Polymorphism of genes associated with infectious lung diseases in Northern Asian populations and in patients with community-acquired pneumonia

The innate Iнн\mmune system is the first to respond to invading pathogens. It is responsible for invader recognition, immune-cell recruitment, adaptive-immunity activation, and regulation of inflammation intensity. Previously, two single-nucleotide polymorphisms of innate-immunity genes – rs5743708 (Arg753Gln) of the TLR2 gene and rs8177374 (Ser180Leu) of the TIRAP gene – have been shown to be associated with both pneumonia and tuberculosis in humans, but the data are contradictory among different ethnic groups. It has also been reported that rs10902158 at the PKP3-SIGGIR-TMEM16J genetic locus belongs to a haplotype race-specifically associated with tuberculosis. Meanwhile, a gradient of its frequency is observed in Asia. The aim of this work was to assess the effect of selection for the genotypes of the above-mentioned SNPs on the gene pools of populations living in harsh climatic conditions that contribute to the development of infectious lung diseases. We estimated the prevalence of these variants in white and Asian (Chukchis and Yakuts) population samples from Northern Asia and among patients with community-acquired pneumonia (CAP). Carriage of the rs5743708 A allele was found to predispose to severe CAP (odds ratio 2.77, p = 0.021), whereas the GG/CT genotype of rs5743708/rs8177374 proved to be protective against it (odds ratio 0.478, p = 0.022) in white patients. No association of rs10902158 with CAP (total or severe) was found among whites. Stratification of CAP by causative pathogen may help eliminate the current discrepancies between different studies. No significant difference in rs5743708 or rs8177374 was found between adolescent and long-lived white samples. Carriage of the alleles studied is probably not associated with predisposition to longevity among whites in Siberia. Both white and Asian populations studied were different from Western European and East Asian populations in the variants’ prevalence. The frequency of the rs8177374 T (Ser180Leu) variant was significantly higher in the Chukchi sample (p = 0, χ² = 63.22) relative to the East Asian populations. This result may confirm the hypothesis about the selection of this allele in the course of human migration into areas with unfavorable climatic conditions.

1. Aguilera E.R., Lenz L.L. Inflammation as a modulator of host susceptibility to pulmonary influenza, pneumococcal, and co-infections. Front. Immunol. 2020;11:105. DOI 10.3389/fimmu.2020.00105.

2. Aibana O., Huang C.C., Aboud S., Arnedo-Pena A., Becerra M.C., Bellido-Blasco J.B., Bhosale R., Calderon R., Chiang S., Contreras C., Davaasambuu G., Fawzi W.W., Franke M.F., Galea J.T., Garcia-Ferrer D., Gil-Fortuño M., Gomila-Sard B., Gupta A., Gupte N., Hussain R., Iborra-Millet J., Iqbal N.T., Juan-Cerdán J.V., Kinikar A., Lecca L., Mave V., Meseguer-Ferrer N., Montepiedra G., Mugusi F.M., Owolabi O.A., Parsonnet J., Roach-Poblete F., Romeu-García M.A., Spector S.A., Sudfeld C.R., Tenforde M.W., Togun T.O., Yataco R., Zhang Z., Murray M.B. Vitamin D status and risk of incident tuberculosis disease: a nested case-control study, systematic review, and individual-participant data meta-analysis. PLoS Med. 2019;16(9):e1002907. DOI 10.1371/journal.pmed.1002907.

3. Arango Duque G., Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases. Front. Immunol. 2014;5:491. DOI 10.3389/fimmu.2014.00491.

4. Barbalat R., Lau L., Locksley R.M., Barton G.M. Toll-like receptor 2 on inflammatory monocytes induces type I interferon in response to viral but not bacterial ligands. Nat. Immunol. 2009;10(11):12001207. DOI 10.1038/ni.1792.

5. Basith S., Manavalan B., Govindaraj R.G., Choi S. In silico approach to inhibition of signaling pathways of Toll-like receptors 2 and 4 by ST2L. PLoS One. 2011;6(8):e23989. DOI 10.1371/journal.pone.0023989.

6. Bernard N.J., O’Neill L.A. Mal, more than a bridge to MyD88. IUBMB Life. 2013;65(9):777-786. DOI 10.1002/iub.1201.

7. Bonham K.S., Orzalli M.H., Hayashi K., Wolf A.I., Glanemann C., Weninger W., Iwasaki A., Knipe D.M., Kagan J.C. A promiscuous lipid-binding protein diversifies the subcellular sites of tolllike receptor signal transduction. Cell. 2014;156(4):705-716. DOI 10.1016/j.cell.2014.01.019.

8. Bystritskaya E.V., Bilichenko T.N. An analysis of pneumonia morbidity in adults and children at Russian Federation, 2010–2014. Pulmonologiya = Russian Pulmonology. 2017;27(2):173-178. DOI 10.18093/0869-0189-2017-27-2-173-178. (in Russian)

9. Caws M., Thwaites G., Dunstan S., Hawn T.R., Lan N.T., Thuong N.T., Stepniewska K., Huyen M.N., Bang N.D., Loc T.H., Gagneux S., van Soolingen D., Kremer K., van der Sande M., Small P., Anh P.T., Chinh N.T., Quy H.T., Duyen N.T., Tho D.Q., Hieu N.T., Torok E., Hien T.T., Dung N.H., Nhu N.T., Duy P.M., van Vinh Chau N., FarrarJ. The influence of host and bacterial genotype on the development of disseminated disease with Mycobacterium tuberculosis. PLoS Pathog. 2008;4(3):e1000034. DOI 10.1371/journal.ppat.1000034.

10. Choi S.H., Hong S.B., Ko G.B., LeeY., Park H.J., Park S.Y., Moon S.M., Cho O.H., Park K.H., Chong Y.P., Kim S.H., Huh J.W., Sung H., Do K.H., Lee S.O., Kim M.N., Jeong J.Y., Lim C.M., Kim Y.S., Woo J.H., Koh Y. Viral infection in patients with severe pneumonia requiring intensive care unit admission. Am. J. Respir. Crit. Care Med. 2012;186(4):325-332. DOI 10.1164/rccm.201112-2240OC.

11. Ferwerda B., Alonso S., Banahan K., McCall M.B.B., GiamarellosBourboulis E.J., Ramakers B.P., Mouktaroudi M., Fain P.R., Izagirre N., Syafruddin D., Cristea T., Mockenhaupt F.P., Troye-Blomberg M., Kumpf O., Maiga B., Dolo A., Doumbo O., Sundaresan S., Bedu-Addo G., van CrevelR., Hamann L., Oh D.-Y., SchumannR.R., Joosten L.A.B., de la Rúa C., Sauerwein R., Drenth J.P.H., Kullberg B.-J., van der Ven A.J.A.M., Hill A.V., Pickkers P., van der Meer J.W.M., O’Neill L.A.J., Netea M.G. Functional and genetic evidence that the Mal/TIRAP allele variant 180L has been selected by providing protection against septic shock. Proc. Natl. Acad. Sci. USA. 2009;106(25):10272-10277. DOI 10.1073/pnas.0811273106.

12. Gopalakrishnan A., Salgame P. Toll-like receptor 2 in host defense against Mycobacterium tuberculosis: to be or not to be – that is the question. Curr. Opin. Immunol. 2016;42:76-82. DOI 10.1016/j.coi.2016.06.003.

13. Guo X.G., Xia Y. The rs5743708 gene polymorphism in the TLR2 gene contributes to the risk of tuberculosis disease. Int. J. Clin. Exp. Pathol. 2015;8(9):11921-11928.

14. Gupta A., Montepiedra G., Gupte A., Zeldow B., Jubulis J., Detrick B., Violari A., Madhi S., Bobat R., Cotton M., Mitchell С., Spector S., IMPAACT NWCS113 and P1041 Study Team. Low vitamin-D levels combined with PKP3-SIGIRR-TMEM16J host variants is associated with tuberculosis and death in HIV-infected and -exposed infants. PLoS One. 2016;11(2):e0148649. DOI 10.1371/journal.pone.0148649.

15. Gurjar M., Raychaudhuri K., Mahadik S., Reddy D., Atak A., Shetty T., Rao K., Karkhanis M.S., Gosavi P., Sehgal L., Gupta S., Dalal S.N. Plakophilin3 increases desmosome assembly, size and stability by increasing expression of desmocollin2. Biochem. Biophys. Res. Commun. 2018;495(1):768-774. DOI 10.1016/j.bbrc.2017.11.085.

16. Harding C.V., Boom W.H. Regulation of antigen presentation by Mycobacterium tuberculosis: a role for Toll-like receptors. Nat. Rev. Microbiol. 2010;8(4):296-307. DOI 10.1038/nrmicro2321.

17. Hong H.L., Hong S.B., Ko G.B., Huh J.W., Sung H., Do K.H., Kim S.H., Lee S.O., Kim M.N., Jeong J.Y., Lim C.M., Kim Y.S., Woo J.H., Koh Y., Choi S.H. Viral infection is not uncommon in adult patients with severe hospital-acquired pneumonia. PLoS One. 2014;9(4):e95865. DOI 10.1371/journal.pone.0095865.

18. Horne D.J., Randhawa A.K., Chau T.T., Bang N.D., Yen N.T., Farrar J.J., Dunstan S.J., Hawn T.R. Common polymorphisms in the PKP3-SIGIRR-TMEM16J gene region are associated with susceptibility to tuberculosis. J. Infect Dis. 2012;205(4):586-594. DOI 10.1093/infdis/jir785.

19. Hu L., Tao H., Tao X., Tang X., Xu C. TLR2 Arg753Gln gene polymorphism associated with tuberculosis susceptibility: an updated meta-analysis. Biomed. Res. Int. 2019;2628101. DOI 10.1155/2019/2628101.

20. Jin M.S., Kim S.E., Heo J.Y., Lee M.E., Kim H.M., Paik S.G., Lee H., Lee J.O. Crystal structure of the TLR1–TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell. 2007;130(6):10711082. DOI 10.1016/j.cell.2007.09.008.

21. Kawai T., Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 2010; 11(5):373-384. DOI 10.1038/ni.1863.

22. Khor C.C., Chapman S.J., Vannberg F.O., Dunne A., Murphy C., Ling E.Y., Frodsham A.J., Walley A.J., Kyrieleis O., Khan A., Aucan C., Segal S., Moore C.E., Knox K., Campbell S.J., Lienhardt C., Scott A., Aaby P., Sow O.Y., Grignani R.T., Sillah J., Sirugo G., Peshu N., Williams T.N., Maitland K., Davies R.J., Kwiatkowski D.P., Day N.P., Yala D., Crook D.W., Marsh K., Berkley J.A., O’Neill L.A., Hill A.V. A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. Nat. Genet. 2007;39(4):523528. DOI 10.1038/ng1976.

23. Kumar V. Inflammation research sails through the sea of immunology to reach immunometabolism. Int. Immunopharmacol. 2019;73:128145. DOI 10.1016/j.intimp.2019.05.002.

24. Kumpf O., Giamarellos-Bourboulis E.J., Koch A., Hamann L., Mouktaroudi M., Oh D.Y., Latz E., Lorenz E., Schwartz D.A., Ferwerda B., Routsi C., Skalioti C., Kullberg B.J., van der Meer J.W., Schlag P.M., Netea M.G., Zacharowski K., Schumann R.R. Influence of genetic variations in TLR4 and TIRAP/Mal on the course of sepsis and pneumonia and cytokine release: an observational study in three cohorts. Crit. Care. 2010;14(3):R103. DOI 10.1186/cc9047.

25. Lancioni C.L., Li Q., Thomas J.J., Ding X., Thiel B., Drage M.G., Pecora N.D., ZiadyA.G., Shank S., Harding C.V., Boom W.H., Rojas R.E. Mycobacterium tuberculosis lipoproteins directly regulate human memory CD4+ T cell activation via Toll-like receptors 1 and 2. Infect. Immun. 2011;79(2):663-673. DOI 10.1128/IAI.00806-10.

26. Li J., Lee D.S., Madrenas J. Evolving bacterial envelopes and plasticity of TLR2-dependent responses: basic research and translational opportunities. Front. Immunol. 2013;4:347. DOI 10.3389/fimmu.2013.00347.

27. Lim W.S., van der Eerden M.M., Laing R., Boersma W.G., Karalus N., Town G.I., Lewis S.A., Macfarlane J.T. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax. 2003;58:377-382. DOI 10.1136/thorax.58.5.377.

28. Liu C.H., Liu H., Ge B. Innate immunity in tuberculosis: host defense vs pathogen evasion. Cell Mol. Immunol. 2017;14(12):963-975. DOI 10.1038/cmi.2017.88.

29. Liu Y., Li J.Y., Chen S.T., Huang H.R., Cai H. The rLrp of Mycobacterium tuberculosis inhibits proinflammatory cytokine production and downregulates APC function in mouse macrophages via a TLR2mediated PI3K/Akt pathway activation-dependent mechanism. Cell. Mol. Immunol. 2016;13(6):729-746. DOI 10.1038/cmi.2015.58.

30. McCullers J.A. The co-pathogenesis of influenza viruses with bacteria in the lung. Nat. Rev. Microbiol. 2014;12(4):252-262. DOI 10.1038/nrmicro3231.

31. Miao R., Li J., Sun Z., Xu F., Shen H. Meta-analysis on the association of TIRAP S180L variant and tuberculosis susceptibility. Tuberculosis (Edinb.). 2011;91(3):268-272. DOI 10.1016/j.tube.2011.01.006.

32. Moens L., Verhaegen J., Pierik M., Vermeire S., De Boeck K., Peetermans W.E., Bossuyt X. Toll-like receptor 2 and Toll-like receptor 4 polymorphisms in invasive pneumococcal disease. Microbes Infect. 2007;9(1):15-20. DOI 10.1016/j.micinf.2006.10.002.

33. Moldoveanu B., Otmishi P., Jani P., Walker J., Sarmiento X., Guardiola J., Saad M., Yu J. Inflammatory mechanisms in the lung. J. Inf lamm. Res. 2009;2:1-11.

34. Molgora M., Barajon I., Mantovani A., Garlanda C. Regulatory role of IL-1R8 in immunity and disease. Front. Immunol. 2016;7:149. DOI 10.3389/fimmu.2016.00149.

35. Morris D.E., Cleary D.W., Clarke S.C. Secondary bacterial infections associated with influenza pandemics. Front. Microbiol. 2017;8:1041. DOI 10.3389/fmicb.2017.01041.

36. Naderi M., Hashemi M., Pourmontaseri Z., Eskandari-Nasab E., Bahari G., Taheri M. TIRAP rs8177374 gene polymorphism increased the risk of pulmonary tuberculosis in Zahedan, southeast Iran. Asian Pac. J. Trop. Med. 2014;7(6):451-455. DOI 10.1016/S19957645(14)60073-0.

37. Nagpal K., Plantinga T.S., Wong J., Monks B.G., Gay N.J., Netea M.G., Fitzgerald K.A., Golenbock D.T. A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP results in loss of MyD88 binding and reduced TLR2/TLR4 signaling. J. Biol. Chem. 2009;284(38):2574225748. DOI 10.1074/jbc.M109.014886.

38. Narayanan K.B., Park H.H. Toll/interleukin-1 receptor (TIR) domainmediated cellular signaling pathways. Apoptosis. 2015;20(2):196209. DOI 10.1007/s10495-014-1073-1.

39. Ozinsky A., Underhill D.M., Fontenot J.D., Hajjar A.M., Smith K.D., Wilson C.B., Schroeder L., Aderem A. The repertoire forpattern recognition of pathogens by the innate immune system is defined by cooperation between Toll-like receptors. Proc. Natl. Acad. Sci. USA. 2000;97:13766-13771. DOI 10.1073/pnas.250476497.

40. Panda A.K., Das B.K., Panda A., Tripathy R., Pattnaik S.S., Mahto H., Pied S., Pathak S., Sharma S., Ravindran B. Heterozygous mutants of TIRAP (S180L) polymorphism protect adult patients with Plasmodium falciparum infection against severe disease and mortality. Infect. Genet. Evol. 2016;43:146-150. DOI 10.1016/j.meegid.2016.04.035.

41. Patarčić I., Gelemanović A., Kirin M., Kolčić I., Theodoratou E., Baillie K.J., de Jong M.D., Rudan I., Campbell H., Polašek O. The role of host genetic factors in respiratory tract infectious diseases: systematic review, meta-analyses and field synopsis. Sci. Rep. 2015; 5:16119. DOI 10.1038/srep16119.

42. Price R.H.M., Graham C., Ramalingam S. Association between viral seasonality and meteorological factors. Sci. Rep. 2019;9(1):929. DOI 10.1038/s41598-018-37481-y.

43. Raieli S., Trichot C., Korniotis S., Pattarini L., Soumelis V. TLR1/2 orchestrate human plasmacytoid predendritic cell response to gram + bacteria. PLoS Biol. 2019;17(4):e3000209. DOI 10.1371/journal.pbio.3000209.

44. Richardson E.T., Shukla S., Sweet D.R., Wearsch P.A., Tsichlis P.N., Boom W.H., Harding C.V. Toll-like receptor 2-dependent extracellular signal-regulated kinase signaling in Mycobacterium tuberculosis-infected macrophages drives anti-inflammatory responses and inhibits Th1 polarization of responding T cells. Infect. Immun. 2015; 83(6):2242-2254. DOI 10.1128/IAI.00135-15.

45. Sambrook J., Russell D.W. Purification of nucleic acids by extraction with phenol:chloroform. Cold Spring Harbor Protoc. 2006;2006(1): 4455. DOI 10.1101/pdb.prot4455.

46. Schröder N.W.J., Diterich I., Zinke A., Eckert J., Draing C., von Baehr V., Hassler D., Priem S., Hahn K., Michelsen K.S., Hartung T., Burmester G.R., Göbel U.B., Hermann C., Schumann R.R. Heterozygous Arg753Gln polymorphism of human TLR-2 impairs immune activation by Borrelia burgdorferi and protects from late stage Lyme disease. J. Immunol. 2005;175(4):2534-2540. DOI 10.4049/jimmunol.175.4.2534.

47. Self W.H., Balk R.A., Grijalva C.G., Williams D.J., Zhu Y., Anderson E.J., Waterer G.W., Courtney D.M., Bramley A.M., Trabue C., Fakhran S., Blaschke A.J., Jain S., Edwards K.M., Wunderink R.G. Procalcitonin as a marker of etiology in adults hospitalized with community-acquired pneumonia. Clin. Infect. Dis. 2017;65(2):183190. DOI 10.1093/cid/cix317.

48. Shukla S., Richardson E.T., Drage M.G., Boom W.H., Harding C.V. Mycobacterium tuberculosis lipoprotein and lipoglycan binding to Toll-like receptor 2 correlates with agonist activity and functional outcomes. Infect. Immun. 2018;86(10). pii: e00450-18. DOI 10.1128/IAI.00450-18.

49. Siebert J.N., Hamann L., Verolet C.M., Gameiro C., Grillet S., Siegrist C.A., Posfay-Barbe K.M. Toll-interleukin 1 receptor domain-containing adaptor protein 180L single-nucleotide polymorphism is associated with susceptibility to recurrent pneumococcal lower respiratory tract infections in children. Front. Immunol. 2018; 9:1780. DOI 10.3389/fimmu.2018.01780.

50. Smelaya T.V., Belopolskaya O.B., Smirnova S.V., Kuzovlev A.N., Moroz V.V., Golubev A.M., Pabalan N.A., Salnikova L.E. Genetic dissection of host immune response in pneumonia development and progression. Sci. Rep. 2016;6:35021. DOI 10.1038/srep35021.

51. Takeda K., Akira S. Toll-like receptors. Curr. Protoc. Immunol. 2015; 109:14.12.1-14.12.10. DOI 10.1002/0471142735.im1412s109.

52. Tapader R., Bose D., Dutta P., Das S., Pal A. SslE (YghJ), a cell-associated and secreted lipoprotein of neonatal septicemic Escherichia coli, induces Toll-like receptor 2-dependent macrophage activation and proinflammation through NF-kB and MAP kinase signaling. Infect. Immun. 2018;86(9):e00399-18. DOI 10.1128/IAI.00399-18.

53. Wilkinson R.J., Llewelyn M., Toossi Z., Patel P., Pasvol G., Lalvani A., Wright D., Latif M., Davidson R.N. Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study. Lancet. 2000;355(9204):618-621. DOI 10.1016/S0140-6736(99)02301-6.

54. Xiong Y., Song C., Snyder G.A., Sundberg E.J., Medvedev A.E. R753Q polymorphism inhibits Toll-like receptor (TLR) 2 tyrosine phosphorylation, dimerization with TLR6, and recruitment of myeloid differentiation primary response protein 88. J. Biol. Chem. 2012; 287(45):38327-38337. DOI 10.1074/jbc.M112.375493.

55. Zavyalova L.G., Denisova D.V., Simonova G.I., Orlov P.S., Voevoda M.I. Association of polymorphisms of genes FTO and TCF7L2 with cadiometabolic parameters of the adolescents in Siberia. Bulleten SO RAMN = Bulleten SB RAMS. 2011;31(5):5-13. (in Russian).