Bovine tuberculosis (bTB) is a zoonotic disease caused by Mycobacterium bovis that is responsible for significant economic losses worldwide. In spite of its relevance, the limited knowledge about the host immune responses that provide effective protection against the disease has long hampered the development of an effective vaccine. The identification of host proteins with an expression that correlates with protection against bTB would contribute to the understanding of the cattle defence mechanisms against M. bovis infection. In this study, we found that ERAP1 and PDE8A were downregulated in vaccinated cattle that were protected from experimental M. bovis challenge. Remarkably, both genes encode proteins that have been negatively associated with immune protection against bTB.

1.
Bhuju S, Aranday-Cortes E, Villarreal-Ramos B, Xing Z, Singh M, Vordermeier HM: Global gene transcriptome analysis in vaccinated cattle revealed a dominant role of IL-22 for protection against bovine tuberculosis. PLoS Pathog 2012;8:e1003077.
[PubMed]
2.
Blanco FC, Bianco MV, Garbaccio S, Meikle V, Gravisaco MJ, Montenegro V, Alfonseca E, Singh M, Barandiaran S, Canal A, Vagnoni L, Buddle BM, Bigi F, Cataldi A: Mycobacterium bovis Δmce2 double deletion mutant protects cattle against challenge with virulent M. bovis. Tuberculosis 2013;93:363-372.
[PubMed]
3.
Brandt L, Skeiky YAW, Alderson MR, Lobet Y, Dalemans W, Turner OC, Basaraba RJ, Izzo AA, Lasco TM, Chapman PL, Reed SG, Orme IM: The protective effect of the Mycobacterium bovis BCG vaccine is increased by coadministration with the Mycobacterium tuberculosis 72-kilodalton fusion polyprotein Mtb72F in M. tuberculosis-infected guinea pigs. Infect Immun 2004;72:6622-6632.
[PubMed]
4.
Brettschneider J, Collin F, Bolstad BM, Speed TP: Quality assessment for short oligonucleotide microarray data. Technometrics 2008;50:241-264.
5.
Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, Mueller R, Nolan T, Pfaffl MW, Shipley GL, Vandesompele J, Wittwer CT: The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem 2009;55:611-622.
[PubMed]
6.
Cliff JM, Andrade INJ, Mistry R, Clayton CL, Lennon MG, Lewis AP, Duncan K, Lukey PT, Dockrell HM: Differential gene expression identifies novel markers of CD4+ and CD8+ T cell activation following stimulation by Mycobacterium tuberculosis. J Immunol 2004;173:485-493.
[PubMed]
7.
Das H, Groh V, Kuijl C, Sugita M, Morita CT, Spies T, Bukowski JF: MICA engagement by human Vγ2Vδ2 T cells enhances their antigen-dependent effector function. Immunity 2001;15:83-93.
[PubMed]
8.
di Rienzo JA, Casanoves F, Balzarini M, Gonzalez L, Tablada M, Robledo C: Infostat: Software Estadístico. Córdoba, Universidad Nacional de Córdoba, 2013. http://www.infostat.com.ar/.
9.
Ehlers S, Hölscher C, Scheu S, Tertilt C, Hehlgans T, Suwinski J, Endres R, Pfeffer K: The lymphotoxin β receptor is critically involved in controlling infections with the intracellular pathogens Mycobacterium tuberculosis and Listeria monocytogenes. J Immunol 2003;170:5210-5218.
[PubMed]
10.
Enomaa N, Heiskanen T, Halila R, Sormunen R, Seppala R, Vihinen M, Peltonen L: Human aspartylglucosaminidase: a biochemical and immunocytochemical characterization of the enzyme in normal and aspartylglucosaminuria fibroblasts. Biochem J 1992;286:613-618.
[PubMed]
11.
Gautier L, Cope L, Bolstad BM, Irizarry RA: affy - analysis of Affymetrix GeneChip data at the probe level. Bioinformatics 2004;20:307-315.
[PubMed]
12.
Huang DW, Sherman BT, Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 2009;4:44-57.
[PubMed]
13.
Janke C, Rogowski K, Wloga D, Regnard C, Kajava AV, Strub JM, Temurak N, van Dijk J, Boucher D, van Dorsselaer A, Suryavanshi S, Gaertig J, Eddé B: Tubulin polyglutamylase enzymes are members of the TTL domain protein family. Science 2005;308:1758-1762.
[PubMed]
14.
Kamanova J, Kofronova O, Masin J, Genth H, Vojtova J, Linhartova I, Benada O, Just I, Sebo P: Adenylate cyclase toxin subverts phagocyte function by RhoA inhibition and unproductive ruffling. J Immunol 2008;181:5587-5597.
[PubMed]
15.
Khader SA, Cooper AM: IL-23 and IL-17 in tuberculosis. Cytokine 2008;41:79-83.
[PubMed]
16.
Kim B-H, Shenoy AR, Kumar P, Das R, Tiwari S, MacMicking JD: A family of IFN-γ-inducible 65-kD GTPases protects against bacterial infection. Science 2011a;332:717-721.
[PubMed]
17.
Kim S, Lee S, Shin J, Kim Y, Evnouchidou I, Kim D, Kim YK, Kim YE, Ahn JH, Riddell SR, Stratikos E, Kim VN, Ahn K: Human cytomegalovirus microRNA miR-US4-1 inhibits CD8+ T cell responses by targeting the aminopeptidase ERAP1. Nat Immunol 2011b;12:984-991.
[PubMed]
18.
Lee Y, Jung JI, Park KY, Kim SA, Kim J: Synergistic inhibition effect of TNIK inhibitor KY-05009 and receptor tyrosine kinase inhibitor dovitinib on IL-6-induced proliferation and Wnt signaling pathway in human multiple myeloma cells. Oncotarget 2017;8:41091-41101.
[PubMed]
19.
Liu X, Lu R, Wu S, Sun J: Salmonella regulation of intestinal stem cells through the Wnt/β-catenin pathway. FEBS Lett 2010;584:911-916.
[PubMed]
20.
Mahmoudi T, Li VSW, Ng SS, Taouatas N, Vries RGJ, Mohammed S, Mohammed S, Heck AJ, Clevers H: The kinase TNIK is an essential activator of Wnt target genes. EMBO J 2009;28:3329-3340.
[PubMed]
21.
Martinez A, Gil C: cAMP-specific phosphodiesterase inhibitors: promising drugs for inflammatory and neurological diseases. Expert Opin Ther Pat 2014;24:1311-1321.
[PubMed]
22.
Neumann J, Schaale K, Farhat K, Endermann T, Ulmer AJ, Ehlers S, Reiling N: Frizzled1 is a marker of inflammatory macrophages, and its ligand Wnt3a is involved in reprogramming Mycobacterium tuberculosis-infected macrophages. FASEB J 2010;24:4599-4612.
[PubMed]
23.
Pfaffl MW, Horgan GW, Dempfle L: Relative expression software tool (REST©) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res 2002;30:e36.
[PubMed]
24.
Pollock JM, Neill SD: Mycobacterium bovis infection and tuberculosis in cattle. Vet J 2002;163:115-127.
[PubMed]
25.
Ramakers C, Ruijter JM, Deprez RHLL, Moorman AF: Assumption-free analysis of quantitative real-time polymerase chain reaction (PCR) data. Neurosci Lett 2003;339:62-66.
[PubMed]
26.
Rausch A, Hessmann M, Hölscher A, Schreiber T, Bulfone-Paus S, Ehlers S, Hölscher C: Interleukin-15 mediates protection against experimental tuberculosis: a role for NKG2D-dependent effector mechanisms of CD8+ T cells. Eur J Immunol 2006;36:1156-1167.
[PubMed]
27.
Rizzi C, Bianco MV, Blanco FC, Soria M, Gravisaco MJ, Montenegro V, Vagnoni L, Buddle B, Garbaccio S, Delgado F, Leal KS, Cataldi AA, Dellagostin OA, Bigi F: Vaccination with a BCG strain overexpressing Ag85B protects cattle against Mycobacterium bovis challenge. PLoS One 2012;7:e51396.
[PubMed]
28.
Robinson TL, Sutherland IA, Sutherland J: Validation of candidate bovine reference genes for use with real-time PCR. Vet Immunol Immunopathol 2007;115:160-165.
[PubMed]
29.
Samten B, Ghosh P, Yi A-K, Weis SE, Lakey DL, Gonsky R, Pendurthi U, Wizel B, Zhang Y, Zhang M, Gong J, Fernandez M, Safi H, Vankayalapati R, Young HA, Barnes PF: Reduced expression of nuclear cyclic adenosine 5′-monophosphate response element-binding proteins and IFN-ү promoter function in disease due to an intracellular pathogen. J Immunol 2002;168:3520-3526.
[PubMed]
30.
Samten B, Howard ST, Weis SE, Wu S, Shams H, Townsend JC, Safi H, Barnes PF: Cyclic AMP response element-binding protein positively regulates production of IFN-ү by T cells in response to a microbial pathogen. J Immunol 2005;174:6357-6363.
[PubMed]
31.
Singh H, Zhao M, Chen Q, Wang Y, Li Y, Kaitu'U-Lino TJ, Tong S, Nie G: Human HtrA4 expression is restricted to the placenta, is significantly up-regulated in early-onset preeclampsia, and high levels of HtrA4 cause endothelial dysfunction. J Clin Endocrinol Metab 2015;100:E936-E945.
[PubMed]
32.
Smyth GK: Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 2004;3:3.
[PubMed]
33.
Soderling SH, Bayuga SJ, Beavo JA: Cloning and characterization of a cAMP-specific cyclic nucleotide phosphodiesterase. Proc Natl Acad Sci USA 1998;95:8991-8996.
[PubMed]
34.
Tomasec P, Braud VM, Rickards C, Powell MB, McSharry BP, Gadola S, Cerundolo V, Borysiewicz LK, McMichael AJ, Wilkinson GW: Surface expression of HLA-E, an inhibitor of natural killer cells, enhanced by human cytomegalovirus gpUL40. Science 2000;287:1031.
[PubMed]
35.
Untergasser A, Nijveen H, Rao X, Bisseling T, Geurts R, Leunissen JAM: Primer3Plus, an enhanced web interface to Primer3. Nucleic Acids Res 2007;35:W71-W74.
[PubMed]
36.
Van Meijgaarden KE, Haks MC, Caccamo N, Dieli F, Ottenhoff THM, Joosten SA: Human CD8+ T-cells recognizing peptides from Mycobacterium tuberculosis (Mtb) presented by HLA-E have an unorthodox Th2-like, multifunctional, Mtb inhibitory phenotype and represent a novel human T-cell subset. PLoS Pathog 2015;11:e1004671.
[PubMed]
37.
Vang AG, Basole C, Dong H, Nguyen RK, Housley W, Guernsey L, Adami AJ, Thrall RS, Clark RB, Epstein PM, Brocke S: Differential expression and function of PDE8 and PDE4 in effector T cells: implications for PDE8 as a drug target in inflammation. Front Pharmacol 2016;7:259.
[PubMed]
38.
Vordermeier HM, Jones GJ, Buddle BM, Hewinson RG, Villarreal-Ramos B: Bovine tuberculosis in cattle: vaccines, DIVA tests, and host biomarker discovery. Annu Rev Anim Biosci 2016;4:87-109.
[PubMed]
39.
Waters WR, Palmer MV, Buddle BM, Vordermeier HM: Bovine tuberculosis vaccine research: historical perspectives and recent advances. Vaccine 2012;30:2611-2622.
[PubMed]
40.
Wedlock DN, Denis M, Painter GF, Ainge GD, Vordermeier HM, Hewinson RG, Buddle BM: Enhanced protection against bovine tuberculosis after coadministration of Mycobacterium bovis BCG with a mycobacterial protein vaccine-adjuvant combination but not after coadministration of adjuvant alone. Clin Vaccine Immunol 2008;15:765-772.
[PubMed]
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