Human genetic susceptibility to mycobacterium tuberculosis 1

Human Genetic Susceptibility
to M. tuberculosis
Credit seminar
2nd semester
Submitted by:
Shweta kaul
Master of life sciences with specialization in Human Genetics
Registration number:15mslshg02
Centre of Human Genetics and Molecular Medicine
School of Health Sciences
Central university of Punjab, Bathinda, 151001
1/29/2016 1

Tuberculosis
 It is a contagious disease caused by the airborne bacterium
M. tuberculosis
 Infects primarily lungs causing primary infection
 Pulmonary TB and Extra pulmonary TB
 Spreads through lymph nodes and bloodstream to any organ
of the body
 Contagious as can spread through cough, sneeze, or speak
 Person suffers cough, weight loss, loss of appetite, fever,
coughing up blood and night sweats
 Difference between active form of disease and infection of
lungs
 Touching someone who has disease does not necessarily
spread the disease
1/29/2016 Central university of Punjab: HGMM 2

Tuberculosis
• Two stages – pulmonary TB and extra
pulmonary TB(in very rare cases example
in immunosuppressed individuals)
Pulmonary TB
Activation of second
line of defence
Formation of
granuloma
Caused by bacilli M.
tuberculosis
Infection of lungs
Dormant form
Macrophage
inflammation
reactivation
3Central university of Punjab: HGMM1/29/2016

History and evidences of TB
susceptibility
• Disease first identified by Robert Koch in
1882
• In 1929, Lubeck , Germany a complete lot of
BCG vaccine was contaminated with M.
tuberculosis
• Vaccine injected in 251 infants
• 4 remained uninfected, 72 died within a year,
175 overcame
• 70% of naive babies survived the infection
Reference: Moller % Hoal; 2010

Reference: Bellamy, 1998
1/29/2016 5Central university of Punjab: HGMM

Epidemiology of the disease
• 1/3rd of world population is affected with this
infection
• But only 1/10th of this develops the active
form of the disease
• 10 million of US population is infected with
this infection
• Amongst top 3 causes of death in India and
2/3rd of all the cases in India are from
underprivileged groups and out of this 36%
new cases are from immigrants
Reference: (Moller andHoal, 2010; Swaminathanand Rekha, 2010)

Figure 3(a). Pie chart showing the
incidences of TB in the year 2012
worldwide
(Source: Global
Tuberculosis report, 2013)
Figure 1. Incidence rate map of the disease in the year 2012 worldwide
(Source: www.cdc.gov; 2012)

Figure 2. Pie chart showing the incidences of TB in the year 2012 worldwide
(Source: Global Tuberculosis report, 2013)

Interaction between human and M.
tuberculosis
Pathogen Associated Molecular Patterns interacting with
Pattern Recognition Receptors' for example Toll Like
Receptors and Non- Toll like receptors (mannose binding
receptors, lipopolysaccharide binding receptors)
Cascade of reactions get activated
Cytokines example Tnfα/ IL 12/ IL 1 are secreted
These cytokines activate second line of defence
Phagocytosis/ apoptosis/ opsonisation/ inflammation
Source:www.docmeg.wordpress.com,2011
Central university of Punjab: HGMM1/29/2016
Source: www.newint.org,2013
www.cdc.org, 2004

Growth of bacterium inside the host
• The bacterium is unique in having lipid cell
wall composition more than peptidoglycan
• Mycolic acid (alpha branched lipids)
• Cord factors (trehalose mycolate)
• Wax-D (peptido-glycolipid)
Reference: Meena ET al., 2012

Survival mechanism adapted by
M. tuberculosis
Figure3. Key survival
mechanisms involved in
phagosome maturation arrest of
M. tuberculosis inside the
macrophages
(Source: Meena et al., 2012)

Some of the Pathogen genes
interacting with host
Gene Function
Erp gene Encodes exported repetitive proteins, these surface proteins
function in virulence
Mas gene Marker assisted selection, encodes mycoserosic acid synthase
that catalyses the synthesis of mycoserosic acids that helps
in protection against macrophages
Fbp A Fibronectin binding protein A, encodes mycolyl transferase
enzyme that helps in growth of bacteria
Omp A Outer membrane protein A precursor, porin like proteins
forms pores in liposomes of host
Hbh A Encodes Heparin binding hemagglutinin protein , binds heparin
and
promotes hemagglutination, this helps in invading the host
defence mechanism
Lam Laminin encoding genes, laminin depress IFNγ production

Host susceptibility mechanisms
• Upon infection there are chances that the
host can either develop or resist the
disease
• Based on expression of resistance and
susceptibility genes
• These genes majorly grouped into two
types HLA and Non HLA genes

This association can be well
understood by below three
hypothesis
• Hypothesis I
Hypothesis I
HLA Antigen is
getting influenced by
the bacterium M.
tuberculosis and
doing its molecular
mimicry.
HLA antigens act as
receptors for the
bacterium M. tuberculosis.
HLA antigens are
involved in weakening
the immune
responses.
reference: selvaraj, 2004

Hypothesis II :
MHC genes are present in closer proximity to
genes that are involved in susceptibility.
Hypothesis III:
Non-HLA genes are involved.
reference: Selvaraj, 2004
1/29/2016 15Central university of Punjab: HGMM

Classification of susceptibility
genes
(A).HLA and
Non HLA gene
type
(B). Genes
involved in
various
immunological
processes

(A). HLA and Non HLA gene
HLA genes
• An increased antigen
recognition range by
different polymorphic
forms is seen
• to antigen specificity
• Susceptibility allele
example: HLADRB1 to
HLADRB14
• In Chinese and Kazak
population: HLADQB1
and HLADRB1 genetic
polymorphismsreference:Khalilullah et al., 2014)
Non HLA genes
• Genes other than HLA
are responsible for
susceptibility
• Haptoglobulin genes
polymorphism
• Three polymorphic forms
of genes:HP1-1; HP2-1;
HP2-2
• HP1-1 is most effective
;HP2-1 is moderately
active while HP2-2 is
Least active

Therefore, the polymorphic form HP2-2 of haptoglobin gene is
responsible for more lymphocytes and this form supports TB
resistance
Hence, lesser immunosupression via Haptoglobin genes and more
inflammatory response by lymphocytes on haemaglobin
Individuals with lesser number of least active form of haptoglobin i.e.
HP2-2 phenotype were found to be active for more lymphocytic
activation and recruitment
Non- HLA genes polymorphism: Example haptoglobin gene
polymorphism {its polymorphic forms are HP1-1; HP2-1; HP2-2}

(B). Genes involved immunological
processes
Transport
er genes
Receptor
encoding
genes
Genes
involved
in
bacterial
killing
Genes
involved
in
apoptosis
of I C
Chemoki
ne
encoding
genes
Cytokine
encoding
genes
Genes
involved
in A P
Genes
involved in
OP of M.
tuberculosi
s
Reference: Moller and Hoal, 2010

Figure4. Various genes involved in susceptibility mechanism
(source: Moller and Hoal,
2010)

Genes involved in antigen
presentation
Type Human leukocyte antigen
Gene name HLA DR, HLA DQ, HLA DP, HLA DM, HLA
DOA, HLA DOB
present on MHCII
HLA A, HLA B and HLA C present on MHCI
Chromosomal location Chromosome 6 , both short and long arms
Function - Encodes cell surface antigen presenting proteins
- MHC I , HLA genes present antigens to CD8+, Cytotoxic T cells and present antigens
from inside the cell
- MHC II, HLA genes present antigens to CD4+, helper T cells and present antigens from
outside the cell
Effect Increased expression of the mutant form or recessive polymorphic form of allele results in
higher susceptibility levels or less expression of wild type allele leads to susceptibility
Polymorphic form/forms HLA DR2
Subtype
-DRB1*1501*1502
-DRB1*0601
HLA DQ1
-DQB1*0601
HLA DP
-DPB1*02
Haplotype
-DRB1 and 1501-DQB1*0601
-DRB1*11, DBB1*10, DQB1*0501
Epidemiological studies Except Haplotype –DRB1*11, DRB1*10, DQB1*0501 leads to resistance, all other
polymorphisms are responsible for susceptibility amongst Indian population studies
References (Kindt et al., 2007 ; Moller and Hoal, 2010; Balamurugan et al.,2004)

Type Non classical HLA
Gene name Tap2 and Tap1
Chromosomal location 6q;(between HLA DQ and HLA DP)
Function - These genes encode transporter associated proteins
- These proteins present antigens to CD8+, Cytotoxic T cells i.e. help in
cellular mediated immune responses
- The polymorphic residues of these genes provide specificity in antigen
presentation
Effect Increased expression of the mutant form or recessive polymorphic form of allele
results in higher susceptibility levels or less expression of wild type allele leads
to susceptibility
Polymorphic form/forms Tap1 -rs1135216A/G
Tap2 -rs241447
Epidemiological studies -rs241447 Decrease risk of TB in Iranian
population studies
-rs1135216A/G In Iranian population homozygote GG
and heterozygote AG increased the risk
of TB as compared to homozygote AA
References (Kindt et al.,2007 ; Naderi et al., 2015)

Cytokine encoding genes
Type Non-HLA genes
Gene name IFNG
Chromosomal location 12q and 10q
Function - It encodes cytokine Interferon-γ , that activates macrophages and is produced by T-cells
- It also helps in antigen presentation to CD8+, Cytotoxic T cells
Effect Increased expression of the mutant form or recessive polymorphic form of allele results in higher
susceptibility levels or less expression of wild type allele leads to susceptibility
Polymorphic
form/forms
IFNG+874(A/T) polymorphism of Intron region
Haplotype- TA, TC, CC
Epidemiological studies - +874(A/T) polymorphism is seen to be responsible for susceptibility in Pakistan, China,
Hong Kong, Sicilian, South Africa; but no association of this SNP is seen in Malawian,
Houston, West Africa, South Indian and Croatian population
- +874 A is responsible for susceptibility while +874 T is responsible for protection against TB
- Polymorphism -56(CC) in promoter and -56(CA) in Intron region are responsible for
susceptibility
- In case of Haplotype – over expression of TA in North Indians is responsible for
susceptibility
References (Kindt et al., 2007; Abhimanyu et al., 2012; Moller andHoal, 2010;
Khalilullah et al., 2014)

Type Non-HLA genes
Gene name IL12B, IL1B, IL1RA, IL6, IL10
Chromosomal location IL12B 5q
IL1B 2q
IL1RA 2q
IL6 7p
IL10 1q
Function IL12B - Encodes cytokine Interleukin12-β that is produced by activated macrophages, monocytes, B lymphocytes and
dendritic cells
- This molecule helps in inducing, maintaining the number and memory of Helper T cells
IL1B - It encodes cytokine Interleukin1β that is a pro-inflammatory molecule and is produced by monocytes,
macrophages, dendritic cells
- Its level increases during defence mechanism
IL1RA - It encodes cytokines IL1μ and IL1β
- It helps in inhibition of IL1 activity on T cells, therefore act as anti-inflammatory cytokine
IL6 - It is expressed in hepatocytes, monocytes, B cell lymphocytes, macrophages and neutrophils as a anti
inflammatory cytokine
- Expression blocks the IFNγ mediated signalling
- It is also involved in macrophage and cytotoxic T cell differentiation it also induces IL-4 production
- Higher levels of IL-6 are involved in resistance
IL10 - It expressed cytokine has anti-inflammatory properties
- The cytokine acts as an antagonist (i.e. opposes) Tnf-α, Ifn-γ and IL-12B production as they are the cytokines
that lead to inflammation
- It is produced after the M. tuberculosis bacterium has been phagocytosed via monocytes, macrophages and
T-lymphocytes
Effect The over expression of IL6, IL1RA and IL10 leads to susceptibility while others are responsible for susceptibility in cases of
less expression
Polymorphic
form/forms
IL10 -1082(G/A) and -592(A/C)(both in promoter region)
-2849A, -819C
IL6 -572C>G, -572(GG)
Epidemiological studies -1082(G/A) and -592(A/C)(both in
promoter region)
-1082A is seen to be responsible for susceptibility in Ghana
-2849A, -819C -2849A is susceptible in Ghana
-572C>T, -572(GG) In Ugandan population SNP-572C>T leads to resistance against TB while SNP-
572GG protects TB by IL-6 production
References (Kindt et al., 2007; Abhimanyu et al., 2012; Santos et al., 2002;
Acton et al., 2013; Khalilullah et al., 2014)

Type Non HLA genes
Gene name TNFA
Chromosomal
location
6p
Function - It encodes cytokine Tumor necrosis factor-α , which is produced
mainly by monocytes and macrophages
- Tnfα also signals these cells to enter the pulmonary system
- It promotes the granuloma formation i.e. inactive form of TB
Effect Increased expression of the mutant form or recessive polymorphic form
of allele results in higher susceptibility levels or less expression of wild
type allele leads to susceptibility
Polymorphic
form/forms
−1031 (T/C), −863 (C/A), −857 (C/T), −308 (G/A), −238 (G/A), −1196
(C/T), −1125 (G/C), −572 (A/C), −316 (G/A), −163 (G/A), and −70
(G/A)
Epidemiological
studies
- -238(G/A) polymorphism is common in many countries
- -238(G/G) polymorphism leads to resistance for the disease
- -857(C/T) polymorphism is responsible for increase in susceptibility
as seen in Iran linkage studies
References (Selvaraj, 2004; Santos et al., 2002; Abhimanyu et al., 2012;
Khalilullah et al., 2014)

Chemokine encoding genes
Type Non-HLA genes
Gene name CCL2
Chromosomal
location
17q
Function The expression of this gene leads to the formation of monocyte chemoattractant
proteins(MCP)
results in higher susceptibility levels or less expression of wild type allele leads to
susceptibility
Polymorphic
form/forms
-2518(A/G) in promoter region
Epidemiological
studies
- -2518(A/G) has been studied as candidate susceptibility gene in Ghana
- -2518A is associated with low MCP production leading to susceptibility for TB
as seen in Mexican, Korean, Chinese and Peruvian population studies
- -2518G is associated with high MCP production leading to resistance
- No association of this polymorphism was found with TB in South Indians,
Coloreds and Ghanians
References (Raja,2004; Khalilullah et al., 2014)

Metal ion transporter associated
genes
NRAMP1expression
Bactericidal effects
Antiports iron bivalent cation
This cation localizes to the membrane of
late endosomes or lysosomes
This makes the phagosomal environment
acidic
Killing M. tuberculosis

Type Non-HLA genes
Gene name NRAMP1/ SLC11A1
Chromosomal location 2q
Function - It encodes Natural resistance associated macrophage protein which acts as
antiporter or transporter
- This protein is expressed inside the macrophages which has bactericidal
effects
to susceptibility
Polymorphic
form/forms
3’UTR, D543N, 5’(GT)n and INT4
-rs3731865, -rs17221959, -rs3731863
Epidemiological
studies
INT4 and D543N - Responsible for more TB
susceptibility in Chinese
population
- In Indonasian population , no
association seen between D543N,
INT4 and TB susceptibility
-rs3731865, -rs17221959, -rs3731863 - Responsible for susceptibility in
US(Caucasians and African
Americans)
References ( Moller and Hoal, 2010; Kozakiewicz, et.al., 2013; Khalilullah et al., 2014)

Receptor encoding genes
Type Non-HLA genes
Gene name CD209
Chromosomal
location
19p
Function - These encode the surface molecules that provide the targets for antigen
presentation on T cells
- These surface molecules are transmembrane protein predominantly expressed on
dendritic cells, whereas its presence on macrophages depends on the tissue type
and state of activation.
- It is induced in alveolar macrophages from M. tuberculosis infected patients. It
directly mediates phagocytosis of M. tuberculosis by dendritic cells.
Effect Increased expression of the mutant form or recessive polymorphic form of allele results
in higher susceptibility levels or less expression of wild type allele leads to
susceptibility
Polymorphic
form/forms
-871
Epidemiological
studies
This polymorphic form has been studied as candidate susceptibility gene in South
Africa
References (Khalilullah et al., 2014; Moller and Hoal ,2010)

Type Non-HLA genes
Gene name VDR
Function - Enhances phagosomal activity of the cell
results in higher susceptibility levels or less expression of wild type allele leads to
susceptibility
Polymorphic form/forms Variants Taq1(TT, Tt, tt), Apal(AA,Aa,aa), Bsml(BB, Bb, bb) and Fokl(FF, Ff, ff)
Epidemiological studies Fokl(FF, Ff, ff) - In Indonasian, Asian and Chinese
population (FF) Fokl variant was
expressed more in TB patients while
levels of other variants didnot more
differ within the groups
Bsml(BB, Bb, bb) - In Turkey, Bsml(BB) is associted
more with TB susceptibility
Apal(AA,Aa,aa) - Apal in West African candidate gene
susceptibility studies
Taq1(TT, Tt, tt) - No association was seen for VDR
polymorphism in African and
American population
References (Zhabagin et al., 2013 ; Moller and Hoal, 2010; Khalilullah et al., 2014;
Gao et al, 2010; Bornman et al., 2004)

Type Non-HLA genes
Gene name TLR2
TLR9
Chromosomal location TLR2 4q
TLR9 3p
Function These encode proteins that binds to PAMP’s
to susceptibility
Polymorphic form/forms TLR2 R753Q(exon),R677(exon), -597(T/C)
and P631H
Insertion/ Deletion (-196 to -174)
TLR9 -rs352143
Epidemiological studies R753Q(exon),R677(exon), -597(T/C), -
975(C/T) and P631H
- -597(T/C) responsible for more
susceptibility for the disease in
children
- -P631H expressed more in
Croatian Caucasian TB patients
- -975(C/T) polymorphism is
responsible for resistance in
against TB in Korean population
studies
Insertion/ Deletion (-196 to -174) Susceptibility in Guinea-Bissau and
US (Caucasians) population for this
polymorphism is seen
-rs352143 Susceptibility in US(African American)
population for this polymorphism is
reported
References (Khalilullah et al., 2014; Moller and Hoal, 2010)

Genes involved in bacterial killing
Type Non-HLA genes
Gene name NOS2A/ iNOS
Function Enzyme encoded by this gene is present in cytosol(nitric oxide synthase)
This enzyme catalyzes the production of nitric oxide
Effect Increased expression of the mutant form or recessive polymorphic form of allele results in
higher susceptibility levels or less expression of wild type allele leads to susceptibility
Polymorphic form/forms -CCTTT
-TAAA
-rs9282799, -rs8078340
-rs2274894
Epidemiological studies -CCTTT High frequency in TB patients in North
Western and Colombian population
-TAAA No association was seen with this
polymorphism
-rs9282799, -rs8078340 Candidate susceptibility gene studied in
South Africa
-rs2274894 Candidate susceptibility gene studied in US(
African American)
References (Khalilullah et al., 2014; Moller and Hoal, 2010)

Genes involved in apoptosis of
infected macrophage
Type Non-HLA gene
Gene name SP110
Function - It encodes speckled proteins that are nuclear body proteins
- These proteins are responsible for apoptosis of infected macrophages
- This process is induced by IFNG signals
Effect Increased expression of the mutant form or recessive polymorphic form of
allele results in higher susceptibility levels or less expression of wild type allele
leads to susceptibility
Polymorphic
form/forms
-rs3948464
-rs2114592
Epidemiological
studies
-rs3948464 -susceptibility in Ghambian population
-rs2114592 -susceptibility in republic of Guinea
and Gambia
References (Khalilullah et al., 2014; Moller and Hoal, 2010 )

Genes involved in opsonisation of
M. tuberculosisType Non-HLA genes
Gene name MBL
Function - It encodes mannose binding protein(secreted by liver), which binds to
mannose and N-acetylglucosamine
- This is further followed by lysis of the cell wall of M. tuberculosis by MAC
formation
- If MBL is in lesser amounts, the macrophage interacts with the bacilli directly
- This interaction leads to opsonisation and phagocytosis
Effect Lesser expression of this gene leads to resistance for the host due to direct
opsonisation by macrophages(i.e. without going to complement pathway)
Polymorphic form/forms Allele B Mutation in codon 54
Allele C Mutation in codon 57
Allele D Mutation in codon 52
Epidemiological studies These variants are associated with resistance to TB in Ghana
References (Kindt et al., 2007;Acton, 2013; Kozakiewicz et al., 2013;
Khalilullah et al., 2014; Soborg et al., 2003; Moller and Hoal, 2010 )

(Source: Soborg et al., 2003)
Figure5. Interaction of MBL and pathogen
A. B.
C.

Applications of studying the
susceptibility genes
Identification of susceptible genes will help
in:
Disease treatment:
Identification will put forward the
susceptibility genes responsible
Protein responsible is identified
Biochemical pathway, Cytokines,
and all the steps can be studied
Gene targeting can be done
37
Central university of Punjab: HGMM
1/29/2016

Genetic testing:
Development of new vaccines: These
studies has revealed majorly the
involvement of Non-HLA genes
• Development of new vaccines as the
targets become more vast
• But this application is still in its infancy
By identification of the gene responsible
population at risk can be identified
Genetic therapy can be processed
Most possible application

Prevention, Diagnosis and
Treatment of Tuberculosis
Prevention of TB
• BCG(Bacillus of Calmette and Guerin) vaccine:
named after two Frenchmen who developed it
• It consists of live attenuated strain(virulent part
removed) of M. bovis (avirulent)
• Drawbacks:
 TB reactivation cannot be prevented
 It prevents the disease formation but not the
infection
 Complicates the way TST operates
 banned in U.S.

Diagnostics of TB
• Ziehl neelson method:
Sputum(coughed up saliva) taken
Treated with NaOH(except M. tuberculosis other pathogens get killed)
Cultured on BACTEC media (Becton Dickinson) , it contains radiolabelled
palmitate as a sole carbon source
As the bacterium divides , palmitate divides liberating radiolabelled carbon
dioxide
Which detects growth within 9-16 days

Mantoux test/ Tuberculin skin test/
PPD(purified protein derivative)
If there susceptibility or the person had been exposed earlier or if the person is
infected, then the antigen will react and develop red burn mark leading to
inflammation, within 3 days
done via placing the little amount of TB antigen under the inner top layer of the
forearm skin
Tuberculin skin test is the type of TB susceptibility test that identifies the levels of
susceptibility to TB

• Treatment of TB: Common TB drugs are:
• Moxifloxacin is a fluroquinolone antibiotic drug that
targets DNA gyrase and kills bacteria by interfering
with its replication process. This drug showed
huge potency against TB than other TB drugs.
This drug can shorter the treatment from 6 months
to 3-4 months
Drug Mode of action
Rifampicin inhibits bacterial RNA
polymerase
Isoniazid inhibits the synthesis of
mycolic acid
Ethambutol obstructs the formation of cell
wall
Streptomycin acts as a protein synthesis
inhibitor

Conclusion
• Various number of susceptibility genes such
as HLA genes and Non-HLA genes and their
polymorphic forms responsible for the
Tuberculosis has been studied
• This gives a vast area of study for treatment
by targeting these genes
• But many genes are yet to be identified
• The challenges for study and treatment are
yet to overcome due to co evolution of the
bacterium and human both
Central university of Punjab: HGMM 431/29/2016

Future perspectives
• Challenges in TB susceptibility studies
- GWAS
• Human and M. tuberculosis co-evolution
• Schistosoma mansoni co-infection
increased M. tuberculosis susceptibility
• MicroRNA-223 in TB susceptibility

References
• Abhimanyu, M. B., Jha, P., and Indian Genome Variation Consortium. (2012). Footprints of
genetic susceptibility to pulmonary tuberculosis: Cytokine gene variants in north Indians. The
Indian journal of medical research, 135(5), 763.
• Bellamy, R. (1998). Genetic susceptibility to tuberculosis in human populations. Thorax, 53(7),
588-593.
• Bornman, L., Campbell, S. J., Fielding, K., Bah, B., Sillah, J., Gustafson, and Sylla, A. (2004).
Vitamin D receptor polymorphisms and susceptibility to tuberculosis in West Africa: a case-control
and family study.Journal of Infectious Diseases, 190(9), 1631-1641.
• Dorhoi, A., Iannaccone, M., Farinacci, M., Faé, K. C., Schreiber, J., Moura-Alves, and Heinemann,
E. (2015). MicroRNA-223 controls susceptibility to tuberculosis by regulating lung neutrophil
recruitment. The Journal of clinical investigation, 123(11), 4836.
• Dunn, P. L., and North, R. J. (1995). Virulence ranking of some Mycobacterium tuberculosis and
Mycobacterium bovis strains according to their ability to multiply in the lungs, induce lung
pathology, and cause mortality in mice.Infection and immunity, 63(9), 3428-3437.
• Gao, L., Tao, Y., Zhang, L., and Jin, Q. (2010). Vitamin D receptor genetic polymorphisms and
tuberculosis: updated systematic review and meta-analysis. The international journal of
tuberculosis and lung disease, 14(1), 15-23.
Central university of Punjab: HGMM 451/29/2016

• Khalilullah, S. A., Harapan, H., Hasan, N. A., Winardi, W., Ichsan, I., and Mulyadi, M. (2014). Host
genome polymorphisms and tuberculosis infection: What we have to say?. Egyptian Journal of Chest
Diseases and Tuberculosis, 63(1), 173-185.
• Meena, L. S. (2010). Survival mechanisms of pathogenic Mycobacterium tuberculosis H37Rv. FEBS
Journal, 277(11), 2416-2427.
• Moller, M., and Hoal, E. G. (2010). Current findings, challenges and novel approaches in human genetic
susceptibility to tuberculosis. Tuberculosis,90(2), 71-83.
• Monin, L., Griffiths, K. L., Lam, W. Y., Gopal, R., Kang, D. D., Ahmed and Kolls, J. K. (2015). Helminth-
induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis. The Journal of
clinical investigation, 125(12).
• Raja, A. (2004). Immunology of tuberculosis. Indian Journal of Medical Research, 120(Oct), 213-232.
• Santos, A. R., Suffys, P. N., Vanderborght, P. R., Moraes, M. O., Vieira, L. M., Cabello, P. H. and
Sampaio, E. P. (2002). Role of tumor necrosis factor–α and interleukin-10 promoter gene polymorphisms
in leprosy. Journal of Infectious Diseases, 186(11), 1687-1691.
• Selvaraj, (2004). Host genetics and tuberculosis susceptibility. Current Science, 86(1), 115-121.
• Soborg, C., Madsen, H. O., Andersen, Å. B., Lillebaek, T., Kok-Jensen, A., and Garred (2003). Mannose-
binding lectin polymorphisms in clinical tuberculosis. Journal of Infectious Diseases, 188(5), 777-782.
• Swaminathan and S.Rekha (2010). Pediatric tuberculosis: global overview and challenges. Clinical
Infectious Diseases, 50(3), 184-194.
• Zhabagin, M., Abilova, Z., Askapuli, A., Rakhimova, S., Kairov, U., Berikkhanova, and Akilzhanova,
(2014). Vitamin D Receptor Gene Polymorphisms in Susceptibility to Tuberculosis in the Kazakh
Population in Almaty and Almaty Area. Central Asian Journal of Global Health,66(2).

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Human genetic susceptibility to mycobacterium tuberculosis 1

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