FEATURED NEW INVESTIGATOR

Tuberculosis and host metabolism: ancient

associations, fresh insights

ANTJE BLUMENTHAL, FLONZA ISOVSKI, and KYU Y. RHEE*

NEW YORK, NY

Epidemiologic studies have repeatedly identified malnutrition as a risk factor for

tuberculosis (TB), which is the leading bacterial cause of deaths worldwide. The
biologic basis for this association, however, remains unclear. Recent work has
uncovered a large array of signaling molecules lying at the intersection of metabolic
and immune signaling, among which nuclear hormone receptors (NHRs) and the
insulin receptor have emerged as 2 prototypic examples. Existing knowledge
indicates that the physiologic functions of many NHRs overlap with known epidemi-
ologic risk factors for TB and that diabetes, itself, predisposes to TB. Here, we assimi-
late these data and identify a potential mechanism that may help to explain the
long-standing clinical association between TB and host metabolism. Together, these
data emphasize the underused potential of interdisciplinary dialog in current TB
research efforts. (Translational Research 2009;154:7–14)

Abbreviations: DM ¼ diabetes mellitus; DTH ¼ delayed-type hypersensitivity; ER ¼ estrogen re-

ceptor; GR ¼ glucocorticoid receptor; IFNg ¼ interferon gamma; IL-12 ¼ interleukin 12; LPS ¼ li-
popolysaccharide; LXR ¼ liver X receptor; Mtb ¼ Mycobacterium tuberculosis; NHR ¼ nuclear
hormone receptor; PPARg ¼ peroxisome proliferator activated receptor gamma; PXR ¼ preg-
nane X receptor; RAR ¼ retinoic acid receptor; RXR ¼ retinoid X receptor; TACO ¼ tryptophan-
aspartate containing coat protein; TB ¼ tuberculosis; TLR ¼ toll-like receptor; TNF-a ¼ tumor
necrosis factor alpha; TZD ¼ thiazolidinedione; VDR ¼ vitamin D receptor

S
ince Koch’s discovery of Mycobacterium tuber-
culosis (Mtb) over 100 years ago, tuberculosis
(TB) has commanded the attention of physicians,
microbiologists, immunologists, and epidemiologists
alike. It is remarkable, therefore, that in 2009, TB re-
mains the leading bacterial cause of deaths worldwide.
Even more remarkable is the fact that, because humans
are the only known reservoir for Mtb, TB is a potentially
eradicable disease.
Thankfully, recent increases in globalization, as well
as the emergence of HIV, have stimulated a major
resurgence in TB research. To date, this investment

*
Kyu Rhee, MD, PhD is Assistant Professor of Medicine, Microbiol-
ogy & Immunology in the Division of International Medicine & Infec-
tious Diseases at Weill Medical College of Cornell University. His
article is based on a presentation given at the Combined Annual Meet-
ing of the Central Society for Clinical Research and Midwestern Sec-
tion American Federation for Medical Research.
From the Department of Microbiology & Immunology, Division of
International Medicine & Infectious Diseases, New York;
Department of Medicine, Division of International Medicine &
Infectious Diseases, New York.
Supported by the Burroughs Wellcome Foundation Career Award in
the Biomedical Sciences and the William Randolph Hearst Foundation.
Submitted for publication April 10, 2007, revision submitted April 21,
2009; accepted for publication April 21, 2009.
Reprint requests: Kyu Y. Rhee, MD, Division of International Medi-
cine & Infectious Diseases, Weill Cornell Medical College, 1300
York Avenue, A-421, New York, NY 10065.; e-mail: kyr9001@
med.cornell.edu.
1931-5244/$ – see front matter
Ó 2009 Mosby, Inc. All rights reserved.
doi:10.1016/j.trsl.2009.04.004

7

8 Blumenthal et al
has yielded major advances in the immunology and
microbial pathogenesis of TB. Translationally visible
advances, however, remain slow to emerge.
One potentially rich, but overlooked, source of trans-
lational ‘‘capital’’ concerns the relationship between
TB and the host metabolism. Epidemiologic studies, dat-
ing to the time of Galen, have repeatedly identified nutri-
tional and/or metabolic disorders as predisposing risk
factors for TB.1-3 More recent studies by McMurray
and Bloom1,4 demonstrated the reversible effects of pro-
tein calorie malnutrition on T-cell mediated control of
Mtb. Rook et al5,6 and Crowle et al7 similarly reported
macrophage-specific roles for vitamin D in immune
control of Mtb. Translational extensions of this work,
however, have gone surprisingly unpursued.1
In the meantime, knowledge of the links between me-
tabolism and immunity has continued to grow. Work
from the field of metabolism has established that meta-
bolic and immune responses often use the same signal-
ing pathways and that this overlap mediates a biologic
‘‘cross talk’’ between metabolism and immunity. This
work has thus redefined many metabolic diseases as
chronic inflammatory disorders. In the case of TB, this
work has shown that many of the same immune signal-
ing pathways affected by vitamin deficiency, diabetes
mellitus (DM), and obesity are also involved in immune
control of Mtb.8-10
Here, we revisit the clinical association between TB
and host metabolism, and we consider the joint immune
and metabolic signaling activities of nuclear hormone
receptors and the insulin receptor as 2 potential media-
tors of this epidemiologic relationship. We first review
evidence from the fields of epidemiology and metabo-
lism, which support the clinical relevance of nuclear hor-
mone receptors and the insulin receptor to immune
control of Mtb. We then highlight work from the fields
of metabolism and immunology showing that the immu-
noregulatory activities of these proteins overlap with key
signaling pathways involved in the immune control of
Mtb. We finally consider the potential for these findings
to transform micronutrient deficiency states and DM
from epidemiologic risk factors into biologically defined
mechanisms of Mtb immune control. Together, these
findings emphasize the underused potential of interdisci-
plinary dialogs to catalyze major advances in control of
the TB pandemic.
VITAMIN DEFICIENCY AND TB SUSCEPTIBILITY
Clinical and epidemiologic evidence. Early studies by
Leitch2 first noted a decrease in TB case rates among
Norwegian naval recruits after improvements in dietary
nutrition that occurred apart from changes in overcrowd-
ing and hygiene. Studies of gastric bypass patients later
Translational Research
July 2009
showed that patients undergoing gastric or jejunoileal
bypass developed TB postoperatively at rates of up to
30-fold over the general population. This risk was great-
est among individuals less than 85% ideal body weight
preoperatively.11,12 Based on the profound malabsorp-
tion syndrome experienced by most bypass patients
postoperatively and the absence of other identifiable
risk factors for TB, this study provided early evidence
of a role for malabsorptive malnutrition in the develop-
ment of TB.
Cross-sectional and cohort-based studies later pro-
vided evidence of more specific associations between
TB case rates and serum levels of vitamins A, C, and
D. Following a cohort of 1100 men with no prior evi-
dence of Mtb infection for up to 5 years, Getz et al13
noted a consistent correlation between low serum levels
of vitamins A and C and subsequent rates of TB. Case
control studies of vitamin D likewise reported an associ-
ation between vitamin D deficiency and TB case rates
alone (odds ratio [OR] 5 2.8; 95% confidence interval
[CI] 5 1.2–6.5), and in combination with polymor-
phisms in the gene encoding the vitamin D receptor
(OR 5 5.1; CI 5 1.4–18.4).14 In light of these studies,
it is particularly interesting to consider whether the his-
torically perceived benefits of cod liver oil, milk, and
sanatorium-based TB treatments may have represented
unrecognized forms of vitamin A- and D-based
therapies.
Admittedly, definitive evidence of a causal relation
between vitamin deficiency and TB susceptibility is
lacking. Nevertheless, in a unique, controlled trial
conducted in the 1940s, Downes15 reported clear
evidence of a beneficial effect of vitamin supplementa-
tion on a cohort of 194 families of TB patients under
public health supervision. These families were matched
for size and composition, prior episodes of TB, and rates
of sputum smear positivity among index cases and
assigned to either receive vitamin supplementation or
not. Remarkably, over a 5-year follow-up period, the
reported risk of developing TB was 2.8 times greater
among family contacts of the control than the vitamin-
treated group. Although the micronutrient composition
of these vitamins was not described, this study provided
compelling evidence for a protective role of vitamin
-supplementation against TB. In a smaller, double-
blinded placebo-controlled trial of vitamin A and zinc
supplementation, Karyadi et al16 similarly reported that
the addition of these micronutrients to standard TB
drug therapies accelerated both clearance of Mtb from
serial sputum samples (a marker of infectivity) and
radiographic evidence of cure. A recent Cochrane Data-
base review of randomized controlled trials comparing
any oral nutritional supplement with no nutritional inter-
vention in the treatment of pulmonary TB also found
Translational Research
Volume 154, Number 1
evidence of salutary benefits of Zn and high-energy
supplements.17 These studies thus provided persuasive,
albeit imperfect, evidence of a clinical association
between TB and host metabolism.
VITAMINS AND IMMUNE DEFENSE
Early experimental evidence. Experimental evidence
for a biologic link between TB and host metabolism
dates similarly to the earliest days of immunology. In
a review of more than 40 animal studies conducted prior
to 1968, Scrimshaw et al3 noted that most (78%) of stud-
ies reported pathologic evidence of disease exacerbation
in response to deficiencies of vitamins A, C, and D. The
clinical relevance of these findings, however, was chal-
lenged by the nonphysiologic nature (route and dose of
infection) of the models used.
Better evidence for the detrimental effects of malnutri-
tion on immune control of Mtb nevertheless reemerged
with the use of isolated macrophages and monocytes.
These studies showed that treatment of cultured human
macrophages with retinoic acid restricted uptake of
Mtb and induced a state of bacteriostasis leading to
a 1–2-log reduction in Mtb bacterial burden.18 Adminis-
tration of vitamin D3 and interferon gamma (IFNg) to
cultured human monocytes likewise showed impaired
control of intracellular Mtb.6,7,19-22
Nuclear hormone receptors (NHRs). Work over the past
decade has since identified explicit links between meta-
bolic and immune signaling. Of these, one particularly in-
teresting class of links to emerge is the superfamily of
NHRs. These proteins are ligand-responsive transcrip-
tion factors that regulate transcription of functionally re-
lated target genes in a wide range of cell types. Where
known, natural ligands for many of these receptors are
metabolic intermediates or end products. NHRs have
thus emerged as major regulators of glucose-, lipid-,
and vitamin-related metabolism.
Surprisingly, several NHRs have also been identified
in leukocytes. These include the glucocorticoid receptor
(GR); the liver X receptor (LXR); and receptors for the
active forms of vitamin D (vitamin D receptor [VDR]),
vitamin A (retinoic acid receptor [RAR] and retinoid X
receptor [RXR]), and vitamin E (pregnane X receptor
[PXR]).23,24 Additional NHRs expressed in immune
cells include the estrogen receptor (ER), and peroxisome
proliferator activated receptor gamma (PPARg), the
therapeutic target of the thiazolidinedione (TZD) class
of insulin-sensitizing drugs commonly used to treat
Type 2 DM.
In immune cells, these NHRs have been shown to
regulate the transcription of a large and overlapping
set of target genes involved in host inflammation (see
Fig 1).24-32 Seminal work from the Seed and Glass
Blumenthal et al 9
laboratories first demonstrated that the PPARg protein,
which is an NHR canonically involved in glucose and
lipid metabolism, downregulated the inflammatory
gene program of macrophages activated by lipopolysac-
charide (LPS), IFNg, or phorbol myristate acetate.25,26
Using a microarray-based approach, Ogawa and col-
leagues27 showed that 6 such NHRs (GR, VDR, RAR,
PPARg, LXR, and ER) repressed (in a ligand dependent
manner) a common set of target proinflammatory genes
activated by the TLR4 agonist LPS (Fig 1). Examples
of such genes include NOS2, IP10, interleukin-12
(IL-12)p40, TNFa, and Ifit1, among others. These stud-
ies also showed that, in the case of the GR, gluco-
corticoid-induced repression of inflammatory target
genes was stimulus-specific, such that target gene regu-
lation occurred only in the context of Toll-like rece-
ptor (TLR) 4-, but not TLR3-, dependent immune
activation.27
Studies of the LXR, which is a nuclear receptor clas-
sically involved in glucose metabolism and cholesterol
efflux, recently expanded the immunoregulatory scope
of NHR actions to include control of pathogen-induced
apoptosis. Using genetically engineered knockout
mice, Joseph et al29 showed that mice deficient for the
LXRa and LXRb isoforms were markedly more suscep-
tible to the intracellular bacterium Listeria monocyto-
genes than wild-type counterparts (as measured by
mean bacterial burden and survival time). This suscepti-
bility was shown to be caused by the loss of an LXRa-
mediated inhibition of macrophage apoptosis. Valledor
et al30 conversely showed that pharmacologic activation
of LXR and RXR could protect macrophages from bac-
terially induced apoptosis caused by Bacillus anthracis,
Escherichia coli, and Salmonella typhimurium. Remark-
ably, both studies identified the antiapoptotic factor
AIM/CT2/SPa as a major target of LXR- and RXR-me-
diated regulation. These results thus established NHRs
as broad mediators of metabolic and immune signaling
(Table 1).
Mtb and NHRs. Although considerably more limited,
evidence for specific roles of NHR in immune control
of Mtb has also begun to emerge. For example, existing
knowledge of the GR and PPARg in steroid-induced im-
munosuppression and Type 2 DM (2 reported risk factors
for TB) suggest that some NHRs may facilitate immune
control of latent Mtb infection.31,33 Indeed, many of the
same proinflammatory target genes downregulated by
the GR, PPARg, and LXR overlap precisely with those
activated by IFNg, the major cytokine required for im-
mune control of Mtb.9,27,34 For example, Reddy et al31
reported that treatment of alveolar macrophages with
PPARg ligands suppressed the induction of NOS2 and
IL12 expression, which are 2 additional proinflammatory
cytokines required for host defense against Mtb.
 Translational Research
10 Blumenthal et al July 2009

Fig 1. Cartoon of immune cell-expressed NHR activities. VDR, PPAR-g, LXR and GR regulate the expression of
immunoregulatory genes in macrophages through a heterodimeric interaction with RXR when in presence of li-
gand. Ligand availability is an important determinant in the activity of NHRs. Vitamin D is converted to
1,25(OH)2 D3 within the macrophage. PPAR-g and LXR ligands derive from locally produced metabolites. GR
regulates gene expression in response to circulating hormone levels. 9-cis-RA, 9-cis retinoic acid; ATRA, all trans
retinoic acid; FA, fatty acid; FFA, free fatty acid; Lt, leukotriene; PG, prostaglandins.

Pharmacologic studies of vitamin D and retinoic acid
have implicated similar roles for the VDR and RAR in
immune control of Mtb. Several authors independently
demonstrated causal links between serum levels of vita-
min D and immune control of Mtb.5,7,20-23 Liu et al fur-
ther showed that the salutary effects of vitamin D against
Mtb could be explained by TLR2-triggered intracellular
conversion of 25-OH vitamin D to the more potent 1, 25
(OH)2 vitamin D (through upregulation of the cyto-
chrome P450, cyp27B1) and upregulation of the VDR
itself. These events were shown to culminate in the
VDR-dependent induction of the antimycobacterial pep-
tide cathelicidin.20
In a separate study, Anand and Kaul32 reported that
vitamin D3 and retinoic acid downregulated the tran-
scription of the tryptophan-aspartate containing coat
protein (TACO/coronin), which is a protein reported to
inhibit phagolysosomal fusion. Retention of TACO at
the mycobacterial phagosome has previously been de-
scribed as a potential virulence mechanism used by
Mtb to promote intramacrophage survival.33 Repression
of this host protein thus identified an additional potential
role of the VDR and RAR in host defense against Mtb.
Studies of T cells have likewise shown that both vita-
min D and retinoic acid can stimulate production of IL-2
and IFNg.33,35 In 1 case, supplementation of vitamin A
acetate into the diet of laboratory mice lead to enhanced
IL-2 production and augmented delayed-type hypersen-
sitivity (DTH) reaction after challenge with Mycobacte-
rium bovis bacille Calmette-Guerin,36 whereas chronic
dietary vitamin D deficiency in Mtb-infected guinea
pigs led to diminished cutaneous DTH reactions to puri-
fied protein derivative of Mtb in the other.37
Together, these studies identify a broad, but untested,
array of potential roles for NHRs as mediators of the link
between TB and host metabolism. It is interesting to note
that although the increased risk of TB associated with
steroid use and Type 2 DM would seem to correlate
with excessive levels of the immunosuppressive activi-
ties of the GR and PPARg, respectively; the increased
risk of TB associated with vitamin D deficiency seem
to correlate with a lack of appropriate VDR-dependent
antimycobacterial activity. Thus, although potentially
significant, definitive knowledge of the significance of
NHR in immune control of Mtb will likely require
systematic study of individual members.
INSULIN SIGNALING AND INFLAMMATION
Studies of DM and obesity have separately uncovered
additional molecular links between metabolism and im-
munity. Hotamisligil and Karasik independently,38,39 in
particular, first demonstrated that adipose tissue from
obese mice overexpressed the inflammatory cytokine tu-
mor necrosis factor alpha (TNF-a) and that exogenous
TNF-a could induce a state of insulin resistance in
wild-type mice. Molecular studies later showed that
this TNF-a–induced resistance was mediated by inhibi-
tory phosphorylation of the insulin receptor and its down-
stream signaling activity.40-42 These findings were later
extended to humans with reports of elevated TNF-a levels
in the adipose tissue of obese individuals.43
Translational Research
Volume 154, Number 1 Blumenthal et al 11

Table I. Immune cell-expressed nuclear hormone receptors

Nuclear hormone receptor name Gene name Immunoregulatory activity Reference

Glucocorticoid receptor GR  Inhibit transcription of LPS -target 23, 27

genes
 Inhibits NF-kB and AP-1 activity
Liver-X-receptor LXR  Inhibit transcription of LPS and IFN-g 23, 27–30
-target genes
 Inhibits NF-kB and AP-1 activity
 Deficiency in LXRa causes suscepti-
bility to Listeria monocytogenes
 Activation protects against pathogen
induced apoptosis in macrophages
Vitamin D receptor VDR  Inhibits transcription of LPS and IFN-g 20, 21, 27, 32
-target genes
 Regulates production of antimycobac-
terial peptide, cathelicidin
 Regulates transcription of TACO gene
Retinoic Acid receptor RAR  Inhibit transcription of LPS and IFN-g 27
target genes
Retinoid-X receptor RXR  Pharmacologic stimulation showed to 30, 36
protect against pathogen-induced ap-
optosis in macrophages
Estrogen receptor ER  Inhibit transcription of LPS -target 27
genes
Peroxisome proliferator activated receptor PPAR-g  Decrease transcription of genes acti- 23–27, 31
gamma vated by LPS and IFN-g
 Macrophage expressed repressed by
LPS and IFN-g
 Inhibits TNFa signaling
 Inhibits NF-kB and AP-1 activity
 Decrease NOS2 and IL-12
 Target for TZD class of drugs
 Gene deficiency is most closely asso-
ciated with type 2 DM

Abbreviations: AP-1, activator protein 1; NF-kB, nuclear factor kappa B.

Histologic studies have shown that the adipose tissue of
obese individuals contain surprising numbers (up to 30%)
of infiltrating macrophages that colocalize with adipo-
cytes.43,44 Adipocytes were shown to be capable of produc-
ing classic immune products (including IL-6, monocyte
chemoattractant protein-1, plasminogen activator inhibi-
tor-1, and angiotensinogen), whereas immune cells were
shown to respond to adipocyte-specific products (such as
leptin, adiponectin, resistin, and visfatin).8,45-48 Studies of
the reversible immunodeficiency associated with leptin de-
ficiency further established the bidirectional nature of these
interactions.49-51 This view was further emphasized by
studies of IL-18, a proinflammatory cytokine whose defi-
ciency was shown to be associated with a reversible hyper-
phagia, obesity, and insulin resistance in mice.52
Molecular studies have shown that the same serine-
threonine kinases activated by TLRs in innate immune
responses (JNK, IKK, and PKC-q) are also activated in
mouse models of genetic and diet-induced obesity. Of
interest, this activation was also associated with inhibi-
tory phosphorylation of the insulin receptor.53 Members
of the suppressor of cytokine signaling family of pro-
teins, which negatively regulate JAK-STAT-dependent
cytokine signaling cascades, were also shown to inter-
fere with insulin signaling.54
Together, these findings have identified an additional
array of molecular overlaps between metabolic and
immune signaling.
DIABETES MELLITUS AND TB
Epidemiologic evidence. Remarkably, reports of an
association between DM and TB date back to as early
as the 1st century.55 Comparative autopsy studies of
patients with Type 1 diabetes first showed that as
many as half of all diabetic patients had pathologic
evidence of pulmonary TB at the time of death.56 Root
et al57 subsequently reported that TB case rates among
juvenile diabetics were 10 times higher than among non-
diabetic school-aged children. In a more recent case con-
trol study of over 5000 TB patients and 37,000 controls,
Pablos-Mendez et al58 estimated the attributable risk of
TB caused by DM to be as high as 25%. Together, these

12 Blumenthal et al
studies have repeatedly implicated Type 1 DM as a risk
factor for progression from latent to active TB; this view
has been independently validated by 2 prospective co-
hort studies.59,60
Surprisingly, recent evidence has extended this associ-
ation to the growing epidemic of Type 2 diabetics. Not-
withstanding the inherent limitations of retrospective
studies, Restrepo et al61 noted a consistently increased
odds ratio of Type 2 DM among patients with active
TB (OR 5 1.3–7.4). In a recent case control study, Alis-
jahbana et al62 similarly noted that patients with active
TB exhibited a significantly greater prevalence of Type
2 DM than age-matched controls (13.3% vs 3.2%).
Experimental perspectives. Given these data, it is espe-
cially interesting to reconsider whether the increased risk
of developing active TB may, in fact, be attributable to
defects in TNF-a signaling associated with insulin resis-
tance. Indeed, despite significant differences in the phys-
iology of Type 1 and Type 2 DM, it remains a fact that
both Type 1 and Type 2 DM represent pathologic states
of relative insulin resistance. In this regard, it is interest-
ing to note significant rates of insulin resistance among
HIV infected individuals; this population is known to
exhibit high rates of TB. Extended study of the epidemi-
ologic association between insulin resistance and TB and
the biologic role of insulin signaling on immune control
of Mtb may thus prove revealing.
It may similarly prove instructive to examine more
broadly the pathophysiologic impact of metabolic disor-
ders on immune control of Mtb using the wide array of
existing animal models currently available. In examining
the immunologic consequences of a wasting form of
malnutrition (modeled by leptin deficiency), Wieland
et al63 showed that leptin-deficient mice produced lower
IFNg levels, diminished antigen-specific T-cell re-
sponses, and poorer levels of immune control of Mtb
following infection. Importantly, these studies also
established that the immunologic defects associated
with leptin deficiency were, in fact, reversible with leptin
replacement therapy.63
Martens et al64 recently showed that streptozocin-
induced diabetic mice exhibited a .1 log higher myco-
bacterial burden, reduced early production of IFN-g, and
a reduced number of T-cells responsive to the Mtb anti-
gen ESAT-6, when compared with euglycemic mice and
that hypercholesterolemic mice lacking apoplipoprotein
E also exhibited impaired immunity to Mtb.65 It will
therefore be of considerable interest to determine the
clinical relevance of these findings and whether these
immunodeficiency states are potentially amenable to nu-
tritionally based interventions. Given the bidirectional
nature of metabolic-immune cross talk, it may prove
equally fruitful to examine the effects of TB on host
metabolism.
Translational Research
July 2009
FUTURE PROSPECTS
Looking forward, it is likely that the importance of bi-
ologic links between TB and the host metabolism will
only continue to grow. In 2007, more than 80% of all
new TB cases worldwide were registered in Africa,
Southeast Asia, and the Western Pacific regions that con-
tinue to be afflicted by famine and starvation.66 At the
same time, diabetes and obesity have emerged as epi-
demics of global proportion. Intersections of TB and
metabolic disorders are thus inevitable.
Thankfully, recognition of this dilemma has begun to
stimulate more scientifically integrated efforts. One
potential example is illustrated by the recent discovery
of the cytochrome P450 enzyme cyp27B1 as an activat-
ing agent of intracellular vitamin D levels following
immune stimulation. This knowledge has specifically
identified a novel potential target to safely deliver and
enhance the antimycobacterial benefits of vitamin D.20
Additional study of NHRs in immune control of Mtb
might inform on the development of rational nutritional
interventions or synthetic NHR ligands that could arrest
or decrease the rate of progression from latent to active
TB (analagous to the case of selective estrogen receptor
modulators).67,68
Expanded knowledge of the molecular cross talk be-
tween metabolic and immune signaling has afforded
similarly fresh insight into the epidemiologic behavior
of the TB pandemic. Recent evidence in particular has
suggested an elevated risk of TB among insulin resistant
diabetics. These data challenge previously held beliefs
that the catabolic state characteristic of Type 1 DM is
responsible for this relationship and further support the
view that insulin resistance itself may be an independent
risk factor for TB susceptibility. Based on existing
knowledge of the cross talk between insulin and TNF-a
signaling, however, it may be of particular importance to
consider the role of insulin resistance, rather than DM
per se, as a predisposing risk factor for progression
from latent infection to active TB.64,69 Given the ever-
increasing global incidence of DM and its potentially
catastrophic intersection with the TB pandemic, impro-
ved knowledge of this association may prove especially
valuable.
From a broader perspective, these examples highlight
the need for increased levels of interdisiciplinary dialog.
Indeed, although scientific knowledge continues to
expand at prolific rates, much of this knowledge remains
confined to the boundaries of traditional scientific disci-
plines. That is, scientific progress has expanded more
deeply than broadly. A major need of many translation-
ally oriented efforts is thus the inclusion of interdisci-
plinary ‘‘translators.’’ Such ‘‘translators’’ would not
only serve to disseminate information between
Translational Research
Volume 154, Number 1
disciplines but also, more importantly, would do so
within the context of field-specific conventions. In the
case of TB and host metabolism, such ‘‘translators’’
could significantly enhance the exchange of information
between epidemiologists, immunologists, and cellular
endocrinologists.
In practical terms, 1 particularly valuable, but absent,
form of ‘‘translator’’ in current TB research efforts is the
biostatistician. Putting aside the case of the randomized
clinical trial, data from clinical studies are largely
descriptive in nature, the significance of which hinges
heavily on the use of statistical assumptions and methods
largely foreign to experimental scientists. Laboratory-
based studies, by contrast, often derive from experimen-
tal studies conducted in highly controlled, nonphysio-
logic settings, the clinical significance of which is
often uninterpretable by clinical researchers. The inter-
positioning of a biostatistician thus represents a poten-
tially powerful, but underrecognized, mechanism to
interface data transfer between these 2 disciplines.
In an era of pandemic TB and HIV, the need for im-
proved knowledge of the clinical pathophysiology of
TB has never been greater. Thankfully, recent reinvest-
ments in TB research have yielded major advances in
knowledge across many disciplines. Control of this
epidemic now awaits increased recognition of the
numerous translational opportunities that have emerged.
As illustrated by the discussion of TB and host metabo-
lism presented here, even though significant challenges
remain, the potential for major translational gains has
never been greater.
Special thanks are due to Warren Lee, Sabine Ehrt, David Gardiner,
and Marshall Glesby for critical reading of this manuscript. The authors
declare no potential conflicts of interest concerning this work.
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