Effect of carbon monoxide on Mycobacterium tuberculosis pathogenesis

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DOI: 10.1186/2045-9912-2-30 · Source: PubMed
Abstract
The intracellular pathogen Mycobacterium tuberculosis (Mtb) is exposed to multiple host antimicrobial pathways, including toxic gases such as superoxide, nitric oxide and carbon monoxide (CO). To survive, mycobacteria evolved mechanisms to resist the toxic environment, and in this review we focus on a relatively new field, namely, the role of macrophage heme oxygenase and its enzymatic product CO in Mtb pathogenesis. In particular, we focus on (i) the induction of heme oxygenase during Mtb infection and its relevance to Mtb pathogenesis, (ii) the ability of mycobacteria to catabolize CO, (iii) the transcriptional reprogramming of Mtb by exposure to CO, (iv) the general antimicrobial properties of CO and (v) new genetic evidence characterizing the ability of Mtb to resist CO toxicity. Developing a complete molecular and genetic understanding of the pathogenesis of Mtb is essential to its eventual eradication.

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R E V I E W Open Access
Effect of carbon monoxide on Mycobacterium
tuberculosis pathogenesis
Vineetha M Zacharia
1
and Michael U Shiloh
2*
Abstract
The intracellular pathogen Mycobacterium tuberculosis (Mtb) is exposed to multiple host antimicrobial pathways,
including toxic gases such as superoxide, nitric oxide and carbon monoxide (CO). To survive, mycobacteria evolved
mechanisms to resist the toxic environment, and in this review we focus on a relatively new field, namely, the role
of macrophage heme oxygenase and its enzymatic product CO in Mtb pathogenesis. In particular, we focus on (i)
the induction of heme oxygenase during Mtb infection and its relevance to Mtb pathogenesis, (ii) the ability of
mycobacteria to catabolize CO, (iii) the transcriptional reprogramming of Mtb by exposure to CO, (iv) the general
antimicrobial properties of CO and (v) new genetic evidence characterizing the ability of Mtb to resist CO toxicity.
Developing a complete molecular and genetic understanding of the pathogenesis of Mtb is essential to its eventual
eradication.
Keywords: Carbon monoxide, Heme oxygenase, Microbiology, Immunology, Mycobacterium tuberculosis, Microbial
pathogenesis
Introduction
The success of a pathogen during infection depends
upon its abilities to respond to and overcome a battery
of host defense mechanisms. In response to bacterial in-
fection, host cells generate a variety of toxic compounds
to mediate microbial killing such as excess hydrogen ion
(H+), hydrogen peroxide (H
2
O
2
), hypochlorous acid
(HOCl), nitric oxide (NO), and carbon monoxide (CO).
To promote intracellular survival, some pathogens such
as Mycobacterium tuberculosis (Mtb) evolved multiple
pathways to evade these host defenses. For example,
mycobacteria utilize superoxide dismutase [1] and cata-
lase [2,3] to convert the toxic reactive oxygen intermedi-
ates superoxide and H
2
O
2
to water and oxygen, while
they also employ multiple mechanisms to resist nitric
oxide toxicity [4-8].
Understanding Mtb resistance mechanisms against
host defenses is of paramount importance as it is an en-
demic and epidemic pathogen that latently infects ap-
proximately one-third of the worlds population [9].
Upon Mtb infection, host immune pathways are
activated, resulting in macrophage and T cell recruit-
ment [10]. The long-term success of Mtb as an intracel-
lular pathogen lies primarily in its ability to remain
dormant and persist within host macrophages for
extended periods of time. This is facilitated in part
by the induction of genes that comprise the dormancy
regulon by stimuli present in the Mtb microenviron-
ment including low oxygen, NO, nutrient starvation, and
CO (Figure 1) [11-14]. The genes in the dormancy regu-
lon, many which are of unknown function, likely con-
tribute to TB persistence by facilitating its long-term
survival [15].
Recent studies have described the deleterious effects of
CO on various microbes, while unveiling the potential
bacterial targets of CO action. In Escherichia coli,
Pseudomonas aeruginosa, and Staphylococcus aureus,
exposure to CO inhibits key enzymes of the electron
transport chain required for bacterial respiration, result-
ing in microbial death [16,17]. In contrast to the afore-
mentioned organisms, Mtb is able to withstand high
concentrations of CO, suggesting a potential CO resist-
ance pathway not previously described in microorgan-
isms [11]. In this review, we describe the role of the
reactive gas compound CO and its relevance during
* Correspondence: Michael.shiloh@utsouthwestern.edu
2
Department of Microbiology, Division of Infectious Diseases, University of
Texas Southwestern Medical Center, Dallas, TX 75229-9113, USA
Full list of author information is available at the end of the article
MEDICAL GAS
RESEARCH
© 2012 Zacharia and Shiloh; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the
Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
Zacharia and Shiloh Medical Gas Research 2012, 2:30
http://www.medicalgasresearch.com/content/2/1/30
microbial infection, while highlighting the ability of Mtb
to withstand CO toxicity.
Mtb infection increases heme oxygenase expression
In humans and mice, three isoforms of heme oxygenase
exist, HO-1, HO-2, HO-3 (encoded by Hmox1,Hmox2,
and Hmox3 genes, respectively). All three isoforms cata-
bolize heme, releasing as products free iron, biliverdin
and CO. HO-2 and HO-3 are constitutively expressed,
whereas HO-1 is induced by bacterial lipopolysacchar-
ide, hypoxia, tumor necrosis factor (TNF), reactive nitro-
gen and oxygen intermediates [18,19] and also by Mtb
infection [11,20]. Upregulation of HO-1 may benefit
host cells since CO and biliverdin/bilirubin can act as
signaling molecules as well as provide cytoprotection.
CO contributes to the cytoprotective effects of HO-1
by preventing free heme accumulation within cells,
suppressing endothelial cell apoptosis, and modulating
an anti-inflammatory response in macrophages upon ex-
posure to bacterial lipopolysaccharide [21-23]. Likewise,
both biliverdin and bilirubin (under the influence of bili-
verdin reductase) can protect cells from a variety of
cytotoxic insults [24].
Notably, HO-1 deficient mice manifest decreased abil-
ity to overcome pathogenic infection and to recover
from inflammatory diseases, xenotransplantation, and
heart diseases (reviewed in [25]). In humans, a poly-
morphism in the Hmox1 promoter result in differential
expression of HO-1 such that individuals with fewer
(GT)n repeats in the Hmox1 promoter transcribe more
HO-1 in response to various stimuli, resulting in
enhanced protection from both infectious and non-
infectious diseases [26]. This strongly indicates that
robust cellular HO-1 expression is crucial to overcome
Figure 1 Role of carbon monoxide in M. tuberculosis pathogenesis. Macrophage infection by Mtb induces HO-1. HO-1 catabolizes heme to
release CO, iron and bilverdin. CO produced by HO1 can alter Mtb gene transcription by activating the DosS/DosR two component signal
transduction system to stimulate a dormancy program. CO-mediated growth inhibition is resisted by the expression of a genetically encoded
Mtb gene. Some mycobacteria can catabolize CO via CO dehydrogenase for growth. Alternatively, CODH may function in resisting host-derived
nitric oxide.
Zacharia and Shiloh Medical Gas Research 2012, 2:30 Page 2 of 7
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infectious and non-infectious diseases by mediating a
wide range of host regulatory pathways.
Previously, we [11] and others [20] found that during
Mtb infection, HO-1 is induced in both infected macro-
phages and mice suggesting that increased levels of CO
might be present during Mtb infection (Figure 1) [11].
This induction occurred very early during mouse infec-
tion, i.e. within 10 days, and was concentrated in nascent
granuloma and tissue macrophages [11]. The precise sig-
naling mechanism of HO-1 induction by Mtb is un-
known, though bacterial factors, free heme, and
inflammatory cytokines likely combine to induce HO-1
transcription. Although the exact concentration of CO
in lungs during Mtb infection is not known, CO concen-
trations can range from 250 ppm, depending on the
physiologic status of the individual. Thus, the average,
nonsmoking human exhales approximately 2 ppm
[27,28] while patients with a variety of infectious and in-
flammatory conditions producing significantly more
[27,29-32].
What might be the function of HO-1 during infection?
Considering that the induction is robust at the direct site
of infection, i.e. macrophages within granuloma, it is
feasible that HO-1 may be involved in controlling Mtb
growth. Given the pleiotropic signaling activity of HO-1
and CO, other mechanisms might also be HO-1/CO
dependent during Mtb infection. For example, HO-1
enhances interferon regulatory factor 3 (IRF3) phosphor-
ylation and interferon-β(IFN-β) production in Listeria
or virally infected macrophages [33] and Mtb infection
of macrophages rapidly induces IRF3 phosphorylation
and IFN-βproduction [34]. Thus, the observed activa-
tion of the IRF-3/IFN-βpathway during Mtb infection
[34] may also be HO-1 dependent. In addition to regu-
lating cytokine production, HO-1 and CO may also be
involved in triggering the autophagy pathway for eradi-
cation of intracellular bacteria termed xenophagy [35].
Autophagy plays a major role in controlling Mtb infec-
tion infection [36,37] and recent work found that inhib-
ition of HO-1 prevented endotoxin-induced autophagy
[38], suggesting that during Mtb infection, upregulation
of HO-1 with concomitant CO production enhances
multiple innate immunity mechanisms.
Carbon monoxide as a carbon and electron source in
mycobacteria
Albeit a toxic gas, carbon monoxide also functions as an
intermediate molecule in bacterial metabolic pathways.
Certain aerobic and anaerobic microorganisms, particu-
larly those that utilize CO as the sole carbon and energy
source (carboxydotrophs), employ the enzyme carbon
monoxide dehydrogenase (CODH) to convert reactive
carbon monoxide into more stable compounds [39].
Specifically, CODH catalyzes the reaction CO + H
2
O->
CO
2
+2e
-
+2H
+
when organic carbon is absent (auto-
trophic growth) and carbon monoxide is present [40].
CO dehydrogenase is a complex metalloprotein com-
posed of 3 polypeptides. In the carboxydotroph Oligotro-
pha carboxydovorans, the three structural genes of
CODH are coxL (for CO oxidation protein, Large sub-
unit), coxM (medium subunit) and coxS (small subunit)
(Figure 1). The entire cox cluster is transcriptionally
induced when the bacteria are grown under autotrophic
conditions in the presence of CO but not under hetero-
trophic conditions (organic carbon rich) [40]. Although
the mechanism of this transcriptional induction remains
unknown, these genes are necessary for autotrophic
growth [41]. In aerobes, CODH coordinates molyb-
denum in its active site to oxidize CO to CO
2
and the
electrons generated from the oxidation reaction is trans-
ferred to the final electron acceptor such as ferredoxin,
cytochromes, FMN or FADH
2
, which are then subse-
quently coupled to other energy requiring processes
[42,43]. CODH in anaerobic microbes also catalyzes CO
oxidation, but instead of coordinating molybdenum in
its active site, it contains a Ni-Fe active site. When
coupled to acetyl-CoA synthase (ACS), CODH converts
CO
2
to CO in the Wood-Ljungdahl pathway for subse-
quent synthesis of a major carbon source, acetyl-CoA
[44,45]. Thus, oxidation of CO can simultaneously pro-
duce energy for the cell and additional sources of carbon.
More recent evidence suggests that CO utilization via
CODH is widespread among diverse microbial species,
including the mycobacterial species M.bovis BCG, M.
gordonae,M.smegmatis, and M. tuberculosis [43,46,47].
Mtb encodes for orthologues of CODH subunits [40].
The CODH structural genes are arranged in the tran-
scriptional order 5coxM (Rv0375c) -> coxS (Rv0374c)
-> coxL (Rv0373c) 3, a genome structure shared by the
majority of bacteria with cox homologues [40]. All three
of the putative Mtb CODH proteins demonstrate high
overall sequence similarity with O. carboxydovorans and
all sequenced mycobacterial genomes including that of
M. avium,M. bovis,M. leprae, and M. smegmatis en-
code for cox homologues with extremely high sequence
similarity to Mtb [48]. Notably, as more genomes have
been sequenced, cox homologues have been identified in
several additional pulmonary pathogens, including Bur-
kholderia sp., Rhodococcus sp., and Pseduomonas sp.
(our unpublished observations).
The identification of cox homologues in various myco-
bacteria species prompted Park et al. to test the ability
of mycobacteria to grow in vitro on CO as the sole car-
bon source [48]. Strikingly, all of the mycobacteria tested
were able to grow on CO at 30% atmosphere as the sole
carbon source, albeit more slowly [48]. Growth on CO
required a long lag period after the bacteria were first
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subjected to CO-growth media, suggesting transcrip-
tional induction of CO utilization genes [48]. Notably,
CO-dependent growth of virulent Mtb was not tested.
Additionally, Mtb and some of its relatives were found
to utilize CO at <1-5 parts per million (ppm), an envir-
onmentally and physiologically relevant range since CO
in the atmosphere and lungs measure at approximately
0.1 to 0.5 ppm and <3 ppm, respectively [27,47]. To
date, no mutants in the cox genes have been reported in
Mtb. However, that Mtb has retained these large genes
during its evolution as a pathogen without a known
ex vivo existence suggest that Mtb might utilize CO as
an alternative carbon source, which may confer a select-
ive advantage for Mtb within the nutrient-limited con-
fines of a macrophage. An alternative explanation may
be that the cox genes serve another function, namely, ni-
tric oxide detoxification [49]. Although recombinant
CODH from mycobacteria was able to oxidize NO and
protect E. coli from NO mediated toxicity [49], direct
genetic evidence that the cox genes are required by Mtb
in vitro or in vivo to protect Mtb is lacking. Thus, myco-
bacterial CODH may have at least two activities, namely,
CO uptake and NO detoxification, and further patho-
genesis assays will be needed to dissect the precise func-
tion(s) of Mtb CODH (Figure 1).
Gene expression of Mtb in the presence of carbon
monoxide
Since Mtb resides within the lung, and since CO is
exhaled continuously, it is reasonable to predict that
Mtb might have evolved mechanisms to detect and re-
spond to changing CO fluxes, partly to sense the host
immune status. In fact, both prokaryotes and eukaryotes
have developed systems for sensing carbon monoxide
[29,50-52]. For example, in eukaryotes the transcription
factor NPAS2, implicated in regulating circadian rhythm,
was shown to bind CO resulting in decreased DNA
binding activity [53]. Likewise, the bacterium Rhodospir-
illum rubrum expresses a CO-binding transcription fac-
tor, CooA, whose function is to stimulate production of
a CO oxidation system distinct from the one found in O.
carboxydovorans [54-57]. How do organisms sense and
measure CO? Commonly, these proteins contain an
associated heme moiety which is not surprising given
the propensity of CO to bind heme [50]. However, the
physiologic conditions and precise mechanisms used by
these proteins to bind both heme and CO are diverse.
For instance, CooA from R. rubrum can only bind CO
when its heme is in the ferrous (Fe
2+
) state, a reduced
condition found stably only under purely anaerobic con-
ditions [57-59]. Thus, an organism like Mtb, which
expresses a CO oxidation system under aerobic con-
ditions [48] would be unlikely to express a CooA
homologue, and in fact no CooA homologue can be
identified in the Mtb genome.
To test the response of Mtb to CO, we exposed Mtb
to CO in vitro and assessed the effects using transcrip-
tional profiling [11]. We found that CO induces the
transcription of a cohort of genes known as the dor-
mancy (dos) regulon [11]. This induction occurred at
CO concentrations as low as 20 ppm headspace CO, but
was most robust at concentrations above 2000 ppm [11].
Mtb lacking the DosS/DosT two component system was
unresponsive to CO, indicating that DosS is the primary
sensor for CO. Notably, DosS also sense NO and hyp-
oxia via its heme binding domain (Figure 1) [60]. To
confirm CO sensing can occur in vivo, we infected wild-
type mouse macrophages and macrophages deficient in
HO-1 and found a significant abrogation of dormancy
gene induction in the absence of HO-1 [11]. Similar
results were obtained by Kumar et. al, confirming that
Mtb can sense CO in vitro and in vivo [20].
General antimicrobial properties of carbon monoxide
It has been nearly four decades since preliminary studies
have described the antibacterial effects of carbon mon-
oxide. Specifically, CO was found to inhibit DNA repli-
cation in E. coli and it was postulated that CO may
disrupt unwinding of the DNA duplex during replica-
tion, rather than directly inhibiting DNA polymerase ac-
tivity [61]. However, it was later discovered that CO
halts DNA replication by reducing the intracellular con-
centration of ATP and dNTPs. By disrupting enzymes in
the electron transport and ATP production pathways,
it was found that the presence of CO led to the deple-
tion of deoxynucleoside triphospate pools in E. coli
[62]. CO was also found to inhibit growth of the air-
borne bacteria Serratia marcescens by causing a flux in
energy-generating pathways, namely the electron trans-
port system [63].
Recently there has been revived interest in examining
the role of exogenous CO on bacterial growth using
lipid-soluble carbon monoxide-releasing molecules
(CORMs). The original CORMs were metal carbonyl
compounds that release CO at physiologically relevant
concentrations in biological systems [64]. More recently,
newer CORMs have been synthesized that represent
unique chemistry [65] and multiple CORM compounds
are effective antimicrobial molecules against both gram
negative and gram-positive bacteria. In a recent study by
Nobre et al., cultures of E. coli and S. aureus were trea-
ted with CORM-2 and CORM-3 under aerobic and an-
aerobic conditions to determine cell viability [66]. In the
presence of either CORM, the strains suffered the toxic
effects of CO as marked by a significant reduction of
CFU/mL compared to cells not treated with a CORM.
Furthermore, the study reveals that the bactericidal
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effects of CO were observed under both aerobic and an-
aerobic conditions, indicating that there are additional
bacterial targets for CO aside from the components
involved in aerobic respiration [66]. The potency of
CORMs as antimicrobial compounds is further under-
scored by a study that described reduced cell viability of
laboratory and antibiotic-resistant strains of P. aerugi-
nosa when treated with CORM3 [16]. ALF-62, a differ-
ent class of CO-RM containing molybdenum, and
CORM2 were recently tested on E. coli to elucidate the
mechanism by which CO inhibited bacterial growth [65].
In their study, Tavares et al. report an accumulation of
endogenous reactive oxygen species (ROS) in the pres-
ence of these CORMs and observe rescued growth of
CORM treated E. coli when supplemented with various
antioxidants [65].
In vitro survival of mycobacteria in the presence of CO
and identification of CO resistance gene in Mtb
Although CO toxicity is widespread among diverse bac-
terial species, Mtb can withstand elevated CO concen-
trations with only minimal growth inhibition [11].
Under aerobic conditions, when Mtb are treated with
CO during log phase, the bacteria are able to effectively
resist CO-mediated growth inhibition [11]. Considering
that Mtb senses CO in vitro via the DosS/DosT two-
component system and its growth in vitro is not severely
diminished in the presence of CO (unlike other bacteria
when treated with CO), we hypothesized that Mtb CO
resistance is genetically encoded. To identify such a
gene, we generated an Mtb transposon mutant library
and screened for mutants that did not grow in the pres-
ence of CO when compared to its growth in the pres-
ence of air (Zacharia, et. al, submitted). Interestingly, we
identified such a mutant and mapped the transposon in-
sertion to a gene region conserved in mycobacterial spe-
cies and even phylogenetically distinct organisms such
as Thermatoga maritima and Rhodococcus fascians.To
confirm that the newly identified gene does indeed con-
fer CO resistance, Zacharia et al. complemented the mu-
tant with the cloned gene of interest, and observed a
rescued growth phenotype in the presence of CO
(Zacharia, et. al, submitted). Importantly, the mutants
ability to survive inside wild type macrophages was con-
siderably less than that of wild type Mtb. Moreover, the
mutant Mtb strain is attenuated for virulence in a mouse
aerosol model of Mtb infection. Thus, host-derived CO
can limit Mtb growth in macrophages and mice
(Zacharia, et. al, submitted). This discovery of a novel
protein involved in CO resistance marks the initial iden-
tification of a CO resistance gene in a pathogen. Mul-
tiple lines of experimentation are being actively pursued
(biochemical, genetic, bioinformatics) to characterize the
molecular function of this mycobacterial CO resistance
protein to ultimately determine its role in contributing
to Mtb pathogenesis.
Concluding remarks
The effects of CO on bacterial and mammalian cells are
diverse including acting as a signaling molecule involved
in regulating gene expression [52,53] to serving as a po-
tent, toxic gas capable of inhibiting bacterial growth
(Zacharia, et. al, submitted). Amongst human pathogens,
Mycobacterium tuberculosis is currently the only one
known to change its gene expression in response to
varying CO concentrations. Some mycobacteria can use
CO as a source of energy, but whether Mtb does so dur-
ing infection remains unknown. However, when host
macrophages produce CO Mtb responds by expressing
its own CO resistance genes. The ability of Mtb to sur-
vive in the presence of CO, in contrast to other known
pathogens, indicates that Mtb has uniquely evolved
mechanisms to bypass CO toxicity. The identification
and characterization of a CO resistance gene and its
associated pathways will provide a more comprehensive
understanding of Mtb pathogenesis and on a broader
scale, host-pathogen interactions.
Abbreviations
ATP: Adenosine triphosphate; CO: Carbon monoxide; CODH: Carbon
monoxide dehydrogenase; CORM: Carbon monoxide releasing molecule;
DNA: Deoxyribonucleic acid; dNTP: Deoxyribonucleotide; H
2
O
2
: Hydrogen
peroxide; HO: Heme oxygenase; IFN-β: Interferon beta; IRF3: Interferon
regulatory factor 3; Mtb: Mycobacterium tuberculosis; NO: Nitric oxide;
TNF: Tumor necrosis factor.
Competing interests
The authors declare no competing interests.
Authorscontributions
Both VMZ and MUS conceived of and drafted the manuscript. Both authors
read and approved the final manuscript.
Acknowledgements
Work by the authors was funded by the Disease Oriented Clinical Scholars
program at UT Southwestern and NIH R01 AI099439 (M.U.S.) and by NIH T32
training grant 5T32AI007520 (V.M.Z.).
Author details
1
Department of Medicine, Division of Infectious Diseases, University of Texas
Southwestern Medical Center, Dallas, TX 75229-9113, USA.
2
Department of
Microbiology, Division of Infectious Diseases, University of Texas
Southwestern Medical Center, Dallas, TX 75229-9113, USA.
Received: 24 September 2012 Accepted: 4 December 2012
Published: 17 December 2012
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doi:10.1186/2045-9912-2-30
Cite this article as: Zacharia and Shiloh: Effect of carbon monoxide on
Mycobacterium tuberculosis pathogenesis. Medical Gas Research 2012 2:30.
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    • "Also, in at least one study, HO-1 is found to be induced by and protective against non-tuberculous mycobacterial infection [186]. HO-1 is also induced during tuberculosis infection, however it is unclear whether this promotes or reduces infection [187]. Herpes simplex virus-1 (HSV-1) encephalitis induces a strong HO-1 response in macrophages in the brain [188, 189]; and infection of neurotropic Borna disease virus (BSV) in the brain leads to sustained HO-1 induction in activated microglia, reactive astrocytes and mononuclear infiltrates for up to 4 weeks post-infection, presumably as a neuroprotective response [190]. "
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    • "In 2007, CORMs were reported to have antimicrobial properties against Escherichia coli and Staphylococcus aureus [15]. Since then, other bacteria such as Pseudomonas aeruginosa and Mycobacterium tuberculosis showed to be susceptible to CORMs [16,17]. Importantly, Ru 2+ complexes structurally similar to CORM-2 and CORM-3 but devoid of CO do not kill bacteria, an observation that is consistent with the inhibition of bacterial components by CO [15,18]. "
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