Immune Mediators of protective and pathogenic immune responses in patients with mild and fatal human monocytotropic ehrlichiosis

BMC Immunology

Yi-Wei Tang¹  Purnima Ghose²  David H Walker³  Nahed Ismail⁴ 

[1] Departments of Pathology and Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA;Department of Pathology, Meharry Medical College, Nashville, TN, USA;Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA;Department of Pathology, University of Pittsburgh, S739 Scaife Hall, 3550 Terrace St, 15261, Pittsburgh, PA, USA

关键词: Th1 response;    Death Receptors;    Pro-inflammatory cytokines;    Ehrlichiosis;    Apoptosis;    Chemokines;    Cytokines;    T cells;    Toxic shock;    Human ehrlichiosis;   

Others  :  1077915
DOI  :  10.1186/1471-2172-13-26

 received in 2012-02-03, accepted in 2012-05-03,  发布年份 2012

【 摘 要 】

Background

Ehrlichia chaffeensis is a bacterial pathogen that causes fatal human monocytic ehrlichiosis (HME) that mimic toxic shock-like syndrome. Murine studies indicate that over activation of cellular immunity followed by immune suppression plays a central role in mediating tissue injury and organ failure during fatal HME. However, there are no human studies that examine the correlates of resistance or susceptibility to severe and fatal HME.

Results

In this study, we compared the immune responses in two patients with mild/non fatal and severe/fatal HME who had marked lymphopenia, thrombocytopenia and elevated liver enzymes. The levels of different immunological factors in the blood of those patients were examined and compared to healthy controls. Our data showed that fatal HME is associated with defective production of Th1 cytokines such as ( IFNγ and IL-2), increased anti-inflammatory (IL-10 and IL-13) and pro-inflammatory (TNF-α, IL-1α, IL-1β, and IL-6) cytokines, increased levels of macrophages, T cells, and NK cells chemokines such as MCP-1, MIP-1α, MIP-1β, but not RANTES and IP-10, increased levels of neutrophils chemokine and growth factor (IL-8 and G-CSF), and elevated expression of tumor necrosis factor receptor (TNFR), and toll like receptors 2 and 4 compared to patients with non fatal HME and healthy controls.

Conclusions

Fatal Ehrlichia-induced toxic shock is associated with defective Th1 responses, possible immune suppression mediated by IL-10. In addition, marked leukopenia observed in patients with fatal disease could be attributed to enhanced apoptosis of leukocytes and/or elevated chemokine production that could promote migration of immune cells to sites of infection causing tissue injury.

【 授权许可】

   
2012 Ismail et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Dumler JS, Walker DH: Tick-borne Ehrlichiosis. Lancet Infectious disease 2001, 121:21-28.
• [2]Dumler JS, Dawson JE, Walker DH: Human Ehrlichiosis: Hematopathology and immunohistologic detection of Ehrlichia chaffeensis. Hum Pathol 1993, 24:391-396.
• [3]Paddock CD, Childs JE: Ehrlichia chaffeensis: a prototypical emerging pathogen. Clin Microbiol Rev 2003, 16:37-64.
• [4]Fichtenbaum CJ, Peterson LR, Weil GJ: Ehrlichiosis presenting as a life- threatening illness with features of the toxic shock syndrome. Am J Med 1993, 95:351-357.
• [5]Olano JP, Masters E, Cullman L, Hogrefe W, Yu X-J, Walker DH: Human monocytotrophic Ehrlichiosis (HME): Epidemiological, clinical and laboratory diagnosis of a newly emergent infection in the United States. In Rickettsiae and Rickettsial Diseases at the Turn of the Third Millenium. Edited by Raoult D, Brouqui P. Paris: Elsevier; 1999:262-268.
• [6]Sehdev AE, Dumler JS: Hepatic pathology in human monocytic Ehrlichiosis. Ehrlichia chaffeensis infection. Am J Clin Pathol 2003, 119:859-865.
• [7]Ismail N, Soong L, McBride JW, Valbuena G, Olano JP, Feng HM, Walker DH: Overproduction of TNF-alpha by CD8+ type 1 cells and down-regulation of IFN-gamma production by CD4+ Th1 cells contribute to toxic shock-like syndrome in an animal model of fatal monocytotropic Ehrlichiosis. J Immunol 2004, 172:1786-1800.
• [8]Ratnasamy N, Everett ED, Roland WE, McDonald G, Caldwell CW: Central nervous system manifestations of human Ehrlichiosis. Clin Infect Dis 1996, 23:314-319.
• [9]Thomas LD, Hongo I, Bloch KC, Tang YW, Dummer S: Human ehrlichiosis in transplant recipients. Am J Transplant 2007, 7:1641-1647.
• [10]Ismail N, Stevenson HL, Walker DH: Role of tumor necrosis factor alpha and interleukin-10 in the pathogenesis of severe murine monocytotropic Ehrlichiosis: increased resistance of TNF receptor p55- and p75-deficient mice to fatal ehrlichial infection. Infect Immun 2006, 74:1846-1856.
• [11]Stevenson HL, Jordan JM, Peerwani Z, Wang HQ, Walker DH, Ismail N: An intradermal environment promotes a protective type-1 response against lethal systemic monocytotropic Ehrlichial infection. Infect Immun 2006, 74:4856-4864.
• [12]Ismail N, Crossely EC, Stevenson HL, Walker DH: Relative importance of T-cell subsets in monocytotropic Ehrlichiosis: a novel effector mechanism involved in Ehrlichia-induced immunopathology in murine Ehrlichiosis. Infect Immun 2007, 2007(75):4608-4620.
• [13]Stevenson HL, Crossely EC, Walker DH, Ismail N: Regulatory roles of CD1d-restricted NKT cells in the induction of toxic shock-like syndrome in an animal model of fatal Ehrlichiosis. Infec Immun 2006, 76:1434-1444.
• [14]Mattner J, Debord KL, Ismail N, Goff RD, Cantu C 3rd, Zhou D, Saint-Mezard P, Wang V, Gao Y, Yin N, Hoebe K, Schneewind O, Walker D, Beutler B, Teyton L, Savage PB, Bendelac A: Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature 2005, 434:525-529.
• [15]Bitsaktsis C, Huntington J, Winslow G: Production of IFN-γ by CD4 T cells is essential for resolving Ehrlichia infection. J Immunol 2004, 172:6894-6901.
• [16]Ganta RR, Wilkerson MJ, Cheng C, Rokey AM, Chapes SK: Persistent Ehrlichia chaffeensis infection occurs in the absence of functional major histocompatibility complex class II genes. Infect Immun 2002, 70:380-388.
• [17]Feng HM, Walker DH: Mechanisms of immunity to Ehrlichia muris: a model of monocytotropic Ehrlichiosis. Infect Immun 2004, 72:966-971.
• [18]Stevenson HL, Estes DM, Thirumalapura RN, Walker DH, Ismail N: Natural killer cells promote tissue injury and systemic inflammatory responses during fatal Ehrlichia-induced toxic shock-like syndrome. Am J Pathology 2010, 177:766-776.
• [19]Doyle CK, Labruna MB, Breitschwerdt EB, Tang YW, Corstvet RE, Hegarty BC, Mcbride JW: Detection of medically important Ehrlichia by quantitative multicolor TaqMan real-time polymerase chain reaction of the dsb gene. J Mol Diag 2005, 7:504-510.
• [20]Tang YW, Sefers SE, Li H, Kohn DJ, Procop GW: Comparative evaluation of three commercial systems for nucleic acid extraction from urine specimens. J Clin Microbiol 2005, 43:4830-4833.
• [21]Greenhill CJ, Rose-John S, Lissilaa R, Ferlin W, Ernst M, Hertzog PJ, Mansell A, Jenkins BJ: IL-6 trans-signaling modulates TLR4-dependent inflammatory responses via STAT3. J Immunol 2011, 186:1199-1208.
• [22]Sims GP, Rowe DC, Rietdijk ST, Herbst R, Coyle AJ: HMGB1 and RAGE in inflammation and cancer. Annu Rev Immunol 2010, 28:367-388.
• [23]Papadaki HA, Pontikoglou C: Pathophysiologic mechanisms, clinical features and treatment of idiopathic neutropenia. Expert Rev Hematol 2008, 1:217-229.
• [24]Alves-Filho JC, de Freitas A, Spiller F, Souto FO, Cunha FQ: The role of neutrophils in severe sepsis. Shock 2008, 1:3-9.
• [25]Pease JE, Sabroe I: The role of interleukin-8 and its receptors in inflammatory lung disease: implications for therapy. Am J Respir Med 2002, 1:19-25.
• [26]Glattard E, Welters ID, Lavaux T, Muller AH, Laux A, Zhang D, Schmidt AR, Delalande F, Laventie BJ, Dirrig-Grosch S, Colin DA, Van Dorsselaer A, Aunis D, Metz-Boutigue MH, Schneider F, Goumon Y: Endogenous morphine levels are increased in sepsis: a partial implication of neutrophils. PLoS One 2010, 5:e8791.
• [27]Ghose P, Ali A, Forbes D, Ballard B, Ismail N: The interaction between IL-18 and IL-18R limits the magnitude of protective immunity and enhances pathogenic responses following infection with intracellular bacteria. J Immunol 2011, 187:1333-1346.
• [28]Emmanuilidis K, Weighardt H, Maier S, Gerauer K, Fleischmann T, Zheng XX, Hancock WW, Holzmann B, Heidecke CD: Critical role of Kupffer cell-derived IL-10 for host defense in septic peritonitis. J Immunol 2001, 167:3919-3927.
• [29]Yu H, Karunakaran KP, Kelly I, Shen C, Jiang X, Foster LJ, Brunham RC: Immunization with live and dead Chlamydia muridarum induces different levels of protective immunity in a murine genital tract model: correlation with MHC class II peptide presentation and multifunctional Th1 cells. J Immunol 2011, 186:3615-3621.
• [30]de Vos AF, Pater JM, van den Pangaart PS, de Kruif MD, van Veer C, Van’t der Poll T: In vivo lipopolysaccharide exposure of human blood leukocytes induces cross-tolerance to multiple TLR ligands. J Immunol 2009, 183:533-542.