Centennial Review
The Pathogenesis of Tuberculosis
The First One Hundred (and Twenty-Three) Years
Neil W. Schluger
Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, New York, New York
The clinical manifestations of tuberculosis represent a complex
interaction between the causative organism, Mycobacterium tu-
berculosis, and the human host immune response. Although the
disease of consumption was recognized many centuries ago, the
modern understanding of what has remained one of the world’s
great public health problems is usually traced to the work of
Robert Koch. Koch assuredly deserves his status as one of the
great founding figures of medicine and microbiology, although
at least two other individuals made major contributions during
the “pre-history” that led to Koch’s discovery. One of these men
is familiar to most students of medical history; the other is not.
Before Koch: Laennec and Villemin
René Théophile Hyacinthe Laennec (1781–1826) was a French
physician known for, among other accomplishments, his inven-
tion of the stethoscope. However, Laennec also holds an impor-
tant place in medical history for being among the pioneers of
clinical-pathological correlations, and his descriptions of the pul-
monary lesions in patients who had died of consumption really
mark the beginning of our understanding of the pathology and
pathogenesis of tuberculosis. In his landmark work A Treatise
on Diseases of the Chest, which was translated into English by
John Forbes and published in London in 1821, Laennec provided
figures illustrating tuberculous cavities and described in detail
the pathologic changes now so familiar as caseous necrosis:
Whatever the form in which the tuberculous matter develops, it
begins as a grey, semi-transparent matter that little by little becomes
yellow, opaque, and dense. Then it softens, and slowly acquires a
liquidity like pus, and, when it is expelled through the airways, it
leaves cavities, commonly called ulcers of the lung, that we will
designate as tuberculous excavations. (1)
Laennec’s careful autopsy studies also established that patho-
logically similar lesions in different parts of the body were in
fact due to the same disease, tuberculosis, although he could
not and did not state what was the cause of that illness.
Less well known perhaps, but quite important scientifically
(and a true forerunner of Koch) was Jean-Antoine Villemin, a
French physician who published a landmark study in 1868 in
Paris, entitled Etudes sur la Tuberculosis (Studies on Tuberculo-
(Received in final form February 4, 2005)
Supported in part by a Career Investigator Award (K24 HL004074) from the
National Institutes of Health, National Heart, Lung and Blood Institute
Correspondence and requests for reprints should be addressed to Neil W.
Schluger, Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia
University College of Physicians and Surgeons, PH-8E, Room 101, 622 West 168th
Street, New York, NY 10032. E-mail: ns311@columbia.edu
Am J Respir Cell Mol Biol Vol 32. pp 251–256, 2005
DOI: 10.1165/rcmb.F293
Internet address: www.atsjournals.org
sis). Villemin clearly established the infectious nature of tubercu-
losis. In the seventh study in his series (described in Part 4 of
his book), he describes the transmission of tuberculosis from
humans to rabbits, from cows to rabbits, from rabbits to rabbits,
and so on. The precision of the proof of the transmissible nature
of tuberculosis is exemplified in the following description from
Villemin’s book:
March 6, 1865, we took two rabbits about three weeks old, very
healthy. . . . In one of these rabbits we introduced into a little subcuta-
neous wound behind each ear, two small fragments of tubercle and
a small amount of purulent liquid from a tuberculous cavity, removed
from the lung and the intestine of a consumptive, who had been
dead twenty-three hours.
June 20th, that is, at the end of three months and fourteen days,
there was no appreciable change in the health of the animal, [and
so] we sacrificed it and noted the following: The lungs are full of
large tubercular masses, formed, in an obvious manner, from the
agglomeration of numerous granulations . . The other rabbit, who
had shared the same conditions of life with the inoculated rabbit . . .
did not show a single tubercle.” (2)
Villimin had certainly established that tuberculosis was a
transmissible disease, but he did not identify the causative agent.
This of course was left to Robert Koch, who announced his
achievement at a meeting of the Physiological Society of Berlin
on March 24, 1882. The paper describing his work, “Der Aetiolo-
gie der Tuberculose,” was published in Berliner Klinische Wo-
chenschrift on April 10, 1882.
Koch’s Studies on Tuberculosis
Koch’s contributions to the study of tuberculosis, and to medi-
cine and microbiology in general, were enormous. He developed
staining techniques for M. tuberculosis, developed culture media
in which to grow the organism, demonstrated the mode of trans-
mission of the illness, and based on his understanding of the
spread of the disease, recommended isolation of patients with
tuberculosis. His approach to the proof that M. tuberculosis was
in fact the causative agent of the illness remains the standard
to this day for implicating a microorganism as a causative agent
of disease:
To prove that tuberculosis is caused by the invasion of bacilli, and
that it is a parasitic disease primarily caused by the growth and
multiplication of bacilli, it is necessary to isolate the bacilli from the
body, to grow them in pure culture, until they are freed from every
disease product of the animal organism, and, by introducing isolated
bacilli into animals, to reproduce the same morbid condition that
is known to follow from inoculation with spontaneously developed
tuberculous material [emphasis added]. (3)
Ironically, another significant contribution of Koch was based
on what was really a failed attempt to treat tuberculosis. Several
252 AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY VOL 32 2005
years after identifying the microorganism responsible for the
disease, Koch reported on a mysterious substance which he felt
could cure, or alter least ameliorate the disease. The substance,
he later revealed, was made from supernatants of M. tuberculosis
grown in broth, and was what we now know as tuberculin. Al-
though to Koch’s frustration and probable shame, tuberculin
did not cure the disease, he was able to demonstrate for the first
time, unwittingly perhaps, cell-mediated immune responses that
we now recognize as the driving forces behind the clinical mani-
festations of tuberculosis. (In addition, a refinement of Koch’s
preparation of tuberculin remains a key component of tuberculo-
sis diagnostics even today, which he himself predicted: “I assume
that the material will be valuable diagnostic measure in the
future. It will become possible to diagnose questionable cases
of phthisis even in those cases where bacilli cannot be detected
in the sputum.” (4))
The Modern Era
The Host
In the decades following Koch, several investigators established
the nature and importance of host immune responses, and spe-
cifically cell-mediated host immune responses, in the pathogene-
sis of tuberculosis. Experiments by Bail (5), Landesteiner (6),
Chase (7), and Lawrence established that immune responses
could be elicited by serum-free cells; Lawrence also transferred
immune reactivity between patients by transferring leukocytes
alone (8). That lymphocytes specifically were the primary com-
ponent of the cellular immune response was further established
by experiments in animals performed by Wesslén (9) and Coe
(10). The important role of macrophages as effector cells in
host defense against M. tuberculosis was initially identified and
elucidated by scientists such as Patterson, Youmans, Bloom,
Bennett, David, Lurie, and Suter (11–15). These aforementioned
researchers and their work set the stage for later studies which
have led to our understanding of the important role both of
granuloma formation in the containment of infection as well as
the complex interplay between effector cells such as lympho-
cytes, macrophages, and dendritic cells, as mediated by chemo-
kines and cytokines, interferon-␥ (IFN-␥) chief among them,
in human immune reponses to M. tuberculosis. Overall, our
understanding of the pathogenesis of tuberculosis supports a
framework of immune responses which include the initial re-
sponse to inhaled organisms (outright elimination or establish-
ment of a latent state), granuloma formation and establishment
of a state of latent infection, and reactivation of latent infection.
A large body of epidemiologic evidence supports the notion that
90% of persons with latent tuberculosis infection will never
develop clinical illness. In the last several years, the important
components of a successful and sustained host response have
been described more fully. Given space constraints, the remain-
der of this review will focus on selected highlights in the advance-
ment of our understanding of tuberculosis pathogenesis in the
past several years.
Genetic susceptibility to tuberculosis. It has long been recog-
nized that certain populations appear to have a high degree of
vulnerability to tuberculosis. Extreme susceptibility to the dis-
ease has been observed in Eskimo populations in North America,
in Yanomami Indians in the Brazilian Amazon, and in black
populations in the United States (16–18). These observations
have led researchers to assume that tuberculosis probably origi-
nated in western Europe, creating selection pressure for a mea-
sure of innate resistance among the population there. In the
ages of exploration and colonization, Europeans moved to the
east and south, and tuberculosis was introduced to populations
where no innate resistance was present, with devastating results.
In addition, it has long been known that a substantial percentage
of individuals will recover from tuberculosis without drug treat-
ment. A tragic experience in Lubeck, Germany in 1929, in which
249 infants were accidentally injected with a stock of live, virulent
M. tuberculosis, leading to 76 deaths but leaving 173 survivors,
also supports the notion of some capability for innate resistance.
A clue to the genetic basis of resistance was provided by Gros
and colleagues, who identified a strain of mice with exquisite
vulnerability to overwhelming infection with leishmania, salmo-
nella, and certain mycobacteria, particularly M. bovis (19–21).
Eventually, the genetic basis of this susceptibility was mapped
to a locus encoding a gene on murine chromosome 1 initially
called Bcg, then renamed nramp1, responsible for the production
of a so-called natural resistance–associated macrophage protein.
It appears that the protein product of this gene, which in humans
is located on 2q35 and has been renamed as NRMP1 or Scl11a1
(solute carrier family 11 member 1), is a transmembrane iron
transporter located in the late endosomal compartment of resting
macrophages whose exact function remains somewhat uncertain
(22–24).
Several polymorphisms in the human NRAMP1 gene have
been identified, and population-based studies in several regions
have been conducted which have identified increased relative
risk for moving from latent infection to active disease associated
with certain polymorphisms (25). However, the risk attributable
to these polymorphisms is relatively small, and it is clear that
NRAMP alone explains only a portion of genetic susceptibility
to tuberculosis.
Several other genes and gene families, including those for
vitamin D receptors and the components of IFN-␥–signaling
pathways, have also been studied for their role in susceptibility
to tuberculosis (25–27). It is clear from these investigations that
resistance or susceptibility to tuberculosis is a complex genetic
trait, and there is unlikely to be a single dominant genetic factor
involved.
Macrophages in defense against tuberculosis. Mycobacteria can
be taken up by a variety of receptors on macrophages, including
those for complement and surfactant, and as has been described
more recently, through several of the toll-like receptors, includ-
ing TLR2 and TLR4 (28, 29). The relative importance of these
various receptors remains somewhat unclear. Killing, or growth
inhibition, of mycobacteria by macrophages occurs through acti-
vation of macrophages and the production of both reactive oxy-
gen and nitrogen species. The relative contributions of these two
molecules to the macrophages response to the mycobacterium is
still a somewhat open issue, but in a series of papers Chan,
Bloom, Flynn, and Nathan and their coworkers have certainly
demonstrated the importance of nitric oxide most convincingly,
at least in the mouse model (30–33). These investigators have
demonstrated that mouse macrophages can kill M. tuberculosis
in vitro, but not in the presence of inhibitors of inducible nitric
oxide sythnase (iNOS), such as NMMA, an L-arginine analog.
In the presence of scavengers of oxygen radical such as catalase
or superoxide dismustase, killing of mycobacteia by macro-
phages is unimpeded (33). Mice in which the iNOS gene has
been disrupted are susceptible to overwhelming mycobacterial
infection in a manner reminiscent of immunosuppression in-
duced with corticosteroids (31). Finally, mice with relatively
stable and asymptomatic infection with M. tuberculosis rapidly
develop fatal acute illness when treated with inhibitors of iNOS
(31, 32). Disruption of iNOS function in mice leads to death
from tuberculosis in weeks as compared with the months it takes
for the organism to kill the untreated wild-type murine host (31,
34). In addition, alveolar macrophages from the lungs of patients
with active pulmonary tuberculosis express high levels of the
iNOS gene (35).
Centennial Review
Granuloma formation. The granuloma is the cardinal feature
of the initial host immune response to tuberculosis, and a great
deal of effort has been devoted to understanding granuloma
formation and its role in host defenses against M. tuberculosis
(36, 37). Inhaled mycobacteria enter alveolar macrophages and
a complex series of events follows which will result in either
elimination of the bacterium completely, containment of the
infection in a granuloma for a prolonged period (forever, or
until an alteration in immune status results in breakdown of the
granuloma and reactivation of latent infection), or immediate
progression to active disease with clinical illness. This latter event
usually occurs only in the setting of impaired immunity.
Early insights into the formation and role of granulomas in
tuberculosis pathogenesis were provided by the work of Lurie
and Dannenberg, using a rabbit model, which has both advan-
tages and disadvantages for making observations relevant to
human disease (38–43). Rabbits are extremely susceptible to
infection with M. bovis, more so than with M. tuberculosis. On
the other hand, rabbits with tuberculosis develop caseous necro-
sis and cavity formation which mimic the human situation fairly
closely, at least in terms of histopathology. Using this model,
Dannenberg correctly surmised that after engulfing mycobac-
teria, macrophages send signals to other cells which are then
recruited to the site of infection, forming the familiar pattern
recognized as a granuloma. Necrotic material at the center repre-
sents debris from macrophages which have died, probably
through apoptotic mechanisms (44).
Recent work by Flynn and Chan has yielded several impor-
tant insights into the role of granulomas in maintaining the latent
state of tuberculosis infection, and has demonstrated the impor-
tant role of the cytokine tumor necrosis factor-␣ (TNF-␣) in
maintaining granuloma function. Using a murine model of latent
infection in which mice inoculated via the tail vein with M.
tuberculosis remain clinically well until the disease “reactivates”
roughly 9 mo later, these investigators first showed that in vivo
inhibition of the production of reactive nitrogen species led to
reactivation of disease, as mentioned above. They also observed
that TNF-␣ was expressed throughout the period of latent or
quiescent infection, suggesting that this cytokine may have a
role in maintaining the latent state. In addition, it was known
that TNF-deficient mice are susceptible to overwhelming tuber-
culosis, and that TNF, along with IFN-␥, stimulates production
of reactive nitrogen species by macrophages. These investigators
then used the low-dose model of persistent murine tuberculosis
to further analyze the role of TNF in the immune response
during latency. Six months after inoculation with a virulent lab
strain of M. tuberculosis, mice were treated with a murine TNF-
␣–specific IgG-neutralizing antibody. Following administration
of the anti-TNF antibody, bacterial burden in the lungs of treated
animals increased 10-fold within 20 d, as compared with rats
receiving IgG controls, which showed no increase. All mice that
had received the anti-TNF IgG died within 120 d of being treated,
whereas none of the control mice succumbed during that time.
Histopathologic examination of the lungs from anti-TNF–treated
mice demonstrated what disorganized granulomas without sig-
nificant recruitment or migration of inflammatory cells to the
granuloma. In contrast, control animals showed well-demarcated
granulomas with conspicuous lymphoid aggregates.
This work, demonstrating the critical role of TNF in main-
taining granuloma structure and function in mice, has received
striking confirmation in humans. Keane and colleagues reported
70 cases of tuberculosis which developed after treatment with
infliximab, a humanized monoclonal antibody against TNF (45).
Of note, most of these cases developed within 12 wk after begin-
ning administration of infliximab, most were in patients from
countries with a low prevalence of tuberculosis, and disseminated
253
disease was common. Since that initial report, many similar cases
have been reported both in patients receiving infliximab as well
as the somewhat less potent TNF receptor antagonist etanercept
(46). The recognition of the important role of TNF in maintaining
the latent state has led to the development of guidelines for
screening and treatment for latent tuberculosis infection in pa-
tients receiving anti-TNF therapy (47).
T cells in the host immune response to tuberculosis. The critical
role of T lymphocytes in tuberculosis host defense and pathogen-
esis has been brought into sharp focus by the worldwide epidemic
of HIV/AIDS. In regions where HIV infection is common, such
as sub-Saharan Africa, tuberculosis rates have increased rapidly.
In patients with latent infection, HIV infection, particularly in
the absence of antiretroviral therapy, is the leading risk factor
for the development of active disease, occurring at a rate as high
as 10% per year, as compared with 10% across a lifetime in
otherwise healthy, HIV-negative persons. Patients with HIV
infection who develop tuberculosis have different clinical presen-
tations and have higher mortality early in the course of therapy
than those with tuberculosis without HIV infection (48–58). Al-
though treatment with antiretroviral agents can restore some
of the immune responses beneficial in tuberculosis (59), these
therapies are not widely available in places where HIV/TB co-
infection is most common.
Following the demonstration in mice that CD4⫹ T-lympho-
cytes can become polarized and phenotypically distinguishable
into so-called TH1 and TH2 cells on the basis of patterns of
cytokine secretion (with IFN-␥ as the prototypical TH1 cytokine,
and interleukin [IL]-4, IL-5, and IL-10 as TH2 cytokines), Modlin
and colleagues published an important study in patients with
leprosy which suggested that T cell polarization could substan-
tially affect the clinical manifestations of chronic mycobacterial
infections (60). Patients with necrotic, clinically advanced, heav-
ily infected lepromatous leprosy lesions had skin biopsies that
contained largely TH2-type CD4⫹ cells. Skin biopsies from so-
called tuberculoid leprosy lesions, which are paucibacillary and
do not demonstrate extensive necrosis, were infiltrated by TH1-
type CD4⫹ lymphocytes.
Since that report, many groups have attempted to demon-
strate that host immune responses in tuberculosis could be simi-
larly polarized and could explain at least some of the clinical
manifestations of disease. Condos and coworkers demonstrated
that a TH1-predominant host immune response, as defined by a
marked alveolar lymphocytosis of IFN-␥–secreting cells detected
by bronchoalveolar lavage from radiographically abnormal lung
segments in patients with tuberculosis, was associated with
milder clinical disease, as defined by lack of cavity formation
and a low bacterial burden (61). In contrast, patients with more
clinically advanced disease, as defined by cavitary lesions and
sputum smear positivity, did not have evidence of a TH1 response.
This study suggested an association between the ability to mount
a TH1-type response in the setting of active disease and a more
benign clinical course, consistent perhaps with the observation
from the pre-antibiotic era that a significant percentage of pa-
tients with tuberculosis in fact recovered. The same investigators
extended their observation by administering IFN-␥ by aerosol
to patients with symptomatic, refractory multidrug-resistant tu-
berculosis and demonstrating clinical improvement (62).
Balancing the beneficial effects of a TH1-type cytokine re-
sponse, and likely contributing importantly to reactivation of
latent infection, is the elaboration of transforming growth factor
(TGF)-␤ by circulating blood monocytes. Both in vitro and in
vivo, this cytokine is capable of suppressing both IFN-␥ produc-
tion and granuloma function (63–65).
254 AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY VOL 32 2005
The Microorganism
The pathogenesis of tuberculosis involves a dynamic interaction
between host and pathogen. From the time of Koch’s identifica-
tion of the causative agent of tuberculosis until relatively re-
cently, progress had been relatively slow in understanding the
basic biology of M. tuberculosis. However, key developments in
several areas have accelerated the pace of progress recently.
These include notably the opening up of the entire field of
mycobacterial genetics, made possible by the work of Jacobs
and colleagues by using plasmids capable of transfecting M.
tuberculosis; the development of the entire field of molecular
epidemiology, centered on RFLP analysis of isolates and made
possible by the identification of the IS6110 insertion element in
the M. tuberculosis genome; and finally the sequencing of the
entire M. tuberculosis genome, accomplished by investigators at
the Pasteur Institute.
Mycobacterial Genetics. In 1987, Jacobs, Tuckman, and Bloom
reported the construction of recombinant shuttle plasmids, which
are chimaeras containing mycobacteriophage DNA into which
an Escherichia coli cosmid was inserted (66). These plasmids
replicate in E. coli as plasmids and in mycobacteria as phages,
and transfer DNA across both genera. These shuttle vectors
permitted for the first time the introduction of foreign DNA by
infection into M. smegmatis and BCG, the vaccine strain of M.
bovis. This advance created a powerful new tool for the study
of mycobacterial biology, and has led to the identification of
putative virulence factors, immunogenic determinants, drug tar-
gets, and novel vaccine candidates. An example of this was work
by Glickman and Jacobs that determined the genetic basis for
cording, the formation of strand-like clumps of mycobacteria in
culture, a phenotype long associated with virulence (an associa-
tion noted by Koch himself). Cording behavior was found to be
dependent on normal function of the pcaA gene, responsible
for a step in the synthesis of a-mycolic acids, important compo-
nents of the M. tuberculosis cell wall (67). When the gene was
mutated, and used to infect mice, in a model which is usually
lethal, the organisms did not persist or kill the animals, indicating
that the pcaA gene product is indeed a virulence factor.
Molecular Epidemiology. Using a repetitive genetic element
found in the M. tuberculosis complex as the basis of restriction
fragment length polymorphism (RFLP) analysis of clinical iso-
lates, investigators in several laboratories pioneered the develop-
ment of tuberculosis molecular epidemiology to study transmis-
sion dynamics of tuberculosis in communities (68–70). These
studies have led to fundamental changes in the understanding
of how tuberculosis is spread in communities, and have been
useful in identifying outbreaks and previously unsuspected clus-
ters of tuberculosis. Studies in New York and San Francisco
done during the tuberculosis epidemic of the late 1980s and early
1990s revealed that as many as 40% of cases of tuberculosis
could be linked, through RFLP analysis, to other cases (71, 72).
As tuberculosis control efforts aimed at rapid diagnosis and
treatment took hold, case rates fell as a direct result of decreased
transmission in the community; many of the cases that remain
are the result of reactivation of latent transmission in persons
originally from high-prevalence countries, and the strategies
needed to identify and reduce active disease in these populations
will differ from those for active cases (73).
The M. tuberculosis Genome. The announcement of the com-
plete DNA sequence of M. tuberculosis in 1998 will stand as a
signal event in understanding the pathogenesis of this disease
(74). The sequencing of the virulent laboratory strain H37Rv
revealed the genome to contain 4,411,529 base pairs encoding
over 4,000 genes. Notable features of the genome were the high
percentage of GC-rich sequences and the large numbers of genes
devoted to synthesis of fatty acids. Since the sequencing of the
initial lab isolates, additional laboratory strains and clinical iso-
lates have been sequenced in whole or in part, including a strain
associated with apparent hypervirulence in a community, and
the vaccine strain of M. bovis (75, 76). Comparisons of M. tuber-
culosis and the vaccine strain of M. bovis have been particularly
interesting. As compared with M. tuberculosis, the vaccine strain
lacks an entire genomic region, known as RD1, which contains
genes for secreted proteins such as ESAT-6 (77); this knowledge
has been exploited to develop novel diagnostics for latent tuber-
culosis infection that can distinguish in theory between true
infection and delayed-type hypersensitivity reactions caused by
prior vaccination with BCG (78). In addition, comparative geno-
mics of mycobacteria have allowed the construction of evolution-
ary trees that provide important insights into the historical devel-
opment of human disease (79). Of greatest interest, of course,
is the potential to use genomics to distinguish virulent from
avirulent strains, and immunonogenic strain from nonimmuno-
genic strains. Such information should be extremely valuable in
the effort to develop better tuberculosis vaccines.
Conclusion
Tuberculosis remains among the world’s great public health chal-
lenges, and the advances discussed in this article hold promise
for the development of better prevention and treatment of the
disease. The 123 yr since the identification of M. tuberculosis by
Robert Koch have seen great advances in our understanding of
many of the crucial events in disease pathogenesis, but tuberculo-
sis is nowhere near eradication or even control in many areas
of the globe. It is worth recalling the words of Rene and Jean
Dubos in their prescient book, The White Plague: “Tuberculosis,
it has been said, is a disease of incomplete civilization. Vague
as this statement appears at first, it underlines the fact that the
antituberculosis movement cannot be properly understood if
seen only in its medical perspective, for the historical and social
backgrounds loom large in the picture. However desirable a
goal, the complete elimination of tubercle bacilli is rendered
impossible by economic and social factors.”
Conflict of Interest Statement : N.W.S. has no declared conflicts of interest.
Acknowledgments : The author is grateful for the helpful comments of Rany Con-
dos, Joseph Burzynski, and Charles Powell. Excellent discussions of the early scien-
tists who studied tuberculosis can be found in Pioneers in Medicine and Their
Impact on Tuberculosis, by Thomas M. Daniel (University of Rochester Press, 2000).
Much of the discussion of Laennec, Villemin, and Koch in this article was informed
by Daniel’s essays. Finally, the most rudimentary Medline search for the term
“tuberculosis pathogenesis” yields over 50,000 citations. The author apologizes
to the scores of outstanding investigators whose important contributions were
not mentioned in this article, either due to lack of space or his own ignorance in
not realizing their significance.
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