the relatively anaerobic environment of the tuberculous granuloma, thereby optimizing the functions of critical intracellular oxygen-dependent
enzymes. Finally, the ability of these trHb?s to avidly bind oxygen
may protect Mtb against oxidative damage. To begin testing these hypotheses,
we will take a genetic approach, by generating glbN and glbO mutants, to
rigorously test the in vivo significance of Mtb trHb?s in survival and/or
persistence using murine experimental TB models. We will also evaluate the
roles of HbN and HbO in Mtb respiration and in protection against the adverse
effects of NO on the respiratory process. Establishment of the significance of
HbN and HbO in persistence and unraveling the biochemical and physiochemical
properties of these hemeproteins will set the stage for developing novels
anti-tuberculous agents effective against Mtb, particularly those in the
dormant state.
StatusFinished
Effective start/end date8/1/027/31/05

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)