- Email: [email protected]
Human and tuberculosis co-evolution: An integrative view
Accepted Manuscript Human and tuberculosis co-evolution: an integrative view Pascale Perrin PII:
S1472-9792(15)00017-7
DOI:
10.1016/j.tube.2015.02.016
Reference:
YTUBE 1277
To appear in:
Tuberculosis
Please cite this article as: Perrin P, Human and tuberculosis co-evolution: an integrative view, Tuberculosis (2015), doi: 10.1016/j.tube.2015.02.016. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT HUMAN AND TUBERCULOSIS CO-EVOLUTION : AN INTEGRATIVE VIEW
Pascale PERRIN
RI PT
MIVEGEC Maladies infectieuses et Vecteurs : Ecologie, Génétique, Evolution et Contrôle (CNRS 5290-IRD 224-UM1)/ Université Montpellier 2, DYSMI team Centre IRD de Montpellier 911 Avenue Agropolis - BP 64501
SC
34394 Montpellier Cedex – France Tel : +33 (0)4 67 41 64 44 and Fax : +33 (0)4 67 41 63 30
AC C
EP
TE D
M AN U
Corresponding author : [email protected]
1
ACCEPTED MANUSCRIPT Abstract Tuberculosis (TB) ranks as the second cause of death from an infectious disease worldwide after HIV. Archaeogenetics and evolutionary scenario for the Mycobacterium tuberculosis complex (MTBC) are in favour of a long-term interaction between tuberculosis and humans, predating the Neolithic period, contrary to the traditional belief. If tuberculosis
RI PT
evolved as a human pathogen in Africa and has spread outside Africa about more than tenthousand years ago, its life history traits have been shaped by the immune system. Numerous studies described a variety of human susceptibility factors to TB, suggesting that MTBC strains have evolved different ways to overcome this system. However, the results of these
SC
studies reveal some inconsistencies even within populations. The temporally varying history of epidemics and ever-varying genetic diversity of pathogens and strains could easily
M AN U
contribute to blur out signal of selection in our human genome. Palaeomicrobiology gives the opportunity to genotype ancient TB strains circulating in past populations. Accessing ancient human pathogens allows us to a better understanding of infectious agents over a longer time scale and confrontation with the dynamic of modern TB strains. Nevertheless, we have to consider tuberculosis as a multifactorial disorder in which environmental factors interact
TE D
tightly with human and pathogen genetic.
Keywords : Tuberculosis/Community of pathogens/Human diversity/ Genetic
AC C
EP
background/Environmental factors
2
ACCEPTED MANUSCRIPT
Introduction
In 2011, the estimation of new cases of tuberculosis was 8.7 millions and this number is higher than at any other time in history, with a peak of incident cases in 2004. 1.4 million
RI PT
people died from TB, about two-thirds of whom were HIV-negative individuals1.
TB remains clearly an infectious disease of poverty tightly associated with overcrowding, under-nutrition (diabetes) and addiction behaviors (alcohol consumption and smoking), together with HIV co-infection (twenty-fold increase). New genetic tools and knowledge
SC
about the genome (GWA and whole-genome-sequencing) are now available and offer a revolutionary increase in power to identify variants in genes or genome region involved in susceptibility to infectious agents. It is clear that we are facing a complex puzzle with a
M AN U
potentially large range of powerful factors such as the human genetic background, changes in environmental, socio-economic and cultural factors (urbanization, lifestyle, human health control, globalization of exchanges and migrations). We have to unravel a complex tangle in
AC C
EP
TE D
order to develop an integrative view.
3
ACCEPTED MANUSCRIPT Origin and history of tuberculosis
Until a few years ago, the traditional belief was that Tuberculosis mycobacterium originated in animals and was transferred to humans during the domestication process in the so-called “fertile crescent”. The first human settlements provided new ecological niches by
RI PT
concentrating humans and by increasing contacts with animals. Comparative genomic and molecular markers analyses suggested a very different scenario, making the human strain, M. tuberculosis, the most ancient strain2.
SC
High death rates from TB were observed in Europe from the 17th to 19the centuries (20-30% of all mortality) and in North America during the 18th and 19th centuries. Then it declines until
M AN U
1993 when the World Health Organization declared tuberculosis to be a ‘global emergency’. Looking for characteristic bone TB lesions (mainly spinal ones) in human (or animal) remains and identifying the ancient strain by molecular analysis are the only ways to confirm this hypothesis. The earliest molecular identification of tuberculosis and M. tuberculosis lineage (characterized by the TbD1 deletion) dates back to approximately 7000 BC3 from a PrePottery Neolithic period site where both animal domestication and agriculture is attested. It
TE D
supports the hypothesis of an evolution from an ancestral progenitor strain. Unfortunately, no analysis has been performed on cattle remains. A large collection of 160 Ancient Egyptian bone samples has been tested for the molecular presence of tuberculosis. They all came from Abydos (Upper Egypt) and Thebes-West, covering the period of 3000-500 BC4,5. They used
EP
spoligotyping to identify the mycobacterial strains. This typing reveals evidence for ancestral (no deletion of TbD1 but presence of RD9) M. tuberculosis strains in pre-and early Egyptian
AC C
dynasty (3500-2650 BC). They also found possible M. africanum signatures in the MiddleKingdom tomb of Thebes-West (2050-1650 BC). Modern strains of tuberculosis were identified in samples from the New Kingdom to Late Period tombs (1500-500 BC)6. No M. africanum strain has been detected in Medieval or more recent human series5. Aymyrlyg in South Siberia (dating from the iron age period in South Siberia), is the only site where M. bovis was found in archeological remains7. There is no doubt of pre-Colombian cases of tuberculosis in North America, Mexico and South America8. It seems obvious that going through our history, the successively occurrences of settlement, domestication and more recently urbanization/industrialization and global exchanges have considerably modified the infectious landscape. 4
ACCEPTED MANUSCRIPT Human genetic susceptibility to tuberculosis
Variation in TB susceptibility across humans is well established and genetic factors determine, in part, differences in host resistance to infection with Mycobacterium. Numerous studies including twin analysis, case-control studies, genome-wide linkage and genome-wide
RI PT
association analysis show that different specific variations seem to be involved in resistance to TB. First, for a better understanding, it is necessary to have an overview of the TB immune response. Both innate and adaptive responses are involved in the defence of the body against tuberculosis. The severity, localization and outcome depend largely on the balance of M.
SC
tuberculosis and host immune mechanisms.
Cellular uptake of M. tuberculosis is performed by five major types of cell membranebound receptors: the macrophage mannose receptor (MR or CD206), the complement receptor
M AN U
3 (CR3 or CD11b/CD18) the dendritic cell-specific ICAM-3 grabbing non-integrin (DC-SIGN or CD209), dectin-1 and Toll-like receptors (TLR, specially TLR1, TLR2, TLR6 and TLR9) on many cell types. An inflammatory response follows, regulated by production of proinflammatory cytokines (TNF, Il-1β, Il-6, Il-12, Il-10 and Il 18) and chemokines responsible for recruitment of inflammatory cells to the site of infection (Il-8 or CXCL8, MCP-1 or CCL2,
TE D
RANTES or CCL5, CXCL10 or IP-10). Some other innate molecules play a key role NOS2 (iNOS) with a bactericidal activity and NRAMP1 (coded by SLC11A1), part of the phagosome.
First, susceptibility to TB in humans seems to involve many loci and types of genes.
EP
Second, a large variability in genetic and allelic association is observed when comparing studies between populations. It means that a geographic and/or genetic component occurs.
AC C
What could be the cause of these discrepancies between the association of immune genes and TB?
We have to take into account the fact that a lot of analysis was performed on patients with clinical TB (pulmonary TB or extra-pulmonary TB). Patients with latent TB or during the primary infection (asymptomatic) are never considered. This is specifically critical because innate genes are at the frontline of the fight against TB pathogens. Different levels of defence are successively or specifically implicated in disease progression and in the clinical manifestations of TB (extra-pulmonary, pulmonary and Tuberculosis meningitis). All the data now collected clearly demonstrate that the host’s genetic background plays a key role in TB infection.
5
ACCEPTED MANUSCRIPT The challenge is to have a more integrative view, conducting multiloci and multigene studies to define genetic pluri-loci profiles. Previous analyses are really promising9 concerning the association of different human HLA types and M. tuberculosis strain genotype. It could easily explain why single variant associations have replicated inconsistently as the association is detectable only in the presence of specific variants within other genes. We have to consider
RI PT
the gene-gene interactions (epistasis). We cannot exclude some other regulating factors such as microRNA (22 nucleotide short non-coding RNAs) or other epigenetic elements (methylation patterns) which are able to regulate the transcriptional rate10,11,12.
SC
Human-pathogens co-evolution
The collection of 1605 patient isolates, pooling the data of Reed and colleagues13 and
M AN U
Gagneux and collaborators14 shows the highly geographical structure of the TB lineages (Figure 1). The association of the 5 main lineages with a particular geographical region is obvious. The East-Asian lineage including the Beijing strain, is largely preponderant in Eastern and Southeast Asia. On the contrary, the European-American/African lineage is clearly the most frequent lineage in Europe, Near- and Middle-East and different African
TE D
subregions. The Indo-Oceanic lineage is dominant in either Southeast Asia or Indian subcontinent, specially the Philippines, Vietnam and India. Around sixty-eight percent of isolates within the East African/Indian lineage come from the Indian subcontinent (including India, Pakistan and Bangladesh) or, for a small proportion to the East Africa region. Finally,
EP
the atypical MTC strains are restricted to West-African populations, strains that have been usually named M. africanum because of the RD9 deletion. The trends observed in the global
AC C
structure of genetic populations are strong arguments for mycobacterial lineages adapted to particular human populations.
Human populations on the earth live in different climatic zones and environments. Species richness in human pathogens is strongly correlated with latitude, tropical areas harboring the higher diversity comparing to more temperate areas15. The recurrent exposure to specific pathogen community and epidemics probably acted as selective pressures on human genetic pattern. One can imagine that a long-time period of exposure to TB probably results in a strong positive selection favoring resistance to TB. The first signs of urbanization in the world are described in the fertile crescent. We can make the assumption that this major event was the beginning of a strong selective force in Near-East and European populations according the 6
ACCEPTED MANUSCRIPT scenario of Europe colonization. Two studies are very interesting from this point of view. The first one points on the correlation between the duration of urban settlement and the frequency of the SLC11A1 (Nramp1) 1729 +55del4 (rs17235416)16. The second one concerns the regional pattern of three Toll-Like Receptor 2 polymorphisms. The 2029 C/T polymorphism is absent in European and non-European populations with the exception in the Vlax-Romani
RI PT
population. The 1892 C/G is exclusively found in European populations and the last one 2258 G/A is present in Europeans including Vlax-Roma even if it is at a very low frequency17. Both of these receptors are involved in the first line of defence against pathogenic microorganisms, the innate immune system: SCL11A1 is one of the major determining factor of natural
SC
resistance to intracellular infections and TLR 2 recognizes a large array of pathogenassociated molecular patterns. These findings argue for an occurrence of variants after the split of the populations in the Middle-East. In the presence of selection pressure, different variants
M AN U
in the same gene may have emerged independently. A large number of studies revealed different HLA associations in various ethnic population18. Tuberculosis was found to be the only phenotypic manifestation in several children with genetic defects of the IL-12/23IFNgamma circuit, and particularly those with complete deficiency. HLA-class II is crucial in modulating the adaptive immune response. This could be the result of the extreme diversity of HLA loci leading to the selection of different alleles within a group of related HLA molecules
TE D
sharing the same kinds of epitopes19. On another hand, the presence of geographically distinct strains of M. tuberculosis, expressing different antigenic motifs is plausible considering the last findings reporting the association of HLA class-I type and specific M. tuberculosis
EP
strains9. Similar results were obtained showing a correlation between variants in IRGM20, SCL11A121 and TLR222 genes and TB genotypes.
AC C
Genome and Evolution
M. tuberculosis genome shows no evidence of genome erosion (a few number of insertion sequences and pseudogenes). The human-adapted members of the M. tuberculosis complex probably emerged from a bottleneck. It is generally admitted that M. tuberculosis evolved clonally on the basis of spoligotyping, presence-absence of deletions (RD) and interspersed repetitive units (MIRU/VNTR) studies. We know that these types of markers are prone to homoplasy and are not the best ones to evaluate genetic diversity. Studies using different tools like SNP23, large sequence polymorphism LSPs24 and genome analysis25 show a clear genetic diversity. The question of what could generate such a diversity arises. Several reasons could 7
ACCEPTED MANUSCRIPT explain this fact. The first one proposes that emergence of diversified strains is the result of genetic drift and human demography, migrations and socio-economic factors like urbanization23. Namouchi and collaborators25 highlight mutations, recombination and natural selection as the major drivers of diversification. Surprisingly, an analysis of more than twenty genomes sequences, representative of the range of diversity of M. tuberculosis, revealed that
RI PT
T-cell antigen proteins are equally conserved as essential genes and epitope parts are more conserved than non-epitopes26: this finding excludes an immune evasion. The benefit for M. tuberculosis could be to maintain on a longstanding period (latent time and pathologic time) a potential reservoir for further infections. It contrasts deeply with HIV or Plasmodium.
SC
In TB, if a lot of studies described associations between human genetic variants or polymorphisms with specific M. tuberculosis lineages (see above), no experimental analysis has confirmed the direct interaction between human and TB variation contrary to what has
M AN U
been done for Helicobacter pylori27. Nevertheless, recent findings demonstrate that IL-12Rβ1 deficiency causes a severe TB phenotype and clearly reflects a mendelian predisposition28. Similarly, Fenner and collaborators showed that the level of immunodeficiency caused by HIV infection, disrupts the sympatric host-pathogen relationship in human TB29.
TE D
Community of pathogens and co-infection
Adaptation to hosts does not preclude co-infections. We know that humans are confronted with cohorts of infectious agents depending on the geographical zones in which they
EP
originated. Then it is not excluded that competition occurred between them. We have not to forget that man is also colonized by site-specific microbial communities. M. tuberculosis and
AC C
H. pylori are the most prevalent bacterial pathogens in the world and coexist throughout most of the life span. Henceforth we know that disturbances in the bacterial microbiome is a major regulator of inflammatory disorders30, it can acts as modulator in non-infectious diseases like obesity and autoimmune diseases. H. pylori infection affects response to tuberculosis in humans and non-primate animals involving the interferon-gamma pathway. Historical literary gave evidence for the existence of leprosy and tuberculosis in historical times. But a very important event occurred in the post-medieval time period in Europe, the decline of leprosy in Europe in parallel with the increase of the tuberculosis rate. Both tuberculosis and leprosy often result in characteristic bone lesions or morphological changes on skeletons that makes easier the identification of potential co-infected individuals. The DNA
8
ACCEPTED MANUSCRIPT of both M. Leprae and M. tuberculosis was detected in human remains spanning from Roman Egypt, first century Palestine, tenth century Hungary and medieval Sweden31. A recent review shows that dual infection is not so uncommon in modern endemic areas, it has been also reported from throughout the world32. Toll-like receptors (TLRs) are an essential family of innate immune pattern recognition receptors which plays a pivotal role in host defence against
RI PT
microbes, and particularly mycobacteria such as tuberculosis and leprae. Several disease association studies have revealed a protective role for the deficient TLR1 I602S (rs5743618) variant against the development of both clinical leprosy and tuberculosis.
SC
Conclusion
Elucidating the role of genetic susceptibility is critical to improving the health system. The further challenge is to stratify human populations for risk of infectious disease. Characterizing
M AN U
mycobacterial lineages from the earliest Old World human remains is crucial to identify the types of circulating strains and assess whether the increase in prevalence was due to the spread of new strains or not.
High-throughput whole genome sequencing is a very promising approach improving resolution for population-based studies. First it makes possible the estimation of the mutation rate of M. tuberculosis within host as 0.1/Mb/year in some lineages far higher than suspected
TE D
(latent period)33. Secondly, it gives too the opportunity to identify the range of strains within persistent patients. Investigating at a fine scale the diversity of genotypes within host is a good way to understand the evolutionary dynamics involved in disease progression. Third, this tool
EP
gives the opportunity to look for and to identify multi-loci combination of variants and to define population-specific genetic profiles, TB strain-dependant; it is obvious that different
AC C
loci determine or modulate susceptibility to tuberculosis. A recent study using a wholegenome approach identified gene sets enriched for signal of positive selection: they are involved in different immune pathways such as Il-6 signaling pathway and cytokine-cytokine receptor interaction34.
A large survey on primate samples from all over the world testing for the presence of M. tuberculosis will help to understand the relationship between strains found in humans and nonhuman primates. The comparison of humans and primates gives no evidence of enrichment in immunity-related genes, among genes that have been selected in the human lineage. Probably, adaptive changes in the gene regulation occurred. Among the various environmental factors that acted as selective pressure, pathogen load has been proposed to have a strong influence and to have shaped some regions of our 9
ACCEPTED MANUSCRIPT genome35,36: it is the case for HLA genes. A recent analysis gives a more nuanced conclusion concerning the level of influence and shows distinct evolutionary strategies for HLA-A, -B, -C and HLA-DRB1 (balancing selection) and HLA-DQA1 and –DQB1 genes (purifying selection) to provide efficient protection in pathogen-rich environment37. Humans have been confronted over time to pathogens. It means that past epidemics and pathogens have left strong
RI PT
marks on human (and primate) genomes. We still need to identify these marks and find what kinds of pathogens have produced a selective pressure on our genome.
As we can see, a wide range of factors influences TB epidemics (Figure 2). Tuberculosis still kills million of people all around the world, despite the fact it is a curable infectious
SC
disease. The challenge is to adopt a multidisciplinary approach to control it. This integrative approach is essential to understanding the evolution of a specific pathogen over a long-time period in the context of the human evolution, pathogen community and cultural and societal
M AN U
changes. It will impact our concepts of the evolution of infectious diseases and will amend the practice of public health in their control.
References
TE D
1. Global Tuberculosis Report 2012. World Health Organization. WHO Library Cataloguing-in-Publication Data. NLM classification: WF 300. 2. Brosch R, Gordon SV, Marmiesse M, Brodin P, Buchrieser C, Eiglmeier K, Garnier T, Gutierrez C, Hewinson G, Kremer K, Parsons LM, Pym AS, Samper S, van Soolingen
EP
D, Cole ST. A new evolutionary scenario for the Mycobacterium tuberculosis complex. Proc Natl Acad Sci U S A. 2002;99:3684-9
AC C
3. Hershkovitz I, Donoghue HD, Minnikin DE, Besra GS, Lee OY, Gernaey AM, Galili E, Eshed V, Greenblatt CL, Lemma E, Bar-Gal GK, Spigelman M Detection and molecular characterization of 9,000-year-old Mycobacterium tuberculosis from a Neolithic settlement in the Eastern Mediterranean. PLoS One. 2008;3:e3426, doi: 10.1371/journal.pone.0003426. 4. Zink AR, Sola C, Reischl U, Grabner W, Rastogi N, Wolf H, Nerlich AG. Characterization of Mycobacterium tuberculosis complex DNAs from Egyptian mummies by spoligotyping. J Clin Microbiol. 2003;41:359-67.
10
ACCEPTED MANUSCRIPT 5. Nerlich AG, Lösch S. Paleopathology of human tuberculosis and the potential role of climate.
Interdiscip
Perspect
Infect
Dis.
2009;2009:437187.
doi:
10.1155/2009/437187. 6. Zink AR, Molnár E, Motamedi N, Pálfy G, Marcsik A, Nerlich AG. Molecular history of tuberculosis from ancient mummies and skeletons. Int. J Osteoarchaeology
7. Taylor GM, Murphy E,
Hopkins R,
RI PT
2007;17 :380–391. Rutland P, Chistov Y.
First report of
Mycobacterium bovis DNA in human remains from the Iron Age. Microbiology 2007;153:1243-1249.
SC
8. Mackowiak PA, Blos VT, Aguilar M, Buikstra JE. On the Origin of American Tuberculosis. Clin Infect Dis. 2005;41: 515-518.
9. Salie M, van der Merwe L, Möller M, Daya M, van der Spuy GD, van Helden PD,
M AN U
Martin MP, Gao XJ, Warren RM, Carrington M, Hoal EG. Associations Between Human Leukocyte Antigen Class I Variants and the Mycobacterium tuberculosis Subtypes Causing Disease. J Infect Dis. 2013. doi: 10.1093/infdis/jit443. 10. Andraos C, Koorsen G, Knight JC, Bornman L. Vitamin D receptor gene methylation is associated with ethnicity, tuberculosis, and TaqI polymorphism. Hum Immunol.
TE D
2011;72: 262-268.
11. Liu Y, Wang X, Jiang J, Cao Z, Yang B, Cheng X. Modulation of T cell cytokine production by miR-144* with elevated expression in patients with pulmonary tuberculosis. Mol Immunol. 2011;48:1084-1090.
EP
12. Wang C, Yang S, Sun G, Tang X, Lu S, Neyrolles O, Gao Q. Comparative miRNA expression profiles in individuals with latent and active tuberculosis. PLoS One. 2011;
AC C
6:e25832.
13. Reed MB, Pichler VK, McIntosh F, Mattia A, Fallow A, Masala S, Domenech P, Zwerling A, Thibert L, Menzies D, Schwartzman K, Behr MA. Major Mycobacterium tuberculosis lineages associate with patient country of origin. J Clin Microbiol.
2009;47:1119-28. doi: 10.1128/JCM.02142-08.
14. Gagneux S, DeRiemer K, Van T, Kato-Maeda M, de Jong BC, Narayanan S, Nicol M, Niemann S, Kremer K, Gutierrez MC, Hilty M, Hopewell PC, Small PM. Variable host-pathogen compatibility in Mycobacterium tuberculosis. Proc Natl Acad Sci USA. 2006;103:2869-73. 15. Guernier V, Hochberg ME, Guégan JF. Ecology drives the worldwide distribution of human diseases. PLoS Biol. 2004;2:e141. 11
ACCEPTED MANUSCRIPT 16. Barnes I, Duda A, Pybus OG, Thomas MG. Ancient urbanization predicts genetic resistance to tuberculosis. Evolution. 2011;65:842-848. 17. Ioana M,, Ferwerda B,, Plantinga TS, Stappers M, Oosting M, McCall M,, Cimpoeru A, Burada F, Panduru N, Sauerwein R, Doumbo O, van der Meer JWM, van Crevel R, .Joosten LAB, Netea MG. Different Patterns of Toll-Like Receptor 2
RI PT
Polymorphisms in Populations of Various Ethnic and Geographic Origins Infect. Immun. 2012 ;80: 1917-1922
18. Möller M, De Wit E, Hoal EG. Past, present and future directions in human genetic susceptibility to tuberculosis. FEMS Immunol Med Microbiol. 2010 ;58:3-26. doi:
SC
10.1111/j.1574-695X.2009.00600.x.
19. Balamurugan A, Sharma SK, Mehra NK. Human leukocyte antigen class I supertypes influence susceptibility and severity of tuberculosis. J Infect Dis. 2004;189:805-11.
M AN U
20. Intemann CD, Thye T, Niemann S, Browne EN, Amanua Chinbuah M, Enimil A, Gyapong J, Osei I, Owusu-Dabo E, Helm S, Rüsch-Gerdes S, Horstmann RD, Meyer CG. Autophagy gene variant IRGM -261 T contributes to protection from tuberculosis caused by Mycobacterium tuberculosis but not by M. africanum strains. PLoS Pathog 2009;5:e1000577. doi: 10.1371/journal.ppat.1000577.
TE D
21. van Crevel R, Parwati I, Sahiratmadja E, Marzuki S, Ottenhoff TH, Netea MG, van der Ven A, Nelwan RH, van der Meer JW, Alisjahbana B, van de Vosse E. Infection with Mycobacterium
tuberculosis
Beijing
genotype
strains
is
associated
with
polymorphisms in SLC11A1/NRAMP1 in Indonesian patients with tuberculosis. J
EP
Infect Dis 2009;200:1671-1674. doi: 10.1086/648477. 22. Caws M, Thwaites G, Dunstan S, Hawn TR, Lan NT, Thuong NT, Stepniewska K,
AC C
Huyen MN, Bang ND, Loc TH, Gagneux S, van Soolingen D, Kremer K, van der Sande M, Small P, Anh PT, Chinh NT, Quy HT, Duyen NT, Tho DQ, Hieu NT, Torok E, Hien TT, Dung NH, Nhu NT, Duy PM, van Vinh Chau N, Farrar J. The influence of host and bacterial genotype on the development of disseminated disease with Mycobacterium tuberculosis. PLoS Pathog. 2008;4:e1000034. doi: 10.1371.
23. Hershberg R, Lipatov M, Small PM, Sheffer H, Niemann S, Homolka S, Roach JC, Kremer K, Petrov DA, Feldman MW, Gagneux S. High functional diversity in Mycobacterium tuberculosis driven by genetic drift and human demography. PLoS Biol. 2008;6:e311. doi: 10.1371/journal.pbio.0060311. 24. Alland D, Lacher DW, Hazbon MH, Motiwala AS, Qi W, Fleischmann RD, Whittam TS. 2007. Role of large sequence polymorphisms (LSPs) in generating genomic 12
ACCEPTED MANUSCRIPT diversity among clinical isolates of Mycobacterium tuberculosis and the utility of LSPs in phylogenetic analysis. J Clin Microbiol 2007;45: 39–46. 25. Namouchi A, Didelot X, Schöck U, Gicquel B, Rocha EPC. After the bottleneck: Genome-wide diversification of the Mycobacterium tuberculosis complex by mutation, recombination, and natural selection Genome Res. 2012;22:721-734.
RI PT
26. Comas I, Chakravarti J, Small PM, Galagan J, Niemann S, Kremer K, Ernst JD, Gagneux S. Human T cell epitopes of Mycobacterium tuberculosis are evolutionarily hyperconserved. Nat Genet. 2010;42:498-503. doi: 10.1038/ng.590.
27. Falush D, Wirth T, Linz B, Pritchard JK, Stephens M, Kidd M, Blaser MJ, Graham
SC
DY, Vacher S, Perez-Perez GI, Yamaoka Y, Mégraud F, Otto K, Reichard U, Katzowitsch E, Wang X, Achtman M, Suerbaum S. Traces of human migrations in Helicobacter pylori populations. Science 2003;299:1582-1585.
M AN U
28. El Baghdadi J, Grant AV, Sabri A, El Azbaoui S, Zaidi H, Cobat A, Schurr E, BoissonDupuis S, Casanova JL, Abel L. Human genetics of tuberculosis. Pathol Biol (Paris). 2013;61:11-16. doi: 10.1016/j.patbio.2013.01.004.
29. Fenner L, Egger M, Bodmer T, Furrer H, Ballif M, Battegay M, Helbling P, Fehr J, Gsponer T, Rieder HL, Zwahlen M, Hoffmann M, Bernasconi E, Cavassini M, Calmy
TE D
A, Dolina M, Frei R, Janssens JP, Borrell S, Stucki D, Schrenzel J, Böttger EC, Gagneux S; Swiss HIV Cohort and Molecular Epidemiology of Tuberculosis Study Groups. HIV infection disrupts the sympatric host-pathogen relationship in human tuberculosis. PLoS Genet. 2013; 9:e1003318. doi: 10.1371/journal.pgen.1003318.
EP
30. Round JL, Mazmanian. SK.The gut microbiota shapes intestinal immune responses during health and disease. Nature Reviews Immunology 2009; 9, 313-323
AC C
doi:10.1038/nri2515.
31. Donoghue HD, Marcsik A, Matheson C, Vernon K, Nuorala E, Molto JE, Greenblatt CL, Spigelman M. Co-infection of Mycobacterium tuberculosis and Mycobacterium
leprae in human archaeological samples: a possible explanation for the historical decline of leprosy. Proc Biol Sci. 2005;272:389-394.
32. Rajagopala S, Devaraj U, D’Souza, G V.V., Aithal VV. Co-infection with M. tuberculosis and M. Leprae case report and systematic Review. J Mycobac Dis. 2012;2:4. http://dx.doi.org/10.4172/2161-1068.1000118. 33. Ford CB, Shah RR, Maeda MK, Gagneux S, Murray MB, Cohen T, Johnston JC, Gardy J, Lipsitch M, Fortune SM. Mycobacterium tuberculosis mutation rate estimates
13
ACCEPTED MANUSCRIPT from different lineages predict substantial differences in the emergence of drugresistant tuberculosis. Nat Genet. 2013;45:784-90. doi: 10.1038/ng.2656. 34. Daub JT, Hofer T, Cutivet E, Dupanloup I, Quintana-Murci L, Robinson-Rechavi M, Excoffier L. Evidence for polygenic adaptation to pathogens in the human genome. Mol Biol Evol. 2013;30:1544-1558. doi: 10.1093/molbev/mst080.
RI PT
35. Prugnolle F, Manica A, Charpentier M, Guégan JF, Guernier V, Balloux F. Pathogendriven selection and worldwide HLA class I diversity. Curr Biol. 2005;15:1022-1027. 36. Qutob N, Balloux F, Raj T, Liu H, Marion de Procé S, Trowsdale J, Manica A. Signatures of historical demography and pathogen richness on MHC class I genes.
SC
Immunogenetics. 2012;64:165-175. doi: 10.1007/s00251-011-0576-y.
37. Sanchez-Mazas A, Lemaître JF, Currat M. Distinct evolutionary strategies of human leucocyte antigen loci in pathogen-rich environments. Phil. Trans. R. Soc. B
AC C
EP
TE D
M AN U
2012;367:830-839. doi: 10.1098/rstb.2011.0312.
14
ACCEPTED MANUSCRIPT Figure 1. Distribution of the main LSP-defined TB lineages by geographic origin of the patients cumulating data from Reed et al.13 and Gagneux et al.14. The 5 different sizes of the pie charts correspond to the number of patients i.e. starting from the largest size to the smallest size : n= ranging from 379 to 257; n ranging from 108 to 80; n ranging from 52 to 43; n
AC C
EP
TE D
M AN U
SC
RI PT
ranging from 32 to 19; n <10.
15
ACCEPTED MANUSCRIPT Figure 2. Diagram of the multiple factors involved (socio-economic, cultural, demographic, genetic) in tuberculosis epidemics. A more integrative approach is necessary to fight the
AC C
EP
TE D
M AN U
SC
RI PT
burden of tuberculosis.
16
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S1472-9792(15)00017-7
DOI:
10.1016/j.tube.2015.02.016
Reference:
YTUBE 1277
To appear in:
Tuberculosis
Please cite this article as: Perrin P, Human and tuberculosis co-evolution: an integrative view, Tuberculosis (2015), doi: 10.1016/j.tube.2015.02.016. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT HUMAN AND TUBERCULOSIS CO-EVOLUTION : AN INTEGRATIVE VIEW
Pascale PERRIN
RI PT
MIVEGEC Maladies infectieuses et Vecteurs : Ecologie, Génétique, Evolution et Contrôle (CNRS 5290-IRD 224-UM1)/ Université Montpellier 2, DYSMI team Centre IRD de Montpellier 911 Avenue Agropolis - BP 64501
SC
34394 Montpellier Cedex – France Tel : +33 (0)4 67 41 64 44 and Fax : +33 (0)4 67 41 63 30
AC C
EP
TE D
M AN U
Corresponding author : [email protected]
1
ACCEPTED MANUSCRIPT Abstract Tuberculosis (TB) ranks as the second cause of death from an infectious disease worldwide after HIV. Archaeogenetics and evolutionary scenario for the Mycobacterium tuberculosis complex (MTBC) are in favour of a long-term interaction between tuberculosis and humans, predating the Neolithic period, contrary to the traditional belief. If tuberculosis
RI PT
evolved as a human pathogen in Africa and has spread outside Africa about more than tenthousand years ago, its life history traits have been shaped by the immune system. Numerous studies described a variety of human susceptibility factors to TB, suggesting that MTBC strains have evolved different ways to overcome this system. However, the results of these
SC
studies reveal some inconsistencies even within populations. The temporally varying history of epidemics and ever-varying genetic diversity of pathogens and strains could easily
M AN U
contribute to blur out signal of selection in our human genome. Palaeomicrobiology gives the opportunity to genotype ancient TB strains circulating in past populations. Accessing ancient human pathogens allows us to a better understanding of infectious agents over a longer time scale and confrontation with the dynamic of modern TB strains. Nevertheless, we have to consider tuberculosis as a multifactorial disorder in which environmental factors interact
TE D
tightly with human and pathogen genetic.
Keywords : Tuberculosis/Community of pathogens/Human diversity/ Genetic
AC C
EP
background/Environmental factors
2
ACCEPTED MANUSCRIPT
Introduction
In 2011, the estimation of new cases of tuberculosis was 8.7 millions and this number is higher than at any other time in history, with a peak of incident cases in 2004. 1.4 million
RI PT
people died from TB, about two-thirds of whom were HIV-negative individuals1.
TB remains clearly an infectious disease of poverty tightly associated with overcrowding, under-nutrition (diabetes) and addiction behaviors (alcohol consumption and smoking), together with HIV co-infection (twenty-fold increase). New genetic tools and knowledge
SC
about the genome (GWA and whole-genome-sequencing) are now available and offer a revolutionary increase in power to identify variants in genes or genome region involved in susceptibility to infectious agents. It is clear that we are facing a complex puzzle with a
M AN U
potentially large range of powerful factors such as the human genetic background, changes in environmental, socio-economic and cultural factors (urbanization, lifestyle, human health control, globalization of exchanges and migrations). We have to unravel a complex tangle in
AC C
EP
TE D
order to develop an integrative view.
3
ACCEPTED MANUSCRIPT Origin and history of tuberculosis
Until a few years ago, the traditional belief was that Tuberculosis mycobacterium originated in animals and was transferred to humans during the domestication process in the so-called “fertile crescent”. The first human settlements provided new ecological niches by
RI PT
concentrating humans and by increasing contacts with animals. Comparative genomic and molecular markers analyses suggested a very different scenario, making the human strain, M. tuberculosis, the most ancient strain2.
SC
High death rates from TB were observed in Europe from the 17th to 19the centuries (20-30% of all mortality) and in North America during the 18th and 19th centuries. Then it declines until
M AN U
1993 when the World Health Organization declared tuberculosis to be a ‘global emergency’. Looking for characteristic bone TB lesions (mainly spinal ones) in human (or animal) remains and identifying the ancient strain by molecular analysis are the only ways to confirm this hypothesis. The earliest molecular identification of tuberculosis and M. tuberculosis lineage (characterized by the TbD1 deletion) dates back to approximately 7000 BC3 from a PrePottery Neolithic period site where both animal domestication and agriculture is attested. It
TE D
supports the hypothesis of an evolution from an ancestral progenitor strain. Unfortunately, no analysis has been performed on cattle remains. A large collection of 160 Ancient Egyptian bone samples has been tested for the molecular presence of tuberculosis. They all came from Abydos (Upper Egypt) and Thebes-West, covering the period of 3000-500 BC4,5. They used
EP
spoligotyping to identify the mycobacterial strains. This typing reveals evidence for ancestral (no deletion of TbD1 but presence of RD9) M. tuberculosis strains in pre-and early Egyptian
AC C
dynasty (3500-2650 BC). They also found possible M. africanum signatures in the MiddleKingdom tomb of Thebes-West (2050-1650 BC). Modern strains of tuberculosis were identified in samples from the New Kingdom to Late Period tombs (1500-500 BC)6. No M. africanum strain has been detected in Medieval or more recent human series5. Aymyrlyg in South Siberia (dating from the iron age period in South Siberia), is the only site where M. bovis was found in archeological remains7. There is no doubt of pre-Colombian cases of tuberculosis in North America, Mexico and South America8. It seems obvious that going through our history, the successively occurrences of settlement, domestication and more recently urbanization/industrialization and global exchanges have considerably modified the infectious landscape. 4
ACCEPTED MANUSCRIPT Human genetic susceptibility to tuberculosis
Variation in TB susceptibility across humans is well established and genetic factors determine, in part, differences in host resistance to infection with Mycobacterium. Numerous studies including twin analysis, case-control studies, genome-wide linkage and genome-wide
RI PT
association analysis show that different specific variations seem to be involved in resistance to TB. First, for a better understanding, it is necessary to have an overview of the TB immune response. Both innate and adaptive responses are involved in the defence of the body against tuberculosis. The severity, localization and outcome depend largely on the balance of M.
SC
tuberculosis and host immune mechanisms.
Cellular uptake of M. tuberculosis is performed by five major types of cell membranebound receptors: the macrophage mannose receptor (MR or CD206), the complement receptor
M AN U
3 (CR3 or CD11b/CD18) the dendritic cell-specific ICAM-3 grabbing non-integrin (DC-SIGN or CD209), dectin-1 and Toll-like receptors (TLR, specially TLR1, TLR2, TLR6 and TLR9) on many cell types. An inflammatory response follows, regulated by production of proinflammatory cytokines (TNF, Il-1β, Il-6, Il-12, Il-10 and Il 18) and chemokines responsible for recruitment of inflammatory cells to the site of infection (Il-8 or CXCL8, MCP-1 or CCL2,
TE D
RANTES or CCL5, CXCL10 or IP-10). Some other innate molecules play a key role NOS2 (iNOS) with a bactericidal activity and NRAMP1 (coded by SLC11A1), part of the phagosome.
First, susceptibility to TB in humans seems to involve many loci and types of genes.
EP
Second, a large variability in genetic and allelic association is observed when comparing studies between populations. It means that a geographic and/or genetic component occurs.
AC C
What could be the cause of these discrepancies between the association of immune genes and TB?
We have to take into account the fact that a lot of analysis was performed on patients with clinical TB (pulmonary TB or extra-pulmonary TB). Patients with latent TB or during the primary infection (asymptomatic) are never considered. This is specifically critical because innate genes are at the frontline of the fight against TB pathogens. Different levels of defence are successively or specifically implicated in disease progression and in the clinical manifestations of TB (extra-pulmonary, pulmonary and Tuberculosis meningitis). All the data now collected clearly demonstrate that the host’s genetic background plays a key role in TB infection.
5
ACCEPTED MANUSCRIPT The challenge is to have a more integrative view, conducting multiloci and multigene studies to define genetic pluri-loci profiles. Previous analyses are really promising9 concerning the association of different human HLA types and M. tuberculosis strain genotype. It could easily explain why single variant associations have replicated inconsistently as the association is detectable only in the presence of specific variants within other genes. We have to consider
RI PT
the gene-gene interactions (epistasis). We cannot exclude some other regulating factors such as microRNA (22 nucleotide short non-coding RNAs) or other epigenetic elements (methylation patterns) which are able to regulate the transcriptional rate10,11,12.
SC
Human-pathogens co-evolution
The collection of 1605 patient isolates, pooling the data of Reed and colleagues13 and
M AN U
Gagneux and collaborators14 shows the highly geographical structure of the TB lineages (Figure 1). The association of the 5 main lineages with a particular geographical region is obvious. The East-Asian lineage including the Beijing strain, is largely preponderant in Eastern and Southeast Asia. On the contrary, the European-American/African lineage is clearly the most frequent lineage in Europe, Near- and Middle-East and different African
TE D
subregions. The Indo-Oceanic lineage is dominant in either Southeast Asia or Indian subcontinent, specially the Philippines, Vietnam and India. Around sixty-eight percent of isolates within the East African/Indian lineage come from the Indian subcontinent (including India, Pakistan and Bangladesh) or, for a small proportion to the East Africa region. Finally,
EP
the atypical MTC strains are restricted to West-African populations, strains that have been usually named M. africanum because of the RD9 deletion. The trends observed in the global
AC C
structure of genetic populations are strong arguments for mycobacterial lineages adapted to particular human populations.
Human populations on the earth live in different climatic zones and environments. Species richness in human pathogens is strongly correlated with latitude, tropical areas harboring the higher diversity comparing to more temperate areas15. The recurrent exposure to specific pathogen community and epidemics probably acted as selective pressures on human genetic pattern. One can imagine that a long-time period of exposure to TB probably results in a strong positive selection favoring resistance to TB. The first signs of urbanization in the world are described in the fertile crescent. We can make the assumption that this major event was the beginning of a strong selective force in Near-East and European populations according the 6
ACCEPTED MANUSCRIPT scenario of Europe colonization. Two studies are very interesting from this point of view. The first one points on the correlation between the duration of urban settlement and the frequency of the SLC11A1 (Nramp1) 1729 +55del4 (rs17235416)16. The second one concerns the regional pattern of three Toll-Like Receptor 2 polymorphisms. The 2029 C/T polymorphism is absent in European and non-European populations with the exception in the Vlax-Romani
RI PT
population. The 1892 C/G is exclusively found in European populations and the last one 2258 G/A is present in Europeans including Vlax-Roma even if it is at a very low frequency17. Both of these receptors are involved in the first line of defence against pathogenic microorganisms, the innate immune system: SCL11A1 is one of the major determining factor of natural
SC
resistance to intracellular infections and TLR 2 recognizes a large array of pathogenassociated molecular patterns. These findings argue for an occurrence of variants after the split of the populations in the Middle-East. In the presence of selection pressure, different variants
M AN U
in the same gene may have emerged independently. A large number of studies revealed different HLA associations in various ethnic population18. Tuberculosis was found to be the only phenotypic manifestation in several children with genetic defects of the IL-12/23IFNgamma circuit, and particularly those with complete deficiency. HLA-class II is crucial in modulating the adaptive immune response. This could be the result of the extreme diversity of HLA loci leading to the selection of different alleles within a group of related HLA molecules
TE D
sharing the same kinds of epitopes19. On another hand, the presence of geographically distinct strains of M. tuberculosis, expressing different antigenic motifs is plausible considering the last findings reporting the association of HLA class-I type and specific M. tuberculosis
EP
strains9. Similar results were obtained showing a correlation between variants in IRGM20, SCL11A121 and TLR222 genes and TB genotypes.
AC C
Genome and Evolution
M. tuberculosis genome shows no evidence of genome erosion (a few number of insertion sequences and pseudogenes). The human-adapted members of the M. tuberculosis complex probably emerged from a bottleneck. It is generally admitted that M. tuberculosis evolved clonally on the basis of spoligotyping, presence-absence of deletions (RD) and interspersed repetitive units (MIRU/VNTR) studies. We know that these types of markers are prone to homoplasy and are not the best ones to evaluate genetic diversity. Studies using different tools like SNP23, large sequence polymorphism LSPs24 and genome analysis25 show a clear genetic diversity. The question of what could generate such a diversity arises. Several reasons could 7
ACCEPTED MANUSCRIPT explain this fact. The first one proposes that emergence of diversified strains is the result of genetic drift and human demography, migrations and socio-economic factors like urbanization23. Namouchi and collaborators25 highlight mutations, recombination and natural selection as the major drivers of diversification. Surprisingly, an analysis of more than twenty genomes sequences, representative of the range of diversity of M. tuberculosis, revealed that
RI PT
T-cell antigen proteins are equally conserved as essential genes and epitope parts are more conserved than non-epitopes26: this finding excludes an immune evasion. The benefit for M. tuberculosis could be to maintain on a longstanding period (latent time and pathologic time) a potential reservoir for further infections. It contrasts deeply with HIV or Plasmodium.
SC
In TB, if a lot of studies described associations between human genetic variants or polymorphisms with specific M. tuberculosis lineages (see above), no experimental analysis has confirmed the direct interaction between human and TB variation contrary to what has
M AN U
been done for Helicobacter pylori27. Nevertheless, recent findings demonstrate that IL-12Rβ1 deficiency causes a severe TB phenotype and clearly reflects a mendelian predisposition28. Similarly, Fenner and collaborators showed that the level of immunodeficiency caused by HIV infection, disrupts the sympatric host-pathogen relationship in human TB29.
TE D
Community of pathogens and co-infection
Adaptation to hosts does not preclude co-infections. We know that humans are confronted with cohorts of infectious agents depending on the geographical zones in which they
EP
originated. Then it is not excluded that competition occurred between them. We have not to forget that man is also colonized by site-specific microbial communities. M. tuberculosis and
AC C
H. pylori are the most prevalent bacterial pathogens in the world and coexist throughout most of the life span. Henceforth we know that disturbances in the bacterial microbiome is a major regulator of inflammatory disorders30, it can acts as modulator in non-infectious diseases like obesity and autoimmune diseases. H. pylori infection affects response to tuberculosis in humans and non-primate animals involving the interferon-gamma pathway. Historical literary gave evidence for the existence of leprosy and tuberculosis in historical times. But a very important event occurred in the post-medieval time period in Europe, the decline of leprosy in Europe in parallel with the increase of the tuberculosis rate. Both tuberculosis and leprosy often result in characteristic bone lesions or morphological changes on skeletons that makes easier the identification of potential co-infected individuals. The DNA
8
ACCEPTED MANUSCRIPT of both M. Leprae and M. tuberculosis was detected in human remains spanning from Roman Egypt, first century Palestine, tenth century Hungary and medieval Sweden31. A recent review shows that dual infection is not so uncommon in modern endemic areas, it has been also reported from throughout the world32. Toll-like receptors (TLRs) are an essential family of innate immune pattern recognition receptors which plays a pivotal role in host defence against
RI PT
microbes, and particularly mycobacteria such as tuberculosis and leprae. Several disease association studies have revealed a protective role for the deficient TLR1 I602S (rs5743618) variant against the development of both clinical leprosy and tuberculosis.
SC
Conclusion
Elucidating the role of genetic susceptibility is critical to improving the health system. The further challenge is to stratify human populations for risk of infectious disease. Characterizing
M AN U
mycobacterial lineages from the earliest Old World human remains is crucial to identify the types of circulating strains and assess whether the increase in prevalence was due to the spread of new strains or not.
High-throughput whole genome sequencing is a very promising approach improving resolution for population-based studies. First it makes possible the estimation of the mutation rate of M. tuberculosis within host as 0.1/Mb/year in some lineages far higher than suspected
TE D
(latent period)33. Secondly, it gives too the opportunity to identify the range of strains within persistent patients. Investigating at a fine scale the diversity of genotypes within host is a good way to understand the evolutionary dynamics involved in disease progression. Third, this tool
EP
gives the opportunity to look for and to identify multi-loci combination of variants and to define population-specific genetic profiles, TB strain-dependant; it is obvious that different
AC C
loci determine or modulate susceptibility to tuberculosis. A recent study using a wholegenome approach identified gene sets enriched for signal of positive selection: they are involved in different immune pathways such as Il-6 signaling pathway and cytokine-cytokine receptor interaction34.
A large survey on primate samples from all over the world testing for the presence of M. tuberculosis will help to understand the relationship between strains found in humans and nonhuman primates. The comparison of humans and primates gives no evidence of enrichment in immunity-related genes, among genes that have been selected in the human lineage. Probably, adaptive changes in the gene regulation occurred. Among the various environmental factors that acted as selective pressure, pathogen load has been proposed to have a strong influence and to have shaped some regions of our 9
ACCEPTED MANUSCRIPT genome35,36: it is the case for HLA genes. A recent analysis gives a more nuanced conclusion concerning the level of influence and shows distinct evolutionary strategies for HLA-A, -B, -C and HLA-DRB1 (balancing selection) and HLA-DQA1 and –DQB1 genes (purifying selection) to provide efficient protection in pathogen-rich environment37. Humans have been confronted over time to pathogens. It means that past epidemics and pathogens have left strong
RI PT
marks on human (and primate) genomes. We still need to identify these marks and find what kinds of pathogens have produced a selective pressure on our genome.
As we can see, a wide range of factors influences TB epidemics (Figure 2). Tuberculosis still kills million of people all around the world, despite the fact it is a curable infectious
SC
disease. The challenge is to adopt a multidisciplinary approach to control it. This integrative approach is essential to understanding the evolution of a specific pathogen over a long-time period in the context of the human evolution, pathogen community and cultural and societal
M AN U
changes. It will impact our concepts of the evolution of infectious diseases and will amend the practice of public health in their control.
References
TE D
1. Global Tuberculosis Report 2012. World Health Organization. WHO Library Cataloguing-in-Publication Data. NLM classification: WF 300. 2. Brosch R, Gordon SV, Marmiesse M, Brodin P, Buchrieser C, Eiglmeier K, Garnier T, Gutierrez C, Hewinson G, Kremer K, Parsons LM, Pym AS, Samper S, van Soolingen
EP
D, Cole ST. A new evolutionary scenario for the Mycobacterium tuberculosis complex. Proc Natl Acad Sci U S A. 2002;99:3684-9
AC C
3. Hershkovitz I, Donoghue HD, Minnikin DE, Besra GS, Lee OY, Gernaey AM, Galili E, Eshed V, Greenblatt CL, Lemma E, Bar-Gal GK, Spigelman M Detection and molecular characterization of 9,000-year-old Mycobacterium tuberculosis from a Neolithic settlement in the Eastern Mediterranean. PLoS One. 2008;3:e3426, doi: 10.1371/journal.pone.0003426. 4. Zink AR, Sola C, Reischl U, Grabner W, Rastogi N, Wolf H, Nerlich AG. Characterization of Mycobacterium tuberculosis complex DNAs from Egyptian mummies by spoligotyping. J Clin Microbiol. 2003;41:359-67.
10
ACCEPTED MANUSCRIPT 5. Nerlich AG, Lösch S. Paleopathology of human tuberculosis and the potential role of climate.
Interdiscip
Perspect
Infect
Dis.
2009;2009:437187.
doi:
10.1155/2009/437187. 6. Zink AR, Molnár E, Motamedi N, Pálfy G, Marcsik A, Nerlich AG. Molecular history of tuberculosis from ancient mummies and skeletons. Int. J Osteoarchaeology
7. Taylor GM, Murphy E,
Hopkins R,
RI PT
2007;17 :380–391. Rutland P, Chistov Y.
First report of
Mycobacterium bovis DNA in human remains from the Iron Age. Microbiology 2007;153:1243-1249.
SC
8. Mackowiak PA, Blos VT, Aguilar M, Buikstra JE. On the Origin of American Tuberculosis. Clin Infect Dis. 2005;41: 515-518.
9. Salie M, van der Merwe L, Möller M, Daya M, van der Spuy GD, van Helden PD,
M AN U
Martin MP, Gao XJ, Warren RM, Carrington M, Hoal EG. Associations Between Human Leukocyte Antigen Class I Variants and the Mycobacterium tuberculosis Subtypes Causing Disease. J Infect Dis. 2013. doi: 10.1093/infdis/jit443. 10. Andraos C, Koorsen G, Knight JC, Bornman L. Vitamin D receptor gene methylation is associated with ethnicity, tuberculosis, and TaqI polymorphism. Hum Immunol.
TE D
2011;72: 262-268.
11. Liu Y, Wang X, Jiang J, Cao Z, Yang B, Cheng X. Modulation of T cell cytokine production by miR-144* with elevated expression in patients with pulmonary tuberculosis. Mol Immunol. 2011;48:1084-1090.
EP
12. Wang C, Yang S, Sun G, Tang X, Lu S, Neyrolles O, Gao Q. Comparative miRNA expression profiles in individuals with latent and active tuberculosis. PLoS One. 2011;
AC C
6:e25832.
13. Reed MB, Pichler VK, McIntosh F, Mattia A, Fallow A, Masala S, Domenech P, Zwerling A, Thibert L, Menzies D, Schwartzman K, Behr MA. Major Mycobacterium tuberculosis lineages associate with patient country of origin. J Clin Microbiol.
2009;47:1119-28. doi: 10.1128/JCM.02142-08.
14. Gagneux S, DeRiemer K, Van T, Kato-Maeda M, de Jong BC, Narayanan S, Nicol M, Niemann S, Kremer K, Gutierrez MC, Hilty M, Hopewell PC, Small PM. Variable host-pathogen compatibility in Mycobacterium tuberculosis. Proc Natl Acad Sci USA. 2006;103:2869-73. 15. Guernier V, Hochberg ME, Guégan JF. Ecology drives the worldwide distribution of human diseases. PLoS Biol. 2004;2:e141. 11
ACCEPTED MANUSCRIPT 16. Barnes I, Duda A, Pybus OG, Thomas MG. Ancient urbanization predicts genetic resistance to tuberculosis. Evolution. 2011;65:842-848. 17. Ioana M,, Ferwerda B,, Plantinga TS, Stappers M, Oosting M, McCall M,, Cimpoeru A, Burada F, Panduru N, Sauerwein R, Doumbo O, van der Meer JWM, van Crevel R, .Joosten LAB, Netea MG. Different Patterns of Toll-Like Receptor 2
RI PT
Polymorphisms in Populations of Various Ethnic and Geographic Origins Infect. Immun. 2012 ;80: 1917-1922
18. Möller M, De Wit E, Hoal EG. Past, present and future directions in human genetic susceptibility to tuberculosis. FEMS Immunol Med Microbiol. 2010 ;58:3-26. doi:
SC
10.1111/j.1574-695X.2009.00600.x.
19. Balamurugan A, Sharma SK, Mehra NK. Human leukocyte antigen class I supertypes influence susceptibility and severity of tuberculosis. J Infect Dis. 2004;189:805-11.
M AN U
20. Intemann CD, Thye T, Niemann S, Browne EN, Amanua Chinbuah M, Enimil A, Gyapong J, Osei I, Owusu-Dabo E, Helm S, Rüsch-Gerdes S, Horstmann RD, Meyer CG. Autophagy gene variant IRGM -261 T contributes to protection from tuberculosis caused by Mycobacterium tuberculosis but not by M. africanum strains. PLoS Pathog 2009;5:e1000577. doi: 10.1371/journal.ppat.1000577.
TE D
21. van Crevel R, Parwati I, Sahiratmadja E, Marzuki S, Ottenhoff TH, Netea MG, van der Ven A, Nelwan RH, van der Meer JW, Alisjahbana B, van de Vosse E. Infection with Mycobacterium
tuberculosis
Beijing
genotype
strains
is
associated
with
polymorphisms in SLC11A1/NRAMP1 in Indonesian patients with tuberculosis. J
EP
Infect Dis 2009;200:1671-1674. doi: 10.1086/648477. 22. Caws M, Thwaites G, Dunstan S, Hawn TR, Lan NT, Thuong NT, Stepniewska K,
AC C
Huyen MN, Bang ND, Loc TH, Gagneux S, van Soolingen D, Kremer K, van der Sande M, Small P, Anh PT, Chinh NT, Quy HT, Duyen NT, Tho DQ, Hieu NT, Torok E, Hien TT, Dung NH, Nhu NT, Duy PM, van Vinh Chau N, Farrar J. The influence of host and bacterial genotype on the development of disseminated disease with Mycobacterium tuberculosis. PLoS Pathog. 2008;4:e1000034. doi: 10.1371.
23. Hershberg R, Lipatov M, Small PM, Sheffer H, Niemann S, Homolka S, Roach JC, Kremer K, Petrov DA, Feldman MW, Gagneux S. High functional diversity in Mycobacterium tuberculosis driven by genetic drift and human demography. PLoS Biol. 2008;6:e311. doi: 10.1371/journal.pbio.0060311. 24. Alland D, Lacher DW, Hazbon MH, Motiwala AS, Qi W, Fleischmann RD, Whittam TS. 2007. Role of large sequence polymorphisms (LSPs) in generating genomic 12
ACCEPTED MANUSCRIPT diversity among clinical isolates of Mycobacterium tuberculosis and the utility of LSPs in phylogenetic analysis. J Clin Microbiol 2007;45: 39–46. 25. Namouchi A, Didelot X, Schöck U, Gicquel B, Rocha EPC. After the bottleneck: Genome-wide diversification of the Mycobacterium tuberculosis complex by mutation, recombination, and natural selection Genome Res. 2012;22:721-734.
RI PT
26. Comas I, Chakravarti J, Small PM, Galagan J, Niemann S, Kremer K, Ernst JD, Gagneux S. Human T cell epitopes of Mycobacterium tuberculosis are evolutionarily hyperconserved. Nat Genet. 2010;42:498-503. doi: 10.1038/ng.590.
27. Falush D, Wirth T, Linz B, Pritchard JK, Stephens M, Kidd M, Blaser MJ, Graham
SC
DY, Vacher S, Perez-Perez GI, Yamaoka Y, Mégraud F, Otto K, Reichard U, Katzowitsch E, Wang X, Achtman M, Suerbaum S. Traces of human migrations in Helicobacter pylori populations. Science 2003;299:1582-1585.
M AN U
28. El Baghdadi J, Grant AV, Sabri A, El Azbaoui S, Zaidi H, Cobat A, Schurr E, BoissonDupuis S, Casanova JL, Abel L. Human genetics of tuberculosis. Pathol Biol (Paris). 2013;61:11-16. doi: 10.1016/j.patbio.2013.01.004.
29. Fenner L, Egger M, Bodmer T, Furrer H, Ballif M, Battegay M, Helbling P, Fehr J, Gsponer T, Rieder HL, Zwahlen M, Hoffmann M, Bernasconi E, Cavassini M, Calmy
TE D
A, Dolina M, Frei R, Janssens JP, Borrell S, Stucki D, Schrenzel J, Böttger EC, Gagneux S; Swiss HIV Cohort and Molecular Epidemiology of Tuberculosis Study Groups. HIV infection disrupts the sympatric host-pathogen relationship in human tuberculosis. PLoS Genet. 2013; 9:e1003318. doi: 10.1371/journal.pgen.1003318.
EP
30. Round JL, Mazmanian. SK.The gut microbiota shapes intestinal immune responses during health and disease. Nature Reviews Immunology 2009; 9, 313-323
AC C
doi:10.1038/nri2515.
31. Donoghue HD, Marcsik A, Matheson C, Vernon K, Nuorala E, Molto JE, Greenblatt CL, Spigelman M. Co-infection of Mycobacterium tuberculosis and Mycobacterium
leprae in human archaeological samples: a possible explanation for the historical decline of leprosy. Proc Biol Sci. 2005;272:389-394.
32. Rajagopala S, Devaraj U, D’Souza, G V.V., Aithal VV. Co-infection with M. tuberculosis and M. Leprae case report and systematic Review. J Mycobac Dis. 2012;2:4. http://dx.doi.org/10.4172/2161-1068.1000118. 33. Ford CB, Shah RR, Maeda MK, Gagneux S, Murray MB, Cohen T, Johnston JC, Gardy J, Lipsitch M, Fortune SM. Mycobacterium tuberculosis mutation rate estimates
13
ACCEPTED MANUSCRIPT from different lineages predict substantial differences in the emergence of drugresistant tuberculosis. Nat Genet. 2013;45:784-90. doi: 10.1038/ng.2656. 34. Daub JT, Hofer T, Cutivet E, Dupanloup I, Quintana-Murci L, Robinson-Rechavi M, Excoffier L. Evidence for polygenic adaptation to pathogens in the human genome. Mol Biol Evol. 2013;30:1544-1558. doi: 10.1093/molbev/mst080.
RI PT
35. Prugnolle F, Manica A, Charpentier M, Guégan JF, Guernier V, Balloux F. Pathogendriven selection and worldwide HLA class I diversity. Curr Biol. 2005;15:1022-1027. 36. Qutob N, Balloux F, Raj T, Liu H, Marion de Procé S, Trowsdale J, Manica A. Signatures of historical demography and pathogen richness on MHC class I genes.
SC
Immunogenetics. 2012;64:165-175. doi: 10.1007/s00251-011-0576-y.
37. Sanchez-Mazas A, Lemaître JF, Currat M. Distinct evolutionary strategies of human leucocyte antigen loci in pathogen-rich environments. Phil. Trans. R. Soc. B
AC C
EP
TE D
M AN U
2012;367:830-839. doi: 10.1098/rstb.2011.0312.
14
ACCEPTED MANUSCRIPT Figure 1. Distribution of the main LSP-defined TB lineages by geographic origin of the patients cumulating data from Reed et al.13 and Gagneux et al.14. The 5 different sizes of the pie charts correspond to the number of patients i.e. starting from the largest size to the smallest size : n= ranging from 379 to 257; n ranging from 108 to 80; n ranging from 52 to 43; n
AC C
EP
TE D
M AN U
SC
RI PT
ranging from 32 to 19; n <10.
15
ACCEPTED MANUSCRIPT Figure 2. Diagram of the multiple factors involved (socio-economic, cultural, demographic, genetic) in tuberculosis epidemics. A more integrative approach is necessary to fight the
AC C
EP
TE D
M AN U
SC
RI PT
burden of tuberculosis.
16
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT