1. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 1
INTRODUCTION:
Recent work on novel TB treatment strategies has suggested that
directly targeting host factors is beneficial for TB treatment. Such strategies,
termed host-directed therapeutics (HDTs), focus on host-pathogen interactions.
HDTs are more beneficial than existed TB drugs, which are limited the long
durations of treatment and the emergence of drug-resistant strains. Targets of
HDTs include host factors such as cytokines, immune check points, immune
cell functions, and essential enzyme activities.
Tuberculosis (TB), which is caused by infection with
Mycobacterium tuberculosis (MTB), is a global health problem that has
significant lethality. Current anti-TB drugs have limitations such as adverse
effects and interactions with other drugs. HDTs also reduce pathogen
proliferation and the hyper-inflammatory response by modulating the host
immune system.
2. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 2
GlobalStatus of TB-
According to WHO estimates that about 9.2 million new cases of TB
occurred in 2006.India is the first rank in incidence.The global status of
TB are as follows:
Fig 1: Global Status of TB
3. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 3
History of TB -
Tuberculosis is an Ancient Disease. Spinal Tuberculosis in Egyptian Mummies
History dates to 1550-1080 BC identified by PCR. TB History Timeline as
shown in fig 2.
Fig 2: TB History Timeline
4. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 4
What is T.B.?
Tuberculosis or TB is a disease caused by -
1. Mycobacterium Tuberculosis
2. Mycobacterium Bovis
3. Mycobacterium Africanum
4. Mycobacterium Microti
5. Mycobacterium Canetti, etc.
Characteristics of Mycobacterium tuberculosis-
Fig 3: Mycobacterium tuberculosis
1. They are non- motile
2. Non -sporing
3. Non -capsulated
4. Mycolic acid present in cell wall makes it acid fast
5. Rod shaped 0.2-0.5 µ in D,2-4 µ in L
6. Divided every 15-20 hrs.
7. Unable to digested by microphages
8. Highly aerobic
Non -tuberculosis mycobacteria –
1. Mycobacteria that do not cause TB disease
2. Not usually spread from person to person
3. Example is M. avium complex
Common Symptoms of TB -
1. Cough(2-3 weeks or more)
2. Coughing up blood
3. Chest pains
4. Fever
5. Night sweats
6. Feeling weak and tired
7. Loss of appetite
5. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 5
Tuberculosis Affects Many Parts of the Body -
1. CNS (brain and meninges)
2. Bones ,Spines
3. Intestine, Middle ear
4. Lung, Liver
5. Spleen ,Pericardium
6. Adrenal glands etc.
Types of TB -
Drug-resistant TB –TB caused by organisms that are able to grow in the presence
of a particular drug; TB that is resistant to at least one first-line anti-tuberculosis drug.
Mono-resistant TB – TB that is resistant to one TB treatment drug.
Poly-resistant TB – TB that is resistant to at least two TB treatment drugs (but not
both isoniazid and rifampin); but is not MDR TB
Primary drug-resistant TB – Drug-resistant TB caused by person-to-person
transmission of drug-resistant organisms.
Secondary drug-resistant TB – Also referredto as acquired drug-resistant TB;
develops during TB treatment, either because the patient was not treated with the
appropriate treatment regimen or because the patient did not follow the treatment
regimen as prescribed.
Multidrug-resistant TB (MDR TB) – TB that is resistant to at least the drugs
isoniazid and rifampin; MDR TB is more difficult to treat than drug-susceptible TB.
Extensively drug resistant TB (XDR TB) – A rare type of MDR TB that is
resistant to isoniazid and rifampin, plus resistant to any fluoroquinolone and at least
one of three injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin)
Latent TB infection(LTBI) – Refers to the condition when a person is infected with
tubercle bacilli but has not developed TB disease. Persons with LTBI carry the
organism that causes TB but do not have TB disease symptoms and they cannot
spread TB germs to others.
Extrapulmonary TB – TB disease that occurs in places other than the lungs, such as
the lymph nodes, the brain, the kidneys. Extrapulmonary TB are not infectious.
Pulmonary TB – TB disease that occurs in the lungs. It is usually infectious if
untreated.
6. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 6
Pathogenesis of TB :
The pathogenesis of TB in schematic diagram are as following-
1. Inhalation of droplets infected with Mycobacterium
Tuberculosis.
2. It is trapped first in the upper airways, where the primary defences is activated
referring to the mucus-secreating goblet cell & the cilia.
When the initial prevention of infection is not successful, the bacteria reaches and
deposits itself in the lung periphery usually in the lower part of the upper lobe or the
upper part of the lower lobe; specifically in the alveoli.
The bacteria is quickly surrounded by polymorphonuclear leukocytes and engulfed by
the alveolar macrophages.
Some mycobacterial organisms are carried off by the lymphatics to the hilar lymp nodes
3. It is now called as the Ghon Complex , but it rarely results in the spread to other body organs.
As macrophages (epithelial cells) engulf the bacteria, these cells join and form
into giant cells. that encircle the foreign cell.
As a result of hypersensitivity to the organism, inside the giant cells
caseous necrosis occurs (granular chessy appearance)
4. There is then the proliferation of T- lymphocytes in the surrounding of
the central core of the caseous necrosis causing some lesions.
Fibrosis and calcification happens as the lesion ages resulting to granuloma
formation called as tubercle.
5. Collagenous scar tissue encapsulates the tubercle to separate the organisms from the body.
7. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 7
Pathogenesis ofTB - Pathogenesis of TB as shown in fig.4 are as following-
Fig.4:Pathogenesis of TB
8. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 8
Current Anti-TB drugs and their targets :
Table 1- Current Anti-TB drugs and their targets
Classification Drug Name MOA Structure
F
I
R
S
T
L
I
N
E
D
R
U
G
S
Ethambutol Inhibits mycobacterial
arabinosyl transferases.
Arabinosyl transferases
are involved in the
polymerization reaction
of arabinoglycan ,as
essential component of
the mycobacterial cell
wall.
Isoniazid It blocks mycolic acid
synthesis & kills the cell.
Rifampicin It binds to β –subunit of
bacterial DNA dependent
RNA polymerase and
inhibit RNA synthesis.
Pyrazinamide Pyrazinamide converts
into pyrazinoic acid
(POA).POA decreases
the pH below that retards
the growth of M.tb. and
inhibiting the fatty acid
synthesis.
Streptomycin Irreversibly inhibits
bacterial protein
synthesis.
9. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 9
S
E
C
O
N
D
L
I
N
E
D
R
U
G
S
Salicylates-
Para-amino
benzoic
acid(PABA)
To inhibit folic acid
biosynthesis and uptake
of iron.
Ethionamide Similar to isoniazide.
Cycloserine It inhibits the
incarporation of D-
alanine into
peptidoglycan
pentapeptide by inhibiting
alanine racemase. Inhibits
mycobacterial cell wall
synthesis.
Thiacetazone Bacteriostatic inhibits
cyclopropanaton of cell
wall mycolic acid.
Quinolones-
ciprofloxacin
Inhibits bacterial DNA
synthesis by inhibiting
bacterial topoisomerase
Macrolides-
Azithromycin
Bind to 50s ribosomal
subunits and blocks
dissociation of peptidyl t-
RNA from ribosomes
causing RNA –dependent
protein synthesis.
10. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 10
Amino
glycosides-
Kanamycin
Bacteriocidal and
believed to inhibits
protein synthesis by
binding to 30s ribosomes
subunit
Fig 5 : Antitubercular Drugs and Their Targets
11. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 11
New Anti-TB drugs -
Table 2- New Anti-TB drugs
Drug Name MOA Structure
Rifapentine Inhibits DNA -
dependent RNA
polymerase in
susceptible strains of
M.tb
Clofazimine Release of reactive
oxygen species(ROS)
and cell membrane
distruption
Bedaquilline Inhibition of
mitochondrial ATP
synthase
Delamanid Mycolic acid
biosynthesis inhibition
12. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 12
Pretomanid Inhibition of cell wall
of mycolic acid
biosynthesis
Sutezolide Protein synthesis
inhibitor
13. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 13
Diagnostic tests for TB-
A test used to detect TB infection
(see Mantoux tuberculin skin test
in glossary)
Tuberculin skin test (TST) -
A method of testing for TB infection; a
needle and syringe are used to inject 0.1
ml of 5 tuberculin units of liquid
tuberculin between the layers of the skin
(intradermally), usually on the forearm;
the reaction to this test, usually a small
swollen area (induration), is measured 48
to 72 hours after the injection and is
interpreted as positive or negative
depending on the size of the reaction and
the patient’s risk factors for TB.
Mantoux tuberculinskin test
(TST) –
14. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 14
A type of blood test that measures a
person’s immune reactivity to M.
tuberculosis.
Interferon-gamma release
assay (IGRA) –
A blood test used to determine TB
infection. The QFT-G measures the
response to TB proteins when they are
mixed with a small amount of blood.
QuantiFERON®-TB Gold
test (QFT-G) –
15. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 15
Current TB vaccine-
Microscopy-
The BacilleCalmette-Guérin (BCG) is
the ONLY successfulTB vaccine .Was
introduced in 1921.BCG is the world’s
most widely administered vaccine. Only
prevents serious TB disease in children
(TBM and military TB).WHO estimates
that it save the lives of over 40,000
children per year.
Microscopy of specially stained sputum is the
main test for diagnosing TB (1‐2 days)
•TB bacilli seen in the sputum sample using a
microscope(smear positive )
•Detects only ½of all TB and 1/3rd of HIV re
lated TB•PLHIV higher proportionof
sputum negative pulmonary TB –
extrapulmonary TB.
X‐ray also has a role for diagnosing TB if smea
r -ve .Role of culture: (takes 3 ‐4 wks)
•EPTB may require tissue samples/culture.
X ‐ray-
16. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 16
HOST DIRECTED THERAPY:
Host directed therapies (HDTs) are a relatively new & promising
approach to treatment of tuberculosis. HDTs comprise two strategies for
managing TB: manipulate macrophages function & modulate host immune
response. Current HDTs can potentially inhibit TB development via diverse
host pathways such as signal transduction-mediating cytokines, antimicrobial
processes, immune cell regulation, and epigenetic modulation. The use of
HDTs can be expected to reduce the bacterial burden and fine-tune the host
inflammatory response.
HDTs increase the effect of clinical treatment by reducing morbidity,
mortality, organ damage, and TB therapy duration. By directly targeting host
factors, HDTs enhance immune responses and fine-tune inflammation and can
thus be used to treat bacterial, viral, and parasitic infectious diseases. Current
treatment for MTB-mediated TB has several limitations, including the long
period of treatment, emergence of resistant strains, and toxicity of the drug.
These limitations raise the need for developing novel TB treatme nt strategies.
HDTs play a role in the clearance of MTB and regulation of the excess
inflammatory response to protect the host from permanent organ damage.
Furthermore, the combination of HDTs with current TB drugs reduces drug
dosage and improves benefits.
HDTs can target many mechanisms such as verifying anti-
mycobacterial activity of an approved drug (re-purposed drugs), inhibiting
immune checkpoints, and modulating cytokine production. We have shown
that antigens derived from the intracellular parasite T. gondii modulate the
immune response and might be promising for treating MBT infection.
However, HDTs need to be explored further. Because HDTs directly interact
with host factors, various variables need to consider prior to their application.
Furthermore, it is difficult to establish HDTs that manipulate a human factor
using an animal model. Understanding the host immune response in the TB-
mediated-immune pathology is very important in HDT research.
17. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 17
Targets host factor which are usually part of immune system in order to Therapy
that:
1. Potentiate human antimicobacterial effector mechanism.
2. Modulate innate and adaptive immune response.
3. Limit inflammation
4. Reduce tissue damage (Enzyme activity)
5. Limit long term effects of tissue destruction and fibrosis
The following are objectives of HDT-
1. Activity against antibiotic resistant Mtb strains
2. Possibly synergy with antibiotics
3. Possibly activity against non-replicating Mtb
4. Reduced likehood of resistance
5. Inhibit host factors used for Mtb pathogen
6. Augment innate & adaptive immune response to Mtb
7. Inhibit deterious immune response to Mtb
8. Induce novel immune response to Mtb
9. Inhibit bacterial functions & facilate host response
Advantages of HDT by Anti-T.B. drugs/repurposed drug:
1. Well established safety profile.
2. Shorter therapy duration.
3. Lower risk of relapse or re-infection.
4. Effective against drug -resistant cases.
5. Can be adopted to any chronic infection.
18. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 18
ClassesofHDTs-
These are the Classes of HDTs-
1. Monoclonal antibodies
2. Vitamins
3. Repurposed drugs
4. Cytokines
5. Cellular therapy
6. Recombinant proteins
Fig 6- Classes of HDTs
19. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 19
Strategies ofDevelopmentof TB HDT-
1. Repurposeddrugs-
Drug repositioning (also known as drug repurposing, re-profiling, re-tasking
or therapeutic switching) is the application of known drugs and compounds to treat
new indications (i.e., new diseases).A significant advantage of drug repositioning over
traditional drug development is that since the repositioned drug has already passed a
significant number of toxicity and other tests, its safety is known and the risk of
failure for reasons of adverse toxicology are reduced. More than 90% of drugs fail
during development; and this is the most significant reason for the high costs of
pharmaceutical R&D. In addition, repurposed drugs can bypass much of the early cost
and time needed to bring a drug to market. Examples of repurposed drugs- Imatinib,
Verapamil, Metformin and Ibuprofen etc.Difference between traditional drug
discovery process and Drug Repurposing as shown in fig.8.
Fig. 8-Difference between traditional drug discovery process and Drug
Repurposing
20. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 20
I. Metformin-
Metformin (Glucophage), which acts as an autophagy inducer, is
currently approved for the treatment of type 2 diabetes. Metformin activates
adenosine monophosphate-activated protein kinases, which are sensors of cellular
energy levels. Targeting adenosine monophosphate-activated protein kinases
expected as a potential anti-TB treatment. Metformin inhibits MTB growth by
inducing mitochondrial ROS production in vitro. The effect of current anti-TB
drugs can be enhanced by metformin, which was confirmed in acute and chronic
TB mouse models. Furthermore, metformin reduces the TB-mediated tissue
pathology and enhances IFN-γ-secreting CD8+ and CD4+ T-cell populations.
It also reduces the activity of chronic inflammatory genes in TB
patients, in addition to reducing mortality .Clinically, patients with type 2 diabetes
mellitus (T2DM) on statin therapy (as well as anti-diabetic therapy) seem to be at
lower risk of developing active TB. Metformin (MET) is an essential drug used in
the treatment of T2DM, which acts by affecting the mitochondrial respiratory
chain. In a recent preclinical study, MET was evaluated as an adjunct therapeutic
for drug-susceptible (DS)-TB and MDR-TB. MET treatment induced superoxide
anion production in macrophages infected with DS or MDR M. tb in an- adenosine
monophosphate-activated protein kinase (AMPK)-dependent manner.
A retrospective evaluation of patients with T2DM receiving MET
therapy showed that they are less prone to develop cavitary pulmonary TB. In
addition, T cell non-reactivity to ESAT-6 in a T-SPOT IFN-γ assay also suggested
less incidence of latent TB infection among these individuals. The ability of MET
to promote maintenance of memory CD8 T cells via AMPK-driven fatty acid
oxidation, as seen in mouse models of solid tumours, may be an additional avenue
for its potent immunomodulatory properties in TB.
21. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 21
Fig.9- Metformin, an FDA approved drug for type-II diabetes as a potential
combination therapy for Tuberculosis with existing antibiotics.
a) Antibiotic targeting mycolic acid biosynthesis; b) systems-level changes
resulting into the reduction of flux carrying capacity of glycolysis and
citric acid cycle c) resulting re-routing of metabolic fluxes through de
novo NAD biosynthesis pathway and electron transport through NDH-I
d) possibility of targeting NDH-I with metformin.
1. The bacterial respiratory chain complex NADH-Q oxidoreductase is classified
into three main subunits a) proton (H+) translocating subunit, H+ - NADH-Q
oxidoreductase (designated as NDH-I); b) sodium (Na+) translocating subunit,
Na+ - NADH-Q oxidoreductase (designated as Na+ - NADH) and c) NADH-Q
oxidoreductase that lacks energy coupling site and designated as NDH-II [5].
2. Earlier investigations suggest that bacterial NDH-I is encoded by nuoA~N
operon in E.coli, which is also encoded by Mtb genome.
3. A comparative analysis based on subunit sequence, cofactors and various
inhibitors suggest that NDH-I of bacteria is the counter part of mitochondrial
complex-I system.
4. Investigations also suggest that the bacterial NDH-I can be inhibited by
various inhibitors of mitochondrial complex-I such as pericidin A, capsaicin
and rolliniestain-1 thereby suggesting a common mechanism of NDH-I
inhibition by inhibitors of mitochondrial complex – I.
22. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 22
5. Metformin has been recently confirmed as inhibitor of mitochondrial complex
– I in cancer cells both in vitro and in vivo. Study also suggests implications of
Metformin in reducing tumorigenesis.
II. Imatinib -
Imatinib mesylate (Gleevec) is used to treat leukemia and
gastrointestinal stromal tumors. Imatinib is a small-molecule kinase inhibitor that
blocks tyrosine kinase enzymes. The therapeutic administration of imatinib promotes
the acidification and maturation of MTB-infected macrophage phagosomes, reducing
the number of colony-forming units (CFUs) in MTB-infected mice. Furthermore,
imatinib works synergistically with first-line anti-TB drugs to inhibit drug-resistant
mycobacterial strains.At sub therapeutic concentrations, imatinib strengthens host
defenses by increasing neutrophil and monocyte numbers through myeloproliferation.
III. Ibuprofen
Ibuprofen (Advil, Motrin, Nurofen) is a non-steroidal anti-
inflammatory drug normally used as a painkiller and an antipyretic.
23. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 23
This inhibitor of cyclooxygenase inhibits prostaglandin E2
production and enhances tumor necrosis factor (TNF) production in
macrophages.Although the direct antimycobacterial activity of ibuprofen is not
potent, it reduces lung tuberculous lesions and bacterial burden and enhances the
survival rate in a mouse model that mimics active TB.
24. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 24
2. Modulation of Cytokine Response-
Cytokine therapy can be an alternative method to current TB
chemotherapy limited using. This method uses immunomodulators to boost the
immune system. Cytokines contribute to various cellular responses, including
immune signaling in TB. Cytokine therapy induces the proinflammatory immune
response and antimicrobial activity, which can be beneficial in treating TB. IFN-γ
plays a major role in the host defense against MTB. IFN-γ, as a prototypical
product of Th1 cells, promotes the secretion of Th1 cytokines (such as IL-12) and
inhibits Th2 cytokines (such as IL-4).
In addition, IFN-γ upregulates class I and II antigen-presenting
cells and increases the antimicrobial activity of macrophages. Mutations in the
IFN-γ receptor gene result in high susceptibility to mycobacterial infections.
Granulocyte macrophage colony-stimulating factor (GM-CSF) increases the
number of macrophages, leading to an enhanced inflammatory response. GM-CSF
also shows antimycobacterial activity in human macrophages. Studies on GM-
CSF-deficient mice showed that GM-CSF plays critical immunomodulatory roles
in the host defense against pulmonary TB. Moreover, IL-2 induces the expansion
of T cells. However, recent studies have shown that IL-2 promotes CD4+CD25+
regulatory T-cell expansion, which suppresses the T-cell response. Some clinical
trials checking the effectiveness of IL-2 against TB have been reported.
Excessive proinflammatory cytokine production causes
permanent host tissue damage. Therefore, regulating cytokine production can be an
alternative approach to treat TB by reducing destructive inflammation. The current
monoclonal 23antibody used for cytokine neutralization modulates inflammatory
responses. The anti-TNF therapeutic agent adalimumab has been previously used
to treat TB. 7 IL-6, which accelerates the severity of disease in TB patients, is a
promising candidate. Blockade of the IL-6/IL-6 receptor pathway is considered
therapeutic in treating various diseases. The use of a monoclonal antibody, along
with the IL-6 receptor blockade, enhances anti-TB T-cell responses, decreases the
severe pathology, and reduces the MTB burden in mice. The antivascular
endothelial growth factor (VEGF, bevacizumab) monoclonal antibody inhibits TB
by normalizing vasculature, increasing the delivery of small molecules, and
decreasing hypoxia in tuberculous granuloma.
25. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 25
Advancing host-directedtherapy for tuberculosis-
Fig 10-Advancing host-directed therapy for tuberculosis
26. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 26
3. Inhibition of Immune Check Points- Immune checkpoints are molecules
in the immune system that either turn up a signal (co-stimulatory molecules) or
turn down a signal. Many cancers protect themselves from the immune system
by inhibiting the T cell signal. Ex..Anti PD-,Anti-LAG3, Anti-CTLA-4.Anti
PD-1-Programmed cell death 1 (PD-1) is a protein on the surface of active T
cells. When programmed death-ligand 1 (PD-L1) and PD-L2.Advantage of
targeting PD1 is that it can restore immune function in tumor
microenvironment. Nivolumab/pembrolizumab are PD-1 inhibitors currently
used to treat melanomas and other cancers.Anti-LAG3- Lymphocyte –
activation gene 3 (LAG3) used in cancer treatment. It works to suppress
an immune response by direct effect on CD8+Tcells.Anti-CTLA-4
Cytotoxic T –Lymphocyte Associated protein 4 .Control T cell proliferation.
4. Cellular therapy –Cell therapy (also called cellular therapy or cytotherapy) is
therapy in which cellular material is injected into a patient; this generally
means intact, living cells. For example, T cells capable of fighting cancer cells
via cell-mediated immunity may be injected in the course of immunotherapy.
Bone marrow-derived mesenchymal stromal cells -Reduction of inflammation
and enhancement tissue regeneration Clinical (late phase).Antigen-specific T
cells Cancer and viral infections Targeted killing of MTB- infected host cells.
5. Immunomodulatory antigen from pathogen-Immunomodulation is
modulation (regulatory adjustment) of the immune system. It has natural and
human-induced forms, and thus the word can refer to the
following:Homeostasis in the immune system, whereby the system self-
regulates to adjust immune responses to adaptive rather than maladaptive levels
(using regulatory T cells, cell signaling molecules, and so forth)
Immunomodulation as part of immunotherapy, in which immune responses are
induced, amplified, attenuated, or prevented according to therapeutic goals
GRA7 antigen driven intra cellular parasite T. gondii.- GRA7 controlled the
innate immune response by interacting with host cell proteins.GRA7 is
essential for the interaction between apoptosis-associated speck-like protein
containing a carboxyl-terminal CARD and phospholipase D1. These
interactions induced antibacterial activity against TB.
27. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 27
Fig.11-Host-directed therapies aimed at modulating immune responses in the
tuberculous lung. Overt immune responses characterise the pathological outcome in
tuberculosis (TB).
Neutralisation of pro-inflammatory cytokines such as IL-6, TNF-α, VEGF and IFN-αβ, as
well as anti-inflammatory IL-4 during severe pulmonary disease may help reduce ongoing
parenchymal damage in the lung. Alternatively, suboptimal activation of anti-TB immune
responses due to regulatory T cell activity can be reversed by the use of the anti-cancer drug
cyclophosphamide. Drugs with anti-TB potential, such as metformin, imatinib, ibuprofen,
zileuton, valproic acid, and vorinostat as well as nutraceuticals such as vitamin D3 not only
abate bacterial burden via host-dependent mechanisms, but may also fine-tune the immune
response to Mycobacterium tuberculosis (M. tb). These drugs increase phagocytosis of
extracellular bacteria, improved emergency myeloid response and increased autophagic and
apoptotic killing of bacteria, subsequently editing the T cell response in favour of the host.
Immune checkpoint inhibition with blockade of the PD-1/PD-L1, CTLA-4, LAG3 and TIM3
pathways may improve the quality of the cellular immune response to M. tb epitopes, as seen
in cancer. Abbreviations: VPA, valproic acid; PBA, phenylbutyrate; PD-1, programmed cell
death 1; PD-L1, PD-1 ligand 1; CTLA-4, cytotoxic T lymphocyte-associated antigen 4;
LAG3, lymphocyte-activation gene 3; TIM3, T cell immunoglobulin and mucin domain 3.
28. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 28
Developmentof HDT for TB -
Table 3 - Development of HDT for TB
Category Name Currently approved
indication(s)
Host target
Repurposed
drug
Imatinib Leukemia and
gastrointestinal stromal
tumors
Tyrosine kinase
Verapamil High blood pressure,
chest pain and
supraventricular
tachycardia.
Voltage-dependent calcium
channels
Metformin Diabetes AMP-activated protein
kinase activator
Ibuprofen Pain and fever relief Cyclooxygenase inhibitor
Cytokine
therapy
IL-2 Renal cancer and
melanoma
Cytokine modulation
GM-CSF Acute Myelogenous
Leukemia, after bone
marrow transplantation
Cytokine modulation
IFN-γ Chronic granulomatous
disease
Cytokine modulation
Monoclonal
antibody
Adalimumb
(Anti-TNFα)
Rheumatoid arthritis Cytokine neutralization
Tocilizumab
(Anti-IL6R)
Juvenile arthritis,
Castleman's disease
Cytokine neutralization
Bevacizumv
(Anti-VEGF)
Various cancer types Angiogenesis inhibitor
29. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 29
Monoclonal
antibody
Nivolumab
/pembrolizumab
(Anti-PD-1)
Melanoma, various
other cancers
Immune check point inhibitor
Anti-LAG3 Various cancers Immune check point inhibitor
Ipilimumab
(Anti-CTLA-4)
Melanoma, various
other cancers
Immune check point inhibitor
Cellular
therapy
Bone marrow-
derived
mesenchymal
stromal cells
Various inflammatory
indications
Reduction of inflammation and
enhancement tissue
regeneration
Antigen-
specific T cells
Cancer and viral
infections
Targeted killing of MTB-
infected host cells
30. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 30
Comparisonbetweencurrent anti-TB drugs and potential HDT strategies
for treating TB -
Fig 7 Comparison between current anti-TB drugs and potential HDT strategies for
treating TB
Current anti-TB drugs have been developed by targeting pathogenic
factors such as bacterial proliferation. A spontaneous gene mutation, which is targeted
by these antibiotics, occur drug-resistant TB. To overcome the limitations of current
anti-TB drugs, the development of new drugs is necessary.
HDTs directly affect host factors. Strategies of developing anti-TB
HDTs verify several TB studies. TB, Tuberculosis; HDTs, Host-directed therapeutics;
IL-2, Interleukin-2;GM-CSF,Granulocyte macrophage colony-stimulating factor; IFN-
γ, Interferon gamma; PD-1, Programmed cell death protein 1, LAG3, Lymphocyte
activation gene 3; CTLA-4, Cytotoxic T-lymphocyte-associated antigen 4; GRA7, T.
gondii dense granule antigen 7.
31. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 31
REFERENCES -
1. Zaman K, Tuberculosis s: a global health problem Health Popul Nutr., 28:
111-113.
2. Ye-Ram Kim and Chul-Su Yang, Review on Host –directed therapeutics as
novel angle for tuberculosis treatment, JMB.,7:1-25.
3. World health Organization, Global tuberculosis report 2016.
4. Schnippel K, Rosen S, Shearer K, Martinson N, Long L, Sanne I, Costs of
inpatient treatment for multi-drug-resistant tuberculosis in South
Africa.,Trop Med Int. Health,18: 109-116.
5. Arbex MA, Varella MdCL, Siqueira HRd, Mello FAFd. , Antituberculosis
drugs: drug interactions, adverse effects, and use in special situations-part 1:
first-line drugs, Jornal Brasileiro de Pneumologia. 36: 626-640.
6. Zumla A, Rao M, Parida SK, Keshavjee S, Cassell G, Wallis R, et al. 2015.
Inflammation and tuberculosis: host-directed therapies,J Intern Med. 277:
373-387.
7. Hawn TR, Matheson AI, Maley SN, Vandal O. 2013. Host-directed
therapeutics for tuberculosis: can we harness the host? Microbiol Mol Biol
Rev. 77: 608-627.
8. Zumla A, Maeurer M, Host-Directed Therapies N, Chakaya J, Hoelscher M,
Ntoumi F, et al. 2015. Towards host-directed therapies for tuberculosis. Nat
Rev Drug Discov. 14: 511-512.
9. World health Organization, Initiative ST. 2010. Treatment of tuberculosis:
guidelines, pp. Ed. World Health Organization.
10.D'Ambrosio L, Centis R, Sotgiu G, Pontali E, Spanevello A, Migliori GB.
2015. New anti-tuberculosis drugs and regimens: 2015 update. ERJ Open
Res.1.
11.Timmins GS, Deretic V. 2006. Mechanisms of action of isoniazid. Molecular
microbiology. 62: 1220-1227.
12.Shi W, Zhang X, Jiang X, Yuan H, Lee JS, Barry CE, 3rd, et al. 2011.
Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis.
Science. 333: 1630-1632.
13. Kim JJ, Lee HM, Shin DM, Kim W, Yuk JM, Jin HS, et al. 2012. Host cell
autophagy activated by antibiotics is required for their effective
antimycobacterial drug action. Cell Host Microbe. 11: 457-468.
14. Zullo AJ, Lee S. 2012. Old antibiotics target TB with a new trick. Cell Host
Microbe. 11: 419-420.
32. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 32
15. Kolyva AS, Karakousis PC. 2012. Old and new TB drugs: Mechanisms of
action and resistance, pp. Ed. INTECH Open Access Publisher.
16. Zumla A, Nahid P, Cole ST. 2013. Advances in the development of new
tuberculosis drugs and treatment regimens. Nat Rev Drug Discov. 12: 388-
404.
17. Rattan A, Kalia A, Ahmad N. 1998. Multidrug-resistant Mycobacterium
tuberculosis: molecular perspectives. Emerging infectious diseases. 4: 195.
18. Lange C, Abubakar I, Alffenaar JW, Bothamley G, Caminero JA, Carvalho
AC, et al. 2014. Management of patients with multidrug-resistant/extensively
drug- resistant tuberculosis in Europe: a TBNET consensus statement. Eur
Respir J. 44: 23-63.
19.World health Organization. 2011. Guidelines for the programmatic
management of drug-resistant tuberculosis-2011 update.
20. Sharma D, Cukras AR, Rogers EJ, Southworth DR, Green R. 2007.
Mutational analysis of S12 protein and implications for the accuracy of
decoding by the ribosome. J Mol Biol. 374: 1065-1076.
21. Crofton J, Mitchison D. 1948. Streptomycin resistance in pulmonary
tuberculosis. British medical journal. 2: 1009.
22. Rich M. 2003. The PIH guide to the medical management of multidrug-
resistant tuberculosis. International edition. Boston, MA: Partners in Health.
1-146.
23. Salian S, Matt T, Akbergenov R, Harish S, Meyer M, Duscha S, et al. 2012.
Structure-activity relationships among the kanamycin aminoglycosides: role of
ring I hydroxyl and amino groups. Antimicrob Agents Chemother. 56: 6104-
6108.
24. Tobin DM, Ramakrishnan L. TB: the Yin and Yang of lipid mediators. Curr
Opin Pharmacol. 2013;13(4):641–5.
25.Zelasko S, Arnold WR, Das A. Endocannabinoid metabolism by cytochrome
P450 monooxygenases. Prostaglandins Other Lipid Mediat.
2014.doi:10.1016/j.prostaglandins.2014.11.002.
26. Agarwal S, Reddy GV, Reddanna P. Eicosanoids in inflammation and cancer:
the role of COX-2. Expert Rev Clin Immunol. 2009;5(2):145–65.
27. Tobin DM, Roca FJ, Oh SF, McFarland R, Vickery TW, Ray JP, Ko DC, Zou
Y, Bang ND, Chau TT, et al. Host genotype-specific therapies can optimize
the inflammatory response to mycobacterial infections. Cell. 2012;148(3):434–
46.
28.Vilaplana C, Marzo E, Tapia G, Diaz J, Garcia V, Cardona PJ. Ibuprofen
therapy resulted in significantly decreased tissue bacillary loads and increased
survival in a new murine experimental model of active tuberculosis. J Infect
Dis. 2013;208(2):199–202.
33. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 33
29. Guzman JD, Evangelopoulos D, Gupta A, Birchall K, Mwaigwisya S, Saxty
B, McHugh TD, Gibbons S, Malkinson J, Bhakta S. Antitubercular specific
activity of ibuprofen and the other 2-arylpropanoic acids using the HT- SPOTi
whole-cell phenotypic assay. BMJ Open. 2013;3(6). doi:10.1136/ bmjopen-
2013-002672.
30. Berger W, De Chandt MT, Cairns CB. Zileuton:clinicalimplicationsof 5-
Lipoxygenaseinhibitioninsevereairwaydisease.IntJClinPract.2007;61(4):663–
76.
31. Mayer-Barber KD, Andrade BB, Oland SD, Amaral EP, Barber DL, Gonzales
J, Derrick SC, Shi R, Kumar NP, Wei W, et al. Host-directed therapy of
tuberculosis based on interleukin-1 and type I interferon crosstalk. Nature.
2014;511(7507):99–103.
32. Jain MK, Ridker PM. Anti-inflammatory effects of statins: clinical evidence
and basic mechanisms. Nat Rev Drug Discov. 2005;4(12):977–87.
33.. Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of
immunomodulator. Nat Med. 2000;6(12):1399–402.
34. Thomsen RW, Riis A, Kornum JB, Christensen S, Johnsen SP, Sorensen HT.
Preadmission use of statins and outcomes after hospitalization with
pneumonia: population-based cohort study of 29,900 patients. Arch Intern
Med. 2008;168(19):2081–7.
35.Thomsen RW, Hundborg HH, Johnsen SP, Pedersen L, Sorensen HT,
Schonheyder HC, Lervang HH. Statin use and mortality within 180 days after
bacteremia: a population-based cohort study. Crit Care Med.
2006;34(4):1080–6.
36.Chalmers JD, Singanayagam A, Murray MP, Hill AT. Prior statin use is
associated with improved outcomes in community-acquired pneumonia. Am J
Med. 2008;121(11):1002–7. e1001.
37. Mortensen EM, Restrepo MI, Anzueto A, Pugh J. The effect of prior statin
use on 30-day mortality for patients hospitalized with community-acquired
pneumonia. Respir Res. 2005;6:82.
38. Parihar SP, Guler R, Khutlang R, Lang DM, Hurdayal R, Mhlanga MM,
Suzuki H, Marais AD, Brombacher F. Statin therapy reduces the
mycobacterium tuberculosis burden in human macrophages and in mice by
enhancing autophagy and phagosome maturation. J Infect Dis.
2014;209(5):754–63.
39.Skerry C, Pinn ML, Bruiners N, Pine R, Gennaro ML, Karakousis PC.
Simvastatin increases the in vivo activity of the first-line tuberculosis regimen.
J Antimicrob Chemother. 2014;69(9):2453–7.
40.Kang YA, Choi NK, Seong JM, Heo EY, Koo BK, Hwang SS, Park BJ, Yim
JJ, Lee CH. The effects of statin use on the development of tuberculosis
34. HOST DIRECTED THERAPIES FOR FIGHT AGAINST T.B.
Page 34
among patients with diabetes mellitus. Int J Tuberc Lung Dis. 2014;18(6):717–
24.
41. Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B. Metformin: From
Mechanisms of Action to Therapies. Cell Metab. 2014;20(6):953–66.
42. Singhal A, Jie L, Kumar P, Hong GS, Leow MK, Paleja B, Tsenova L,
Kurepina N, Chen J, Zolezzi F, et al. Metformin as adjunct antituberculosis
therapy. Sci Transl Med. 2014;6(263):263ra159.
43.Eikawa S, Nishida M, Mizukami S, Yamazaki C, Nakayama E, Udono H.
Immune-mediated antitumor effect by type 2 diabetes drug, metformin. Proc
Natl Acad Sci U S A. 2015;112(6):1809–14.
44.Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H, Wang LS, Jones RG,
Choi Y. Enhancing CD8 T-cell memory by modulating fatty acid metabolism.
Nature. 2009;460(7251):103–7.
45.Napier RJ, Norris BA, Swimm A, Giver CR, Harris WA, Laval J, Napier BA,
Patel G, Crump R, Peng Z, et al. Low doses of imatinib induce myelopoiesis
and enhance host anti-microbial immunity. PLoS Pathog.
2015;11(3):e1004770.
46. Napier RJ, Rafi W, Cheruvu M, Powell KR, Zaunbrecher MA, Bornmann W,
Salgame P, Shinnick TM, Kalman D. Imatinib-sensitive tyrosine kinases
regulate mycobacterial pathogenesis and represent therapeutic targets against
tuberculosis. Cell Host Microbe. 2011;10(5):475–85.