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

Bitsaktsis, Constantine; Winslow, Gary M.

doi:10.4049/jimmunol.177.7.4644

Cited by 30 publications

(23 citation statements)

References 48 publications

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“…In contrast, substantial expansion of pathogenic TNF-␣-producing CD8 ϩ T cells in fatal primary ehrlichial infection coincides with a simultaneous decline in the total number of CD4 ϩ T cells due to apoptotic cell death that results also in a weak CD4 ϩ Th1 response (11,12). Although a previous study by Bitsaktsis et al suggested that fatal recall response is mediated by pathogenic memory CD8 ϩ T cells, our current model of fatal secondary ehrlichiosis is different from their study (3). The study by Bitsaktsis et al showed that fatal recall response is associated with high bacterial burden and pathology identical to primary high-dose IOE infection (3).…”

Section: Discussioncontrasting

confidence: 46%

“…Previous studies suggest that TNF-␣ plays an important role in the pathogenesis of fatal primary and secondary ehrlichiosis (3,12,13). However, splenocytes cultured from E. murisprimed mice produce high levels of proinflammatory TNF-␣ in vitro compared to those of IOE-primed mice on day 28 after primary infection and on day 7 after secondary IOE challenge (Fig.…”

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: Discussioncontrasting

confidence: 46%

Section: Discussionmentioning

confidence: 99%

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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“…These results suggest that immune-mediated pathology plays a role in IOEinduced disease and that protective immunity against IOE reinfection in E. muris-primed mice involves at least two components: (i) the protective mechanisms that prevent bacterial replication and eliminate IOE and (ii) the regulatory mechanisms that prevent IOE-induced immune-mediated pathology. Overproduction of tumor necrosis factor alpha by antigenspecific CD8 ϩ T cells and effector/memory CD8 ϩ T cells is implicated in IOE-induced immune-mediated pathology during primary and secondary IOE infections, respectively (6,17).…”

Section: Discussionmentioning

confidence: 99%

Persistent Infection Contributes to Heterologous Protective Immunity against Fatal Ehrlichiosis

Thirumalapura¹,

Crossley²,

Walker

et al. 2009

Infect Immun

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Human monocytotropic ehrlichiosis (HME), an emerging and often life-threatening tick-transmitted disease, is caused by the obligately intracellular bacterium Ehrlichia chaffeensis. HME is modeled in C57BL/6 mice using Ehrlichia muris, which causes persistent infection, and Ixodes ovatus Ehrlichia (IOE), which is either acutely lethal or sublethal depending on the dose and route of inoculation. A persistent primary E. muris infection, but not a sublethal IOE infection, protects mice against an ordinarily lethal secondary IOE challenge. In the present study, we determined the role of persistent infection in maintenance of protective memory immune responses. E. muris-infected mice were treated with doxycycline or left untreated and then challenged with an ordinarily lethal dose of IOE. Compared to E. muris-primed mice treated with doxycycline, untreated mice persistently infected with E. muris had significantly greater numbers of antigen-specific gamma interferon-producing splenic memory T cells, significant expansion of CD4 ؉ CD25 ؉ T regulatory cells, and production of transforming growth factor ␤1 in the spleen. Importantly, E. muris-primed mice treated with doxycycline showed significantly greater susceptibility to challenge infection with IOE compared to untreated mice persistently infected with E. muris. The study indicated that persistent ehrlichial infection contributes to heterologous protection by stimulating the maintenance of memory T-cell responses.

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“…Recombinant IOE OMP-19 was used to immunize mice subcutaneously in the presence of CFA. The mice were challenged at least 30 days later with 2ϫ LD 50 of IOE (approximately 500 bacteria [3]). Mice immunized with IOE OMP-19/CFA, but not CFA alone, were protected from IOE challenge (Fig.…”

Section: Recombinant Omps Mediate Protection Against Fatal Ioe Infectmentioning

confidence: 99%

CD4 T-Cell Epitopes Associated with Protective Immunity Induced following Vaccination of Mice with an Ehrlichial Variable Outer Membrane Protein

et al. 2007

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The ehrlichiae express variable outer membrane proteins (OMPs) that play important roles in both pathogenesis and host defense. Previous studies revealed that OMPs are immunodominant B-cell antigens and that passive transfer of anti-OMP antibodies can protect SCID mice from fatal ehrlichial infection. In this study, we used a model of fatal monocytotropic ehrlichiosis caused by Ehrlichia bacteria from Ixodes ovatus (IOE) to determine whether OMP immunization could generate protective immunity in immunocompetent mice. Immunization of C57BL/6 mice with a purified recombinant OMP expressed by IOE omp19 generated protection from fatal IOE infection and elicited robust humoral and CD4 T-cell responses. To identify CD4 T-cell epitopes within OMPs, we performed enzyme-linked immunospot analyses for gamma interferon (IFN-␥) production using a panel of overlapping 16-mer peptides from IOE OMP-19. Five immunoreactive peptides comprising residues 30 to 45, 77 to 92, 107 to 122, 197 to 212, and 247 to 264 were identified; the strongest response was generated against OMP-19 107-122 . Most of the peptides are conserved between E. muris and E. chaffeensis OMP-19, and they elicited IFN-␥ production in CD4 T cells from E. muris-infected mice, indicating that T-cell epitope cross-reactivity likely contributes to heterologous immunity. Accordingly, CD4 T-cell responses to both OMP-19 and OMP-19 107-122 were of greater magnitude following high-dose IOE challenge of mice that had been immunized by prior infection with E. muris. Our studies cumulatively identify B-and T-cell epitopes that are associated with protective homologous and heterologous immunity during ehrlichial infection.

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

Cited by 30 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

Persistent Infection Contributes to Heterologous Protective Immunity against Fatal Ehrlichiosis

CD4 T-Cell Epitopes Associated with Protective Immunity Induced following Vaccination of Mice with an Ehrlichial Variable Outer Membrane Protein

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