Advertisement

Recent advances on T-cell exhaustion in malaria infection

Review

Abstract

T-cell exhaustion reportedly leads to dysfunctional immune responses of antigen-specific T cells. Investigations have revealed that T cells expand into functionally defective phenotypes with poor recall/memory abilities to parasitic antigens. The exploitation of co-inhibitory pathways represent a highly viable area of translational research that has very well been utilized against certain cancerous conditions. Malaria, at times, evolve into a sustained chronic state where T cells express several co-inhibitory molecules (negative immune checkpoints) facilitating parasite escape and sub-optimal protective responses. Experimental evidence suggests that blockade of co-inhibitory molecules on T cells in malaria could result in the sustenance of protective responses together with dramatic parasite clearance. The role of several co-inhibitory molecules in malaria infection largely remain unclear, and here we discussed the potential applicability of co-inhibitory molecules in the management of malaria with a view to harness protective host responses against chronic disease and associated consequences.

Keywords

Malaria T cell immunity Immune exhaustion 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1.
    World Health Organization. World malaria report 2017. http://www.who.int/malaria/publications/world-malaria-report-2017/en/. Accessed 14 Mar 2018
  2. 2.
    Gething PW, Elyazar IRF, Moyes CL et al (2012) A long neglected world malaria map: Plasmodium vivax endemicity in 2010. PLoS Negl Trop Dis 6:e1814CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Schwartz L, Brown GV, Genton B, Moorthy VS (2012) A review of malaria vaccine clinical projects based on the WHO rainbow table. Malar J 11:11CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Tran TM, Li S, Doumbo S et al (2013) An intensive longitudinal cohort study of Malian children and adults reveals no evidence of acquired immunity to Plasmodium falciparum infection. Clin Infect Dis Off Publ Infect Dis Soc Am 57:40–47CrossRefGoogle Scholar
  5. 5.
    Evans CM, Jenner RG (2013) Transcription factor interplay in T helper cell differentiation. Br Funct Genom 12:499–511CrossRefGoogle Scholar
  6. 6.
    Stephens R, Langhorne J (2010) Effector memory Th1 CD4 T cells are maintained in a mouse model of chronic malaria. PLoS Pathog 6:e1001208CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Su Z, Stevenson MM (2002) IL-12 is required for antibody-mediated protective immunity against blood-stage Plasmodium chabaudi AS malaria infection in mice. J Immunol 168:1348–1355CrossRefPubMedGoogle Scholar
  8. 8.
    Muxel SM, Freitas do Rosário AP, Zago CA et al (2011) The spleen CD4+ T cell response to blood-stage Plasmodium chabaudi malaria develops in two phases characterized by different properties. PLoS One 6:e22434CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Jacobs P, Radzioch D, Stevenson MM (1996) In vivo regulation of nitric oxide production by tumor necrosis factor alpha and gamma interferon, but not by interleukin-4, during blood stage malaria in mice. Infect Immun 64:44–49PubMedPubMedCentralGoogle Scholar
  10. 10.
    McCall MBB, Roestenberg M, Ploemen I et al (2010) Memory-like IFN-γ response by NK cells following malaria infection reveals the crucial role of T cells in NK cell activation by P. falciparum. Eur J Immunol 40:3472–3477CrossRefPubMedGoogle Scholar
  11. 11.
    McCall MBB, Sauerwein RW (2010) Interferon-γ--central mediator of protective immune responses against the pre-erythrocytic and blood stage of malaria. J Leukoc Biol 88:1131–1143CrossRefPubMedGoogle Scholar
  12. 12.
    Podoba JE, Stevenson MM (1991) CD4+ and CD8+ T lymphocytes both contribute to acquired immunity to blood-stage Plasmodium chabaudi AS. Infect Immun 59:51–58PubMedPubMedCentralGoogle Scholar
  13. 13.
    Stephens R, Langhorne J (2006) Priming of CD4+ T cells and development of CD4+ T cell memory; lessons for malaria. Parasite Immunol 28:25–30CrossRefPubMedGoogle Scholar
  14. 14.
    Achtman AH, Bull PC, Stephens R, Langhorne J (2005) Longevity of the immune response and memory to blood-stage malaria infection. Curr Top Microbiol Immunol 297:71–102PubMedGoogle Scholar
  15. 15.
    Wipasa J, Xu H, Stowers A, Good MF (2001) Apoptotic deletion of Th cells specific for the 19-kDa carboxyl-terminal fragment of merozoite surface protein 1 during malaria infection. J Immunol 167:3903–3909CrossRefPubMedGoogle Scholar
  16. 16.
    Hirunpetcharat C, Good MF (1998) Deletion of Plasmodium berghei-specific CD4+ T cells adoptively transferred into recipient mice after challenge with homologous parasite. Proc Natl Acad Sci USA 95:1715–1720CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Xu H, Wipasa J, Yan H et al (2002) The mechanism and significance of deletion of parasite-specific CD4(+) T cells in malaria infection. J Exp Med 195:881–892CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Walther M, Tongren JE, Andrews L et al (2005) Upregulation of TGF-beta, FOXP3, and CD4+ CD25+ regulatory T cells correlates with more rapid parasite growth in human malaria infection. Immunity 23:287–296CrossRefPubMedGoogle Scholar
  19. 19.
    Minigo G, Woodberry T, Piera KA et al (2009) Parasite-dependent expansion of TNF receptor II-positive regulatory T cells with enhanced suppressive activity in adults with severe malaria. PLoS Pathog 5:e1000402CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Couper KN, Blount DG, Wilson MS et al (2008) IL-10 from CD4CD25Foxp3CD127 adaptive regulatory T cells modulates parasite clearance and pathology during malaria infection. PLoS Pathog 4:e1000004CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677–704CrossRefPubMedGoogle Scholar
  22. 22.
    Hofmeyer KA, Jeon H, Zang X (2011) The PD-1/PD-L1 (B7-H1) pathway in chronic infection-induced cytotoxic T lymphocyte exhaustion. J Biomed Biotechnol 2011:451694CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Okazaki T, Chikuma S, Iwai Y, Fagarasan S, Honjo T (2013) A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat Immunol 14:1212–1218CrossRefPubMedGoogle Scholar
  24. 24.
    Fuller MJ, Khanolkar A, Tebo AE, Zajac AJ (2004) Maintenance, loss, and resurgence of T cell responses during acute, protracted, and chronic viral infections. J Immunol 172:4204–4214CrossRefPubMedGoogle Scholar
  25. 25.
    Barber DL, Wherry EJ, Masopust D et al (2006) Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439:682–687CrossRefPubMedGoogle Scholar
  26. 26.
    Shankar EM, Che KF, Messmer D, Lifson JD, Larsson M (2011) Expression of a broad array of negative costimulatory molecules and Blimp-1 in T cells following priming by HIV-1 pulsed dendritic cells. Mol Med 17:229–240CrossRefPubMedGoogle Scholar
  27. 27.
    Che KF, Sabado RL, Shankar EM et al (2010) HIV-1 impairs in vitro priming of naïve T cells and gives rise to contact-dependent suppressor T cells. Eur J Immunol 40:2248–2258CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Saeidi A, Tien Tien VL, Al-Batran R et al (2015) Attrition of TCR Vα7.2+ CD161++ MAIT cells in HIV-tuberculosis co-infection is associated with elevated levels of PD-1 expression. PLoS One 10:e0124659CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Saeidi A, Chong YK, Yong YK et al (2015) Concurrent loss of co-stimulatory molecules and functional cytokine secretion attributes leads to proliferative senescence of CD8(+) T cells in HIV/TB co-infection. Cell Immunol 297:19–32CrossRefPubMedGoogle Scholar
  30. 30.
    Wherry EJ (2011) T cell exhaustion. Nat Immunol 12:492–499CrossRefPubMedGoogle Scholar
  31. 31.
    Yi JS, Cox MA, Zajac AJ (2010) T-cell exhaustion: characteristics, causes and conversion. Immunology 129:474–481CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    See J-X, Chandramathi S, Abdulla MA, Vadivelu J, Shankar EM (2017) Persistent infection due to a small-colony variant of Burkholderia pseudomallei leads to PD-1 upregulation on circulating immune cells and mononuclear infiltration in viscera of experimental BALB/c mice. PLoS Negl Trop Dis 11:e0005702CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Velu V, Titanji K, Zhu B et al (2009) Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 458:206–210CrossRefPubMedGoogle Scholar
  34. 34.
    Barathan M, Gopal K, Mohamed R et al (2015) Chronic hepatitis C virus infection triggers spontaneous differential expression of biosignatures associated with T cell exhaustion and apoptosis signaling in peripheral blood mononucleocytes. Apoptosis 20:466–480CrossRefPubMedGoogle Scholar
  35. 35.
    Yong YK, Tan HY, Saeidi A et al (2017) Decrease of CD69 levels on TCR Vα7.2+ CD4+ innate-like lymphocytes is associated with impaired cytotoxic functions in chronic hepatitis B virus-infected patients. Innate Immun 23:459–467CrossRefPubMedGoogle Scholar
  36. 36.
    Yong YK, Saeidi A, Tan HY et al (2018) Hyper-expression of PD-1 is associated with the levels of exhausted and dysfunctional phenotypes of circulating CD161++ TCR iVα7.2+ mucosal-associated invariant T (MAIT) cells in chronic hepatitis B virus infection. Front Immunol 9:472. https://www.frontiersin.org/articles/10.3389/fimmu.2018.00472/abstract
  37. 37.
    Doe HT, Kimura D, Miyakoda M, Kimura K, Akbari M, Yui K (2016) Expression of PD-1/LAG-3 and cytokine production by CD4(+) T cells during infection with plasmodium parasites. Microbiol Immunol 60:121–131CrossRefPubMedGoogle Scholar
  38. 38.
    Velu V, Shetty RD, Larsson M, Shankar EM (2015) Role of PD-1 co-inhibitory pathway in HIV infection and potential therapeutic options. Retrovirology 12:14CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Wherry EJ, Ahmed R (2004) Memory CD8 T-cell differentiation during viral infection. J Virol 78:5535–5545CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Jurado JO, Alvarez IB, Pasquinelli V et al (2008) Programmed death (PD)-1:PD-ligand 1/PD-ligand 2 pathway inhibits T cell effector functions during human tuberculosis. J Immunol 181:116–125CrossRefPubMedGoogle Scholar
  41. 41.
    Singh A, Mohan A, Dey AB, Mitra DK (2013) Inhibiting the programmed death 1 pathway rescues Mycobacterium tuberculosis-specific interferon γ-producing T cells from apoptosis in patients with pulmonary tuberculosis. J Infect Dis 208:603–615CrossRefPubMedGoogle Scholar
  42. 42.
    Beswick EJ, Pinchuk IV, Das S, Powell DW, Reyes VE (2007) Expression of the programmed death ligand 1, B7-H1, on gastric epithelial cells after Helicobacter pylori exposure promotes development of CD4+ CD25+ FoxP3+ regulatory T cells. Infect Immun 75:4334–4341CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Joshi T, Rodriguez S, Perovic V, Cockburn IA, Stäger S (2009) B7-H1 blockade increases survival of dysfunctional CD8(+) T cells and confers protection against Leishmania donovani infections. PLoS Pathog 5:e1000431CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Bhadra R, Gigley JP, Weiss LM, Khan IA (2011) Control of toxoplasma reactivation by rescue of dysfunctional CD8+ T-cell response via PD-1-PDL-1 blockade. Proc Natl Acad Sci USA 108:9196–9201CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Khandare AV, Bobade D, Deval M, Patil T, Saha B, Prakash D (2017) Expression of negative immune regulatory molecules, pro-inflammatory chemokine and cytokines in immunopathology of ECM developing mice. Acta Trop 172:58–63CrossRefPubMedGoogle Scholar
  46. 46.
    Villegas-Mendez A, Inkson CA, Shaw TN, Strangward P, Couper KN (2016) Long-lived CD4+ IFN-γ+ T cells rather than short-lived CD4+ IFN-γ+ IL-10+ T cells initiate rapid IL-10 production to suppress anamnestic T cell responses during secondary malaria infection. J Immunol 197:3152–3164CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Butler NS, Vaughan AM, Harty JT, Kappe SHI (2012) Whole parasite vaccination approaches for prevention of malaria infection. Trends Immunol 33(5):247–254CrossRefPubMedGoogle Scholar
  48. 48.
    Illingworth J, Butler NS, Roetynck S et al (2013) Chronic exposure to Plasmodium falciparum is associated with phenotypic evidence of B and T cell exhaustion. J Immunol 190:1038–1047CrossRefPubMedGoogle Scholar
  49. 49.
    Chandele A, Mukerjee P, Das G, Ahmed R, Chauhan VS (2011) Phenotypic and functional profiling of malaria-induced CD8 and CD4 T cells during blood-stage infection with Plasmodium yoelii. Immunology 132:273–286CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Hafalla JCR, Claser C, Couper KN et al (2012) The CTLA-4 and PD-1/PD-L1 inhibitory pathways independently regulate host resistance to plasmodium-induced acute immune pathology. PLoS Pathog 8:e1002504CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Zhang Y, Jiang Y, Wang Y et al (2015) Higher frequency of circulating PD-1(high) CXCR5(+)CD4(+) Tfh cells in patients with chronic schistosomiasis. Int J Biol Sci 11:1049–1055CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Karunarathne DS, Horne-Debets JM, Huang JX et al (2016) Programmed death-1 ligand 2-mediated regulation of the PD-L1 to PD-1 axis is essential for establishing CD4(+) T cell immunity. Immunity 45:333–345CrossRefPubMedGoogle Scholar
  53. 53.
    Horne-Debets JM, Faleiro R, Karunarathne DS et al (2013) PD-1 dependent exhaustion of CD8+ T cells drives chronic malaria. Cell Rep 5(5):1204–1213CrossRefPubMedGoogle Scholar
  54. 54.
    Linterman MA, Pierson W, Lee SK et al (2011) Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med 17:975–982CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Ames RY, Ting L-M, Gendlina I, Kim K, Macian F (2017) The transcription factor NFAT1 participates in the induction of CD4+ T cell functional exhaustion during Plasmodium yoelii infection. Infect Immun 85:e00364–e00317CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Gibson HM, Hedgcock CJ, Aufiero BM et al (2007) Induction of the CTLA-4 gene in human lymphocytes is dependent on NFAT binding the proximal promoter. J Immunol 179:3831–3840CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Oestreich KJ, Yoon H, Ahmed R, Boss JM (2008) NFATc1 regulates PD-1 expression upon T cell activation. J Immunol 181:4832–4839CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Liu T, Lu X, Zhao C, Fu X, Zhao T, Xu W (2015) PD-1 deficiency enhances humoral immunity of malaria infection treatment vaccine. Infect Immun 83:2011–2017CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Larsson M, Shankar EM, Che KF et al (2013) Molecular signatures of T-cell inhibition in HIV-1 infection. Retrovirology 10:31CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Walker LSK, Sansom DM (2011) The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat Rev Immunol 11:852–863CrossRefPubMedGoogle Scholar
  61. 61.
    Grosso JF, Jure-Kunkel MN (2013) CTLA-4 blockade in tumor models: an overview of preclinical and translational research. Cancer Immun 13:5PubMedPubMedCentralGoogle Scholar
  62. 62.
    Teft WA, Kirchhof MG, Madrenas J (2006) A molecular perspective of CTLA-4 function. Annu Rev Immunol 24:65–97CrossRefPubMedGoogle Scholar
  63. 63.
    Kaufmann DE, Walker BD (2009) PD-1 and CTLA-4 inhibitory cosignaling pathways in HIV infection and the potential for therapeutic intervention. J Immunol 182:5891–5897CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Kirman J, McCoy K, Hook S et al (1999) CTLA-4 blockade enhances the immune response induced by mycobacterial infection but does not lead to increased protection. Infect Immun 67:3786–3792PubMedPubMedCentralGoogle Scholar
  65. 65.
    Wherry EJ, Ha S-J, Kaech SM et al (2007) Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27(4):670–684CrossRefPubMedGoogle Scholar
  66. 66.
    Ye B, Liu X, Li X, Kong H, Tian L, Chen Y (2015) T-cell exhaustion in chronic hepatitis B infection: current knowledge and clinical significance. Cell Death Dis 6:e1694CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Schurich A, Khanna P, Lopes AR et al (2011) Role of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 on apoptosis-prone CD8 T cells in persistent hepatitis B virus infection. Hepatology 53:1494–1503CrossRefPubMedGoogle Scholar
  68. 68.
    Schlotmann T, Waase I, Jülch C et al (2000) CD4 alphabeta T lymphocytes express high levels of the T lymphocyte antigen CTLA-4 (CD152) in acute malaria. J Infect Dis 182:367–370CrossRefPubMedGoogle Scholar
  69. 69.
    Jacobs T, Graefe SEB, Niknafs S, Gaworski I, Fleischer B (2002) Murine malaria is exacerbated by CTLA-4 blockade. J Immunol 169:2323–2329CrossRefPubMedGoogle Scholar
  70. 70.
    Jacobs T, Plate T, Gaworski I, Fleischer B (2004) CTLA-4-dependent mechanisms prevent T cell induced-liver pathology during the erythrocyte stage of Plasmodium berghei malaria. Eur J Immunol 34:972–980CrossRefPubMedGoogle Scholar
  71. 71.
    Kurup SP, Obeng-Adjei N, Anthony SM et al (2017) Regulatory T cells impede acute and long-term immunity to blood-stage malaria through CTLA-4. Nat Med 23:1220–1225CrossRefPubMedGoogle Scholar
  72. 72.
    Mackroth MS, Abel A, Steeg C, Schulze Zur Wiesch J, Jacobs T (2016) Acute malaria induces PD1+ CTLA4+ effector T cells with cell-extrinsic suppressor function. PLoS Pathog 12:e1005909CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Gonçalves-Lopes RM, Lima NF, Carvalho KI, Scopel KKG, Kallás EG, Ferreira MU (2016) Surface expression of inhibitory (CTLA-4) and stimulatory (OX40) receptors by CD4+ regulatory T cell subsets circulating in human malaria. Microbes Infect 18:639–648CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Che KF, Shankar EM, Muthu S et al (2012) p38 mitogen-activated protein kinase/signal transducer and activator of transcription-3 pathway signaling regulates expression of inhibitory molecules in T cells activated by HIV-1-exposed dendritic cells. Mol Med 18:1169–1182CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Portugal S, Moebius J, Skinner J, Doumbo S, Doumtabe D, Kone Y et al (2014) Exposure-dependent control of malaria-induced inflammation in children. PLoS Pathog 10:e1004079CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Adler G, Steeg C, Pfeffer K, Murphy TL, Murphy KM, Langhorne J et al (2011) B and T lymphocyte attenuator restricts the protective immune response against experimental malaria. J Immunol 187:5310–5319CrossRefPubMedGoogle Scholar
  77. 77.
    Lepenies B, Pfeffer K, Hurchla MA, Murphy TL, Murphy KM, Oetzel J et al (2007) Ligation of B and T lymphocyte attenuator prevents the genesis of experimental cerebral malaria. J Immunol 179:4093–4100CrossRefPubMedGoogle Scholar
  78. 78.
    Costa PAC, Leoratti FMS, Figueiredo MM, Tada MS, Pereira DB, Junqueira C et al (2015) Induction of inhibitory receptors on T cells during Plasmodium vivax malaria impairs cytokine production. J Infect Dis 212:1999–2010CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Hou N, Zou Y, Piao X, Liu S, Wang L, Li S et al (2016) T-cell immunoglobulin- and mucin-domain-containing molecule 3 signaling blockade improves cell-mediated immunity against malaria. J Infect Dis 214:1547–1556CrossRefPubMedGoogle Scholar
  80. 80.
    Hou N, Jiang N, Zou Y, Piao X, Liu S, Li S et al (2017) Down-regulation of Tim-3 in monocytes and macrophages in plasmodium infection and its association with parasite clearance. Front Microbiol 8:1431CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Workman CJ, Vignali DAA (2003) The CD4-related molecule, LAG-3 (CD223), regulates the expansion of activated T cells. Eur J Immunol 33:970–979CrossRefPubMedGoogle Scholar
  82. 82.
    Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A et al (2009) Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 10:29–37CrossRefPubMedGoogle Scholar
  83. 83.
    Richter K, Agnellini P, Oxenius A (2010) On the role of the inhibitory receptor LAG-3 in acute and chronic LCMV infection. Int Immunol 22:13–23CrossRefPubMedGoogle Scholar
  84. 84.
    Zehn D, Wherry EJ (2015) Immune memory and exhaustion: clinically relevant lessons from the LCMV model. Adv Exp Med Biol 850:137–152CrossRefPubMedGoogle Scholar
  85. 85.
    Utzschneider DT, Alfei F, Roelli P, Barras D, Chennupati V, Darbre S et al (2016) High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell expansion and survival. J Exp Med 213:1819–1834CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Rota G, Niogret C, Dang AT, Barros CR, Fonta NP, Alfei F et al (2018) Shp-2 is dispensable for establishing T cell exhaustion and for PD-1 signaling in vivo. Cell Rep 23:39–49CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Infection Biology and Medical Microbiology, Department of Life Sciences (DLS), School of Basic and Applied SciencesCentral University of Tamil Nadu (CUTN)ThiruvarurIndia
  2. 2.Laboratory-Based DepartmentUniversiti Kuala Lumpur Royal College of Medicine Perak (UniKL-RCMP)IpohMalaysia
  3. 3.Central University of Tamil Nadu (CUTN)ThiruvarurIndia

Personalised recommendations