Background Macrophage migration inhibitory factor (MIF) has emerged as a pivotal mediator of innate immunity and has been shown to be an important effector molecule in severe sepsis. Melioidosis, caused by Burkholderia pseudomallei, is an important cause of community-acquired sepsis in Southeast-Asia. We aimed to characterize the expression and function of MIF in melioidosis. Methodology and Principal Findings MIF expression was determined in leukocytes and plasma from 34 melioidosis patients and 32 controls, and in mice infected with B. pseudomallei. MIF function was investigated in experimental murine melioidosis using anti-MIF antibodies and recombinant MIF. Patients demonstrated markedly increased MIF mRNA leukocyte and MIF plasma concentrations. Elevated MIF concentrations were associated with mortality. Mice inoculated intranasally with B. pseudomallei displayed a robust increase in pulmonary and systemic MIF expression. Anti-MIF treated mice showed lower bacterial loads in their lungs upon infection with a low inoculum. Conversely, mice treated with recombinant MIF displayed a modestly impaired clearance of B. pseudomallei. MIF exerted no direct effects on bacterial outgrowth or phagocytosis of B. pseudomallei. Conclusions MIF concentrations are markedly elevated during clinical melioidosis and correlate with patients' outcomes. In experimental melioidosis MIF impaired antibacterial defense.
References
[1]
David JR (1966) Delayed hypersensitivity in vitro: its mediation by cell-free substances formed by lymphoid cell-antigen interaction. Proc Natl Acad Sci U S A 56: 72–77. doi: 10.1073/pnas.56.1.72
[2]
Bloom BR, Bennett B (1966) Mechanism of a reaction in vitro associated with delayed-type hypersensitivity. Science 153: 80–82. doi: 10.1126/science.153.3731.80
[3]
Bucala R, Donnelly SC (2007) Macrophage migration inhibitory factor: a probable link between inflammation and cancer. Immunity 26: 281–285. doi: 10.1016/j.immuni.2007.03.005
[4]
Calandra T, Roger T (2003) Macrophage migration inhibitory factor: a regulator of innate immunity. Nat Rev Immunol 3: 791–800. doi: 10.1038/nri1200
[5]
Ayoub S, Hickey MJ, Morand EF (2008) Mechanisms of disease: macrophage migration inhibitory factor in SLE, RA and atherosclerosis. Nat Clin Pract Rheumatol 4: 98–105. doi: 10.1038/ncprheum0701
[6]
Bernhagen J, Krohn R, Lue H, Gregory JL, Zernecke A, et al. (2007) MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med 13: 587–596. doi: 10.1038/nm1567
[7]
Baugh JA, Bucala R (2002) Macrophage migration inhibitory factor. Crit Care Med 30: S27–S35. doi: 10.1097/00003246-200201001-00004
[8]
Roger T, David J, Glauser MP, Calandra T (2001) MIF regulates innate immune responses through modulation of Toll-like receptor 4. Nature 414: 920–924. doi: 10.1038/414920a
[9]
Roger T, Froidevaux C, Martin C, Calandra T (2003) Macrophage migration inhibitory factor (MIF) regulates host responses to endotoxin through modulation of Toll-like receptor 4 (TLR4). J Endotoxin Res 9: 119–123. doi: 10.1179/096805103125001513
[10]
Bozza M, Satoskar AR, Lin G, Lu B, Humbles AA, et al. (1999) Targeted disruption of migration inhibitory factor gene reveals its critical role in sepsis. J Exp Med 189: 341–346. doi: 10.1084/jem.189.2.341
[11]
Chuang CC, Wang ST, Chen WC, Chen CC, Hor LI, et al. (2007) Increases in serum macrophage migration inhibitory factor in patients with severe sepsis predict early mortality. Shock 27: 503–506. doi: 10.1097/SHK.0b013e31802c024b
[12]
Emonts M, Sweep FC, Grebenchtchikov N, Geurts-Moespot A, Knaup M, et al. (2007) Association between high levels of blood macrophage migration inhibitory factor, inappropriate adrenal response, and early death in patients with severe sepsis. Clin Infect Dis 44: 1321–1328. doi: 10.1086/514344
[13]
Bozza FA, Gomes RN, Japiassu AM, Soares M, Castro-Faria-Neto HC, et al. (2004) Macrophage migration inhibitory factor levels correlate with fatal outcome in sepsis. Shock 22: 309–313. doi: 10.1097/01.shk.0000140305.01641.c8
[14]
Lehmann LE, Novender U, Schroeder S, Pietsch T, von Spiegel T, et al. (2001) Plasma levels of macrophage migration inhibitory factor are elevated in patients with severe sepsis. Intensive Care Med 27: 1412–1415. doi: 10.1007/s001340101022
[15]
Sprong T, Pickkers P, Geurts-Moespot A, van der Ven-Jongekrijg J, Neeleman C, et al. (2007) Macrophage migration inhibitory factor (MIF) in meningococcal septic shock and experimental human endotoxemia. Shock 27: 482–487. doi: 10.1097/01.shk.0000246898.65692.34
[16]
Calandra T, Echtenacher B, Roy DL, Pugin J, Metz CN, et al. (2000) Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat Med 6: 164–170. doi: 10.1038/72262
[17]
Al-Abed Y, Dabideen D, Aljabari B, Valster A, Messmer D, et al. (2005) ISO-1 binding to the tautomerase active site of MIF inhibits its pro-inflammatory activity and increases survival in severe sepsis. J Biol Chem 280: 36541–36544. doi: 10.1074/jbc.C500243200
[18]
Crichlow GV, Cheng KF, Dabideen D, Ochani M, Aljabari B, et al. (2007) Alternative chemical modifications reverse the binding orientation of a pharmacophore scaffold in the active site of macrophage migration inhibitory factor. J Biol Chem 282: 23089–23095. doi: 10.1074/jbc.M701825200
[19]
White NJ (2003) Melioidosis. Lancet 361: 1715–1722. doi: 10.1016/S0140-6736(03)13374-0
[20]
Wiersinga WJ, van der Poll T, White NJ, Day NP, Peacock SJ (2006) Melioidosis: insights into the pathogenicity of Burkholderia pseudomallei. Nat Rev Microbiol 4: 272–282. doi: 10.1038/nrmicro1385
[21]
Currie BJ (2003) Melioidosis: an important cause of pneumonia in residents of and travellers returned from endemic regions. Eur Respir J 22: 542–550. doi: 10.1183/09031936.03.00006203
[22]
Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, et al. (2003) 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 31: 1250–1256. doi: 10.1097/01.CCM.0000050454.01978.3B
[23]
Wiersinga WJ, Wieland CW, Dessing MC, Chantratita N, Cheng AC, et al. (2007) Toll-Like Receptor 2 Impairs Host Defense in Gram-Negative Sepsis Caused by Burkholderia pseudomallei (Melioidosis). PLoS Med 4: e248. doi: 10.1371/journal.pmed.0040248
[24]
Radstake TR, Sweep FC, Welsing P, Franke B, Vermeulen SH, et al. (2005) Correlation of rheumatoid arthritis severity with the genetic functional variants and circulating levels of macrophage migration inhibitory factor. Arthritis Rheum 52: 3020–3029. doi: 10.1002/art.21285
[25]
Spek CA, Verbon A, Aberson H, Pribble JP, McElgunn CJ, et al. (2003) Treatment with an anti-CD14 monoclonal antibody delays and inhibits lipopolysaccharide-induced gene expression in humans in vivo. J Clin Immunol 23: 132–140. doi: 10.1023/A:1022528912387
[26]
Wiersinga WJ, Dessing MC, Kager PA, Cheng AC, Limmathurotsakul D, et al. (2007) High-throughput mRNA profiling characterizes the expression of inflammatory molecules in sepsis caused by Burkholderia pseudomallei. Infect Immun 75: 3074–3079. doi: 10.1128/IAI.01733-06
[27]
DeShazer D (2004) Genomic diversity of Burkholderia pseudomallei clinical isolates: subtractive hybridization reveals a Burkholderia mallei-specific prophage in B. pseudomallei 1026b. J Bacteriol 186: 3938–3950. doi: 10.1128/JB.186.12.3938-3950.2004
[28]
Jeddeloh JA, Fritz DL, Waag DM, Hartings JM, Andrews GP (2003) Biodefense-driven murine model of pneumonic melioidosis. Infect Immun 71: 584–587. doi: 10.1128/IAI.71.1.584-587.2003
[29]
Wiersinga WJ, Veer CT, Wieland CW, Gibot S, Hooibrink B, et al. (2007) Expression Profile and Function of Triggering Receptor Expressed on Myeloid Cells-1 during Melioidosis. J Infect Dis 196: 1707–1716. doi: 10.1086/522141
[30]
Wiersinga WJ, de Vos AF, de Beer R, Wieland CW, Roelofs JJ, et al. (2008) Inflammation patterns induced by different Burkholderia species in mice. Cell Microbiol 10: 81–87. doi: 10.1111/j.1462-5822.2007.01016.x
[31]
Wiersinga WJ, Wieland CW, van der Windt GJ, de Boer A, Florquin S, et al. (2007) Endogenous interleukin-18 improves the early antimicrobial host response in severe melioidosis. Infect Immun 75: 3739–3746. doi: 10.1128/IAI.00080-07
[32]
Wiersinga WJ, Veer CT, Wieland CW, Gibot S, Hooibrink B, et al. (2007) Expression profile and function of triggering receptor expressed on myeloid cells-1 during melioidosis. J Infect Dis 196: 1707–1716. doi: 10.1086/522141
[33]
Roger T, Glauser MP, Calandra T (2001) Macrophage migration inhibitory factor (MIF) modulates innate immune responses induced by endotoxin and Gram-negative bacteria. J Endotoxin Res 7: 456–460. doi: 10.1179/096805101101533089
[34]
Calandra T, Bernhagen J, Mitchell RA, Bucala R (1994) The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor. J Exp Med 179: 1895–1902. doi: 10.1084/jem.179.6.1895
[35]
Grebenchtchikov N, Sweep CG, Geurts-Moespot A, Piffanelli A, Foekens JA, et al. (2002) An ELISA avoiding interference by heterophilic antibodies in the measurement of components of the plasminogen activation system in blood. J Immunol Methods 268: 219–231. doi: 10.1016/S0022-1759(02)00213-2
[36]
Wan CP, Park CS, Lau BH (1993) A rapid and simple microfluorometric phagocytosis assay. J Immunol Methods 162: 1–7. doi: 10.1016/0022-1759(93)90400-2
[37]
Wiersinga WJ, de Vos AF, Wieland CW, Leendertse M, Roelofs JJ, et al. (2008) CD14 Impairs Host Defense against Gram-Negative Sepsis Caused by Burkholderia pseudomallei in Mice. J Infect Dis 198: 1388–1397. doi: 10.1086/592220
[38]
Mizgerd JP (2008) Acute lower respiratory tract infection. N Engl J Med 358: 716–727. doi: 10.1056/NEJMra074111
[39]
Chen LC, Lei HY, Liu CC, Shiesh SC, Chen SH, et al. (2006) Correlation of serum levels of macrophage migration inhibitory factor with disease severity and clinical outcome in dengue patients. Am J Trop Med Hyg 74: 142–147.
[40]
Arjona A, Foellmer HG, Town T, Leng L, McDonald C, et al. (2007) Abrogation of macrophage migration inhibitory factor decreases West Nile virus lethality by limiting viral neuroinvasion. J Clin Invest 117: 3059–3066. doi: 10.1172/JCI32218
[41]
Kibiki GS, van der Ven AJ, Geurts-Moespot A, Shao J, Calandra T, et al. (2007) Serum and BAL macrophage migration inhibitory factor levels in HIV infected Tanzanians with pulmonary tuberculosis or other lung diseases. Clin Immunol 123: 60–65. doi: 10.1016/j.clim.2006.12.004
[42]
McDevitt MA, Xie J, Shanmugasundaram G, Griffith J, Liu A, et al. (2006) A critical role for the host mediator macrophage migration inhibitory factor in the pathogenesis of malarial anemia. J Exp Med 203: 1185–1196. doi: 10.1084/jem.20052398
[43]
Yamada G, Shijubo N, Takagi-Takahashi Y, Nishihira J, Mizue Y, et al. (2002) Elevated levels of serum macrophage migration inhibitory factor in patients with pulmonary tuberculosis. Clin Immunol 104: 123–127. doi: 10.1006/clim.2002.5255
[44]
Awandare GA, Hittner JB, Kremsner PG, Ochiel DO, Keller CC, et al. (2006) Decreased circulating macrophage migration inhibitory factor (MIF) protein and blood mononuclear cell MIF transcripts in children with Plasmodium falciparum malaria. Clin Immunol 119: 219–225. doi: 10.1016/j.clim.2005.12.003
[45]
Wiersinga WJ, van't Veer C, van den Pangaart PS, Dondorp AM, Day NP, et al. (2009) Immunosuppression associated with interleukin-1R-associated-kinase-M upregulation predicts mortality in Gram-negative sepsis (melioidosis). Crit Care Med 37: 569–576. doi: 10.1097/CCM.0b013e318194b1bf
[46]
Makita H, Nishimura M, Miyamoto K, Nakano T, Tanino Y, et al. (1998) Effect of anti-macrophage migration inhibitory factor antibody on lipopolysaccharide-induced pulmonary neutrophil accumulation. Am J Respir Crit Care Med 158: 573–579. doi: 10.1164/ajrccm.158.2.9707086
[47]
Yende S, Angus DC, Kong L, Kellum JA, Weissfeld L, et al. (2009) The influence of macrophage migration inhibitory factor gene polymorphisms on outcome from community-acquired pneumonia. Faseb J 23: 2403–2411. doi: 10.1096/fj.09-129445
[48]
Matsuda N, Nishihira J, Takahashi Y, Kemmotsu O, Hattori Y (2006) Role of macrophage migration inhibitory factor in acute lung injury in mice with acute pancreatitis complicated by endotoxemia. Am J Respir Cell Mol Biol 35: 198–205. doi: 10.1165/rcmb.2005-0272OC
[49]
Sashinami H, Sakuraba H, Ishiguro Y, Munakata A, Nishihira J, et al. (2006) The role of macrophage migration inhibitory factor in lethal Listeria monocytogenes infection in mice. Microb Pathog 41: 111–118. doi: 10.1016/j.micpath.2006.06.001
[50]
Bernhagen J, Calandra T, Mitchell RA, Martin SB, Tracey KJ, et al. (1993) MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature 365: 756–759. doi: 10.1038/365756a0
[51]
Pollak N, Sterns T, Echtenacher B, Mannel DN (2005) Improved resistance to bacterial superinfection in mice by treatment with macrophage migration inhibitory factor. Infect Immun 73: 6488–6492. doi: 10.1128/IAI.73.10.6488-6492.2005
[52]
van der Poll T, Opal SM (2008) Host-pathogen interactions in sepsis. Lancet Infect Dis 8: 32–43. doi: 10.1016/S1473-3099(07)70265-7
