Editorial

Host-directed therapy of
tuberculosis: what is in it for
microRNA?
1. Introduction
Marco Iannaccone, Anca Dorhoi & Stefan HE Kaufmann
2. MiRs and lung disease
Max Planck Institute for Infection Biology, Department of Immunology, Berlin, Germany
3. MiRs and TB
4. MiR delivery techniques Tuberculosis (TB) is a major health threat and current intervention measures
5. Anti-infective therapy with are far from satisfactory. MicroRNAs (miRs) have become major targets of
miRs investigations for different diseases due to their propensity to regulate gene
Expert Opin. Ther. Targets Downloaded from informahealthcare.com by Cornell University on 06/09/14

expression in various biological processes. More recently, miRs have been

6. Expert opinion
found to play key roles in the control of infectious diseases. Consequently,
the potential of miRs for diagnosis and therapy of TB is being considered. In
this editorial, we discuss most recent lines of evidence for regulation of the
immune response in TB by miRs that could form the basis for diagnosis and
host-directed therapy in adjunct to canonical intervention measures in TB.

Keywords: host-directed therapy, lung, microRNA, tuberculosis

Expert Opin. Ther. Targets (2014) 18(5):491-494

1. Introduction
For personal use only.

MicroRNAs (miRs) are small noncoding RNAs that regulate diverse biological
processes, such as cell growth and differentiation, cellular metabolism and immune
response. They control gene expression by targeting RNA transcripts and determin-
ing degradation and/or repression of translation [1]. The multifactorial features of
miRs have fostered investigations on their roles in complex host responses, such as
immunity to chronic bacterial infections [2]. Tuberculosis (TB) is primarily a lung
disease caused by the intracellular bacterium Mycobacterium tuberculosis (Mtb),
which caused 1.3 million deaths in 2012 [3]. After 40 years of quiescence, very
few drugs have been licensed, and increasing incidences of multidrug-resistant
(MDR) and extensively drug-resistant (XDR) TB emphasize the necessity to
develop novel intervention strategies [4]. Although caused by a bacterium, not
only protection against, but also pathology of TB, is driven to a large extent by
the host immune response. Therefore, in addition to standard anti-TB chemother-
apy, host-directed therapy (HDT), which improves protection and/or ameliorates
pathology, are urgently needed [5]. MiRs have been harnessed for treatment of
several disorders, and here, we discuss opportunities and challenges for miR-based
HDT of TB.

2. MiRs and lung disease

Increasing evidence suggests that miRs regulate diverse cellular processes in

pulmonary pathologies. Sato et al. showed that miR-146a [6] is downregulated
when fibroblasts, isolated from chronic obstructive pulmonary disease, are
incubated in vitro with proinflammatory cytokines and point to prostaglandin
E2 as target of miR-146a [6]. In a similar vein, Wu et al. [7] identified specific
miR expression in response to H1N1 pandemic influenza virus revealing new
potential strategies toward HTD against influenza [7]. In a mouse model,
Moschos et al. [8] showed that several miRs are upregulated in response to aerosol-
ized lipopolysaccharide exposition suggesting that miRs play a key role in the host

10.1517/14728222.2014.897696 2014 Informa UK, Ltd. ISSN 1472-8222, e-ISSN 1744-7631 491
All rights reserved: reproduction in whole or in part not permitted
 M. Iannaccone et al.
response to bacterial components in the lung [8]. Furthermore,
miRs have been implicated in pathogenesis accompanying
lung neoplasia. For example, downregulation of let-7 is
associated with shortened postoperative survival and cancer
progression [9]. Altogether these data suggest a key role of
miRs in controlling diverse disease processes affecting the
lung.
3. MiRs and TB
Modulation of host miR expression during bacterial infections
remains incompletely understood. In TB, miRs were exploited
as potential biomarkers to discriminate between healthy
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individuals and TB patients [10]. Various biological samples
have been analyzed, including peripheral blood, serum/plasma
[11], saliva [12], and different cell types. Using a tailored
signature of differentially expressed miRs, Miotto et al. [13]
discriminated healthy controls from TB patients. This study
included differential genetic background to increase sensitivity
and specificity within groups [13]. Using peripheral blood,
Maertzdorf et al. [14] identified a cluster of four miRs that
were differentially regulated between the two granulomatous
lung diseases of similar pathology, active TB and sarcoidosis.
Interestingly, applying a clustering approach, strong correla-
For personal use only.
tions between miRs and gene expression were revealed, sug-
gesting interactions between different biological pathways
[14]. The biomarker findings are complemented by studies
investigating biology of miRs in immunity to TB. The
cytokines IFN-g and TNF-a are key mediators of protective
immunity in TB, and chemokines modulate recruitment of
inflammatory leukocytes to the lungs [15]. Rajaram et al. [16]
showed that bacterial cell-wall components from virulent or
avirulent mycobacterial species induce differential miR expres-
sion in infected macrophages. Lipomannan from pathogenic
Mtb or from the nonpathogenic M. smegmatis stimulated
expression of miR-125b or miR-155, respectively. These two
miRs differentially induced TNF-a. Yet miR-125b directly
targeted TNF-a, while miR-155 modulated the function of
SHIP1, a negative regulator of the PI3K/Akt pathway [16].
Thus, components from related bacterial species, but different
virulence, modulate host miR expression, and consequently,
immunity. Modulation of IFN-g by miR has been recently
analyzed. Ma et al. [17] created a transgenic mouse in which a
sponge blocks the endogenous miR-29. These mice showed
increased resistance against Mtb challenge, mostly due to
reduced inflammation and lower bacterial burden. In a similar
vein, the impact of miR-223 on susceptibility to TB was
dissected in gene knockout mutant mice. Dorhoi et al. revealed
that miR-223 deficiency caused susceptibility to Mtb infec-
tion [18]. Absence of miR-223 resulted in aberrant neutrophil
migration to the site of infection, followed by tissue
destruction and higher bacterial load. CXCL2, CCL3, and
IL-6 were identified as direct targets of miR-223. Using
neutralizing antibodies against these mediators, the resistant
phenotype could be reestablished [18]. As a corollary, distinct
492 Expert Opin. Ther. Targets (2014) 18(5)
miRs are currently being identified as potential targets for
TB therapy.
4. MiR delivery techniques
Novel intervention strategies exploit miR-mimics to restore
optimal miR abundance or anti-miRs to block aberrantly
produced miRs [19]. For efficient delivery of these molecules,
attempts have been made to improve endonuclease resistance
and to optimize binding affinity to the homologous target,
including chemical modifications, for example, in the sugar
backbone or the nucleotide structure. Technologies to deliver
miRs in vivo include lentiviral vectors, lipid conjugates, or
small exosome-like vesicles. Using a vesicle-based system,
primary B cells, transfected with a specific anti-miR, have
been shown to deliver this molecule to antigen-activated
T cells [20]. Moreover, antigen-specific exosome-like nanove-
sicles isolated by affinity chromatography have been trans-
fected with mimics or anti-miR to restore miR expression in
target cells [21]. These techniques hold promise for treatment
of TB, where granulomas, representing the hallmark tissue
response, are not easily accessible to drugs. In this context,
antigen-specific exosome-like vesicles loaded with specific
miRs could modulate cellular composition within granulomas
and fine-tune immune responses in situ. However, these deliv-
ery methods for miR-based HDTs need to be first carefully
assessed in animal models mimicking human TB pathology.
5. Anti-infective therapy with miRs
Attempts to stabilize anti-miR have been advanced for
hepatitis C virus (HCV) treatment. High expression of
miR-122, which is associated with HCV infection, protects
the viral genome by endonuclease degradation. Consequently,
an anti-miR drug composed of locked nucleic acid sequence
complementary to mature miR-122, has been developed [22].
In HCV patients treated with this compound (Miravirsen), a
dose-dependent viral RNA reduction was observed in a
Phase II clinical trial [22]. The miR-mimics are also being devel-
oped as therapeutics. In a mouse model, administration of
exogenous miR-590-3p and miR-199a-3p into the heart was
shown to enhance cardiomiocyte growth after induced heart
damage [23]. Intranasal administration of miR let-7 for lung
cancer HDT maintained tumor suppressor activity [24] leading
to a reduction of tumor size. Thus, anti-miR and miR-mimics
promise to become powerful measures for readjustment of
aberrant miR expression in infection, inflammation, and
malignant disorder.
6. Expert opinion
MiRs represent promising tools as biomarker and as accessible
targets to modulate host immune responses. Early diagnosis is
essential for effective control of TB and analysis of miR
expression supports their applicability as reliable biomarkers
 Host-directed therapy of tuberculosis: what is in it for microRNA?

(alone or combined with other types of markers) for TB
diagnosis and prognosis. In addition, miRs could be targeted
for HDT approaches, to reduce pathology and strengthen
protection. Administration of miR-223 mimics could restrict
migration of inflammatory cells to the site of infection and
thereby diminish inflammation. Anti-miR constructs target-
ing miR-29 and miR-125a could be harnessed to augment
concentrations of IFN-g and TNF-a, respectively. Adminis-
tration of miR-based HDTs to modulate inflammation in
adjunct to canonical drug therapy could shorten the duration
and increase efficacy of treatment of MDR and XDR TB.
Although significant advances have been accomplished
concerning delivery of miRs into the lung, numerous ques-
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TGF-b1 expression via pulmonary delivery of siRNA in
the TB mouse model [25], provide a valid basis for future
miR-based HDTs. Detailed mechanistic insights into the
biological role of miRs remain scarce, and specifics of mode-
of-action of anti-miR/miR-mimics await further clarification.
Yet, although miR HDT options are still in their infancy,
exciting opportunities for the betterment of TB control
appear on the horizon.
Acknowledgements
The authors thank Mary Louise Grossman for help preparing
the manuscript.

tions still await clarification. Further studies will define the

most appropriate route of delivery, kinetics of miR-mimics/ Declaration of interest
anti-miR HDT as well as pharmacovigilance issues. The
encouraging results reported for intranasal administration of The authors state no conflict of interest and have received no
miRs in lung cancer and those describing modulation of payment in preparation of this manuscript.

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Affiliation
Marco Iannaccone, Anca Dorhoi &
Stefan HE Kaufmann

Author for correspondence
Max Planck Institute for Infection Biology,
Department of Immunology,
Chariteplatz 1, D-10117, Berlin, Germany
Tel: +49 30 28460 500;
For personal use only.

Fax: +49 30 28460 501;

E-mail: kaufmann@mpiib-berlin.mpg.de

494 Expert Opin. Ther. Targets (2014) 18(5)