Mycobacterium tuberculosis has the fascinating
ability to persist in the host for long periods of time
despite acquired immunity. During this time the
tubercle bacilli are thought to reside in a state of
nonreplicating persistence (NRP). Cultivation of M.
tuberculosis under conditions leading to the controlled
gradual depletion of oxygen (Wayne Model) produces
two different nonreplicating states. The first stage,
termed NRP-1, occurs when oxygen decreases to the
microaerobic level (1%). The second stage, NRP-2,
occurs when the oxygen levels decreases to anaerobic
levels (0.06%). M. tuberculosis is classified as an
obligate aerobe and so replication abruptly stops when
cultures shift down into NRP-1.
As M. tuberculosis enters NRP-1 there is a
significant increase in the reduction of nitrate. In an
anaerobic environment many bacteria use nitrate as
the final electron acceptor to generate the proton
gradient for ATP production. We have proposed that
during latency M. tuberculosis uses nitrate as an
energy source in place of oxygen.
Our lab focuses on the nitrate reductase system of
M. tuberculosis. We have shown that narGHJI
encodes both the aerobic and the NRP-1 nitrate
reductase enzyme. Expression of this operon is
constitutive and not induced by hypoxia, nitrate or
nitrite. The great induction of activity seen during
shiftdown is due to induction of narK2 which codes for
a nitrate transporter. Our recent work has focused on
the regulation of the activity of NarK2.