Xe[[`^\jkgXk_f^\ejÇXi\k_\Ôijkkf\e-
counter M. tb and that the bacteria live and
multiply in these macrophages. But some
bacteria, such as M. tb, have devised ways to
\mX[\k_XkgifZ\jj%ÈN\cffb\[Xkk_XkXe[
jX`[#ÊN\cc#k_\pZXeËkYfk_Y\Zfdgc\k\cp
right,’ ” says Dr. Ernst.
Dr. Ernst and graduate student Andrea
Nfc]Zi\Xk\[M. tbkX^^\[n`k_XÕlfi\j-
cent green label to allow them to track
the bacteria’s progress through the body.
They found that, in fact, the bacteria
infect different kinds of cells and that the
predominant type of cell infected changes
over time. At the earliest point there is
a three-way tie in the cell types infected
with M. tb: macrophages, dendritic cells,
Xe[e\lkifg_`cjk_\Ôijk`ddle\Z\ccjkf
arrive at a site of infection). By the third
week, dendritic cells, not macrophages,
are the cell type predominantly infected
with M. tb, they reported. “That certainly
calls into question the TB dogma that mac-
rophages are the only cells that harbor M.
tb,” says Dr. Ernst. “It says TB immunity
is in line with the rest of contemporary
cellular immunology.”
The researchers also found the bacteria
in lung-draining lymph nodes, but up to 80
percent of the bacteria were once again in
[\e[i`k`ZZ\ccj%;li`e^k_\Ôijk]\nn\\bj
of infection, Dr. Ernst explains, a large
number of infected dendritic cells carry the
bacteria from the lung to the lymph nodes.
It’s only after the bacteria appear in these
lymph nodes that T cells are activated. The
T cells then have to be transported back to
the lung, the main site of infection. M. tb
takes advantage of this lost time, multiply-
ing to overwhelming numbers. “I think
that’s one of the reasons TB wins,” says Dr.
Ernst. “It rigs the system so that by the time
the T cells are recruited into the lung, there
are a million bacteria.”
Getting the bacteria to the lymph nodes,
which has to happen before the immune
response kicks into gear, appears to be the
time-dependent step that slows down the
whole process. Dr. Ernst says the bacteria
may have evolved to survive in a part of
the lung from which they can’t easily be
moved to the lymph nodes. Some people’s
bodies may be able to get around this bet-
ter than others, which potentially explains
why not everyone exposed to TB develops
a full-blown infection. Unfortunately,
even the infected cells in the lymph nodes
are rather inept at inducing an adequate
immune response.
;i%<iejkËjÔe[`e^j_Xm\jfY\i`e^`d-
plications for vaccine development. If the
`ddle\jpjk\dZXeËk\]]\Zk`m\cpÔ^_kk_\
infection, vaccines designed to activate im-
mune cells may prove powerless — at least
without additional methods to foil M. tb’s
evasive tactics.›
22
05
Fighting Drug- BY: APOORVA
MANDAVILLI
Resistant TB in
DOCTOR:
WILLIAM ROM
New York City
FOR A FEW WEEKS LAST SUMMER,
Americans were riveted by news that Andrew Speaker,
k_\eX*($p\Xi$fc[8kcXekXeXk`m\#dXp_Xm\Y\\eÕp`e^
on commercial airplanes, exposing hundreds of people
to a virtually untreatable type of tuberculosis (TB).
They could be forgiven for having thought of TB as strict-
ly a third-world disease. In 2006, 13,767 people in the U.S.
had TB — the lowest prevalence in the country recorded
since 1953 — while else- the 1960s, and that the available drugs
where 1.5 million people were powerless against some new strains
died of the disease. of M.Tb.
Multi-drug resistant (MDR) TB develops
Speaker was diagnosed in early May when patients don’t complete the pre-
)''.#YlkX^X`ejkd\[`ZXcX[m`Z\_\Õ\n scribed six-month course of isoniazid and
to Greece for his wedding later that month. rifampicin. About one in 20 new cases of TB
Tracked down in Rome on his honeymoon, nfic[n`[\`ji\j`jkXekkfÔijk$c`e\[il^j#
he was told he had extensively drug-resis-
tant tuberculosis (XDR-TB) and was asked
Dr. William Rom stands at the
to stay put. entrance of the Chest Service
@ejk\X[#_\Xe[_`jn`]\#JXiX_#Õ\n on Bellevue’s 7th floor.
to Prague and Montreal and then drove A Bellevue security officer stands
kfE\nPfib:`kp%FeDXp)+#f]ÔZ`Xcj guard in the foreground.
from the Centers for Disease Control and
Prevention directed Speaker to report to
Bellevue Hospital, where he was served
with a federal warrant that isolated him for
d\[`ZXc\mXclXk`fe#k_\ÔijkjlZ_]\[\iXc
order issued in 44 years.
Bellevue is no stranger to TB. The hos-
pital’s Chest Service, established in 1903
to treat the disease, has contributed a great
deal of knowledge about its pathophysiol-
ogy, clinical behavior, and treatment. In
the late 1980s and early 1990s, Bellevue
endured a long bout with this familiar foe,
grappling with nearly 4,000 cases in New
York City, many of them homeless people
addicted to drugs and infected with HIV.
“I came here and I found everything was
XccK9Xe[8@;J#Éi\ZXccjN`cc`XdIfd#
M.D., M.P.H., director of the Chest Service.
He came to NYU in 1989 after a long stint
at the Rocky Mountain Center for Occupa-
tional and Environmental Health, where
his primary experience had been with coal
miners and asbestos workers. Dr. Rom,
the Sol and Judith Bergstein Professor of
Medicine and professor of environmental
medicine, quickly discovered that TB treat-
ment and care had barely changed since
NYU PHYSICIAN
+ SUMMER 2008
 06

accounting for nearly 500,000 of the 9 credited with turning the tide, slashing RESEARCHER:
million new TB cases reported each year, ac- the number of cases from 3,800 in 1992 to SUMAN LAAL
Zfi[`e^kfk_\Nfic[?\Xck_Fi^Xe`qXk`fe% roughly one-third that number today.
Treating these strains is even more Ironically, the city’s epidemic afforded
grueling and expensive: at least four doctors the opportunity to apply advanced Hope TO CONFIRM THAT YOU
have TB, the doctor will
drugs taken daily for up to two years. Not technology to an age-old disease. Grows for ask you to cough up
surprisingly, many patients miss doses Dr. Rom and his colleagues quickly Faster at least a teaspoonful
of phlegm, or sputum.
or abandon treatment entirely, putting
themselves and others at risk of develop-
became TB experts, leading rigorous stud-
ies on the epidemiology of the disease and
TB Test You’ll have to come
back to the hospital
ing the deadlier XDR-TB. It can take weeks the treatment of drug-resistant strains. Of twice more to provide samples, and
technicians will painstakingly culture the
to identify the few drugs to which a par- the 173 patients with MDR-TB admitted slow-growing bacteria from the sputum.
ticular strain is still sensitive. “These have by Bellevue between 1983 and 1994, 72 per- A few weeks after that third visit — by which
to be drugs the patient has never taken cent were cured with second-line drugs. In point you may have exposed others — the
before,” explains Dr. Rom, “so you can be those also infected with HIV, however, the doctor should be able to tell you whether
you have TB.
sure that they’re not resistant.” cure rate was only 20 percent.
Bellevue was one of only two hospitals More recently, researchers have made This crude sputum enormous genome,
diagnostic test is they found that
in New York City with facilities to isolate inroads into understanding the immune 100 years old.“The some 500 of the
those who failed to take their medicines system’s response to M. tb, the effective- situation is fairly bacteria’s 4,000
regularly. Between 1993 and 1998, the city’s ness of linelazid and aerosolized interfer- horrendous,” says Dr. genes belonged
Suman Laal, Ph.D., to a previously
courts allowed Bellevue and Goldwater on-gamma on XDR-TB patients, and the associate professor unknown genetic
Memorial Hospital, which closed its TB interaction between HIV and TB. of pathology and family.
ward in 2001, to detain more than 250 After only 72 hours at Bellevue, Andrew mircrobiology. Applying what
There are a they’ve since
patients for the duration of their treatment. Jg\Xb\inXjÕfnekfEXk`feXcA\n`j_D\[- few expensive learned about the
Dr. Rom took the important step of mod- ical Center in Denver. His diagnosis, based alternatives: bacterium’s proteins,
\ie`q`e^9\cc\ml\ËjK9]XZ`c`k`\j#flkÔkk`e^ on tests conducted there and at Bellevue, fluorescent several teams are
microscopy, trying to develop
k_\`jfcXk`feiffdjn`k_?<G8X`iÔck\ij# was later downgraded to MDR-TB. The automated culture simple TB tests. Dr.
negative air pressure, and UV lights to kill city he left behind is home to nearly 1,300 systems, and tests Laal and other
airborne bacteria. people infected with TB, and Bellevue sees for the bacterial researchers across
Bellevue also instituted hospital-based more than its fair share, including some DNA. But 90 percent the U.S. and in India
of the disease is have been working
Directly Observed Therapy (DOT), in with MDR-TB. “TB is a disease of poverty concentrated in the to develop a urine-
which patients took their TB drugs in and immigrants,” says Dr. Rom. “There’s poorest parts of the or serum-based test
the presence of a hospital worker. DOT is ›
plenty of both in New York City.” world, where these
options are not
feasible.
that would detect
one or more of the
bacterium’s proteins,
Clinically, TB even in someone
symptoms can be infected with HIV.
difficult to distinguish Her quest has taken
from those of Dr. Laal back to her
other bacterial or native India at least
fungal infections, once every year. The
pneumonia, or country has sizable
certain tumors. epidemics of both TB
Diagnosis with and HIV.
X-rays is subjective The combination
and all but useless of proteins made
in people who are by the bacteria
HIV-positive, and change as the
a commonly used infection progresses,
skin test gives false so researchers have
positives in anyone tried to find ones
who has been that are expressed
immunized with the throughout the
BCG vaccine or course of the
has been infected disease. From a
with the TB bug’s promising list of
bacterial cousins. 12 proteins, they
The ideal test for found two in
TB would be fast, particular that
cheap, and would signal active TB
deliver a simple Yes infection well before
or No answer — symptoms become
much like a dipstick obvious and
pregnancy test. But irrespective of HIV
developing a test infection.
like that has proved Researchers
challenging. are now trying to
The DNA of the identify a small
bacterium that piece of each
causes TB twists protein that would
and coils into a be cheaper and
structure that was easier to produce
difficult to unravel en masse. “I think
with old-fashioned we’re pretty close
sequencing to having a set of
techniques. In 1998, peptides that can
when researchers replace the smear
finally decoded its
›
test,” says Dr. Laal.

23