Essential Role for Humoral Immunity during<i>Ehrlichia</i>Infection in Immunocompetent Mice

Yager, Eric J.; Bitsaktsis, Constantine; Nandi, Bisweswar; McBride, Jere W.; Winslow, Gary M.

doi:10.1128/iai.73.12.8009-8016.2005

Cited by 47 publications

(50 citation statements)

References 48 publications

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“…Passive transfer of anti-E. muris polyclonal antibodies completely protects SCID/B6 mice against lethal challenge with E. muris, and the protection is Fc dependent (5). Furthermore, mice deficient in B cells or Fc␥RI fail to resolve ordinarily sublethal IOE infection, suggesting a role for antibodies in protective immunity (40). Lack of a strong IgG antibody response in IOE infection is consistent with the observations reported in the previous studies (12,40).…”

Section: Discussionsupporting

confidence: 81%

“…Furthermore, mice deficient in B cells or Fc␥RI fail to resolve ordinarily sublethal IOE infection, suggesting a role for antibodies in protective immunity (40). Lack of a strong IgG antibody response in IOE infection is consistent with the observations reported in the previous studies (12,40). IgG antibodies are likely to confer protection against Ehrlichia by opsonization of host-cell-free bacteria and facilitation of their phagocytosis and killing (12).…”

Section: Discussionsupporting

confidence: 79%

“…Thus, the lack of antibodies in IOE/IOE mice is most likely due to a defective CD4 ϩ T-cell memory response. Studies from our laboratory and others have demonstrated the importance of polyclonal antibodies in immunity against ehrlichial infections (5,12,16,17,40). Passive transfer of anti-E. muris polyclonal antibodies completely protects SCID/B6 mice against lethal challenge with E. muris, and the protection is Fc dependent (5).…”

Section: Discussionmentioning

confidence: 99%

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Protective Heterologous Immunity against Fatal Ehrlichiosis and Lack of Protection following Homologous Challenge

Thirumalapura¹,

Stevenson²,

Walker

et al. 2008

Infect Immun

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The roles of antibodies and memory T cells in protection against virulent Ehrlichia have not been completely investigated. In this study, we addressed these issues by using murine models of mild and fatal ehrlichiosis caused by related monocytotropic Ehrlichia strains. Mice were primed with either Ehrlichia muris or closely related virulent ehrlichiae transmitted by Ixodes ovatus (IOE) ticks given intraperitoneally or intradermally. All groups were reinfected intraperitoneally, 30 days later, with a lethal high dose of IOE. Priming with E. muris, but not IOE, induced strong CD4؉ and CD8 ؉ memory type 1 T-cell responses, Ehrlichia-specific immunoglobulin G (IgG) antibodies, and persistent infection. Compared to IOE-primed mice, subsequent lethal IOE challenge of E. muris-primed mice, resulted in (i) 100% protection against lethal infection, (ii) strong Ehrlichiaspecific secondary gamma interferon (IFN-␥)-producing effector/effector memory CD4 ؉ and CD8 ؉ T-cell responses, (iii) enhanced secondary anti-ehrlichial antibody response, (iv) accelerated bacterial clearance, and (v) the formation of granulomas in the liver and lung. E. muris-primed mice challenged with IOE had lower levels of serum interleukin-1␣ (IL-1␣), IL-6, and IL-10 compared to unprimed mice challenged with IOE. Interestingly, the fatal secondary response in IOE-primed mice correlated with (i) decline in the Ehrlichiaspecific CD4؉ and CD8 ؉ type 1 responses, (ii) marked hepatic apoptosis and necrosis, and (iii) substantial bacterial clearance, suggesting that fatal secondary response is due to immune-mediated tissue damage. In conclusion, protection against fatal ehrlichial infection correlates with strong expansion of IFN-␥-producing CD4 ؉ and CD8 ؉ effector memory type 1 T cells, which appear to be maintained in the presence of IgG antibodies and persistent infection.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Protective Heterologous Immunity against Fatal Ehrlichiosis and Lack of Protection following Homologous Challenge

Thirumalapura¹,

Stevenson²,

Walker

et al. 2008

Infect Immun

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“…Using one such agent, Ixodes ovatus ehrlichia (IOE), 3 we previously demonstrated that CD4 ϩ T cell-mediated IFN-␥-dependent production is critical for host defenses (19). Other studies from our laboratory support an essential role for Abs during IOE infection, a requirement that is not typical of intracellular bacterial infections (20). In contrast, CD8 T cells were not essential for protection against a low-dose IOE infection (19).…”

mentioning

confidence: 84%

Fatal Recall Responses Mediated by CD8 T cells during Intracellular Bacterial Challenge Infection

Bitsaktsis

Winslow

2006

The Journal of Immunology

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The roles(s) of CD8 T cells during infections by intracellular bacteria that reside in host cell endocytic compartments are not well understood. Our previous studies in a mouse model of human monocytotropic ehrlichiosis indicated that CD8 T cells are not essential for immunity. However, we have observed an unexpected role for these cells during challenge infection. Although immunocompetent mice cleared a primary low-dose (nonfatal) Ixodes ovatus ehrlichia infection, a secondary low-dose challenge infection resulted in fatal disease and loss of control of infection. The outcome was CD8-dependent, because CD8-deficient mice survived secondary low-dose challenge infection. Moreover, effector and/or memory phenotype CD8 T cells were responsible, because adoptive transfer of purified CD44high CD8 T cells to naive mice induced fatal responses following a primary low-dose infection. The fatal responses were perforin- and Fas ligand-independent, and were associated with high serum concentrations of TNF-α and CCL2, and low levels of IL-10. Accordingly, blockade of either TNF-α or CCL2 ameliorated fatal recall responses, and in vitro coculture of memory CD8 T cells and Ixodes ovatus ehrlichia-infected peritoneal exudate cells resulted in substantial increases in TNF-α and CCL2. Thus, during monocytotropic ehrlichiosis, inflammatory cytokine production, by CD8 T cells and/or other host cells, can trigger chemokine-dependent disease. These findings highlight a novel role for CD8 T cells, and reveal that live vaccines for intracellular bacteria can, under some conditions, induce undesirable consequences.

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“…Recently, a number of studies demonstrated that humoral immunity plays an essential role in host defenses against ehrlichial pathogens (10,33,34,36). Furthermore, a small subset of E. chaffeensis proteins, many of which contain tandem repeats (TRs), appear to be the primary targets of the humoral immune response and are considered to be the major immunoreactive proteins (4,5,15,30).…”

mentioning

confidence: 99%

A Variable-Length PCR Target Protein of Ehrlichia chaffeensis Contains Major Species-Specific Antibody Epitopes in Acidic Serine-Rich Tandem Repeats

Luo¹,

Zhang²,

Wakeel³

et al. 2008

Infect Immun

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109

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Ehrlichia chaffeensis and E. canis have a small subset of tandem repeat (TR)-containing proteins that elicit strong host immune responses and are associated with host-pathogen interactions. In a previous study, we molecularly characterized a highly conserved 19-kDa major immunoreactive protein (gp19) of E. canis and identified the corresponding TR-containing ortholog variable-length PCR target (VLPT) protein in E. chaffeensis. In this study, the native 32-kDa VLPT protein was identified and the immunodeterminants defined in order to further understand the molecular basis of the host immune response to E. chaffeensis. Synthetic and/or recombinant polypeptides corresponding to various regions of VLPT were used to localize major antibody epitopes to the TR-containing region. Major antibody epitopes were identified in three nonidentical repeats (R2, R3, and R4), which reacted strongly with antibodies in sera from an E. chaffeensis-infected dog and human monocytotropic ehrlichiosis patients. VLPT-R3 and VLPT-R2 reacted most strongly with antibody, and the epitope was further localized to a nearly identical proximal 17-amino-acid region common between these repeats that was species specific. The epitope in R4 was distinct from that of R2 and R3 and was found to have conformational dependence. VLPT was detected in supernatants from infected cells, indicating that the protein was secreted. VLPT was localized on both reticulate and dense-core cells, and it was found extracellularly in the morula fibrillar matrix and associated with the morula membrane.Ehrlichia chaffeensis is a tick-transmitted, obligately intracellular bacterium which causes human monocytotropic ehrlichiosis (HME), an emerging life-threatening disease in humans, and also causes mild to severe disease in canines (28). Recently, a number of studies demonstrated that humoral immunity plays an essential role in host defenses against ehrlichial pathogens (10,33,34,36). Furthermore, a small subset of E. chaffeensis proteins, many of which contain tandem repeats (TRs), appear to be the primary targets of the humoral immune response and are considered to be the major immunoreactive proteins (4,5,15,30). However, the characteristics of the immunodeterminants that shape the humoral immune response to Ehrlichia species are not fully defined, nor has their role in protective immunity been determined.Major immunoreactive proteins of E. chaffeensis include 30). Some of these proteins (200-, 120-, 47-, and 28-kDa proteins) have been identified and molecularly characterized, including the corresponding orthologs in Ehrlichia canis respectively) (7,16,20,25,27,(38)(39)(40). Most recently, a strongly acidic 19-kDa major immunoreactive protein (gp19) of E. canis was identified. The gp19 gene has the same relative chromosomal location as and substantial amino acid homology in a C-terminal cysteine-tyrosine-rich domain to the previously reported variable-length PCR target (VLPT) protein identified in E. chaffeensis (19). The VLPT gene has 90-bp TRs that vary in number (2 t...

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Essential Role for Humoral Immunity duringEhrlichiaInfection in Immunocompetent Mice

Cited by 47 publications

References 48 publications

Protective Heterologous Immunity against Fatal Ehrlichiosis and Lack of Protection following Homologous Challenge

Protective Heterologous Immunity against Fatal Ehrlichiosis and Lack of Protection following Homologous Challenge

Fatal Recall Responses Mediated by CD8 T cells during Intracellular Bacterial Challenge Infection

A Variable-Length PCR Target Protein of Ehrlichia chaffeensis Contains Major Species-Specific Antibody Epitopes in Acidic Serine-Rich Tandem Repeats

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