CD8+ T cell knockout mice are less susceptible to Cowdria ruminantium infection than athymic, CD4+ T cell knockout, and normal C57BL/6 mice

Byrom, B.; Barbet, Anthony F.; Obwolo, M. J.; Mahan, Suman M.

doi:10.1016/s0304-4017(00)00336-8

Cited by 27 publications

(20 citation statements)

References 45 publications

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“…In the present reported studies, the importance of CD8 and CD4 T lymphocytes, antibodies, and IFN-␥ combined with TNF-␣ in protective immunity of mice against E. muris was demonstrated for the first time. The data confirmed some principles previously proposed for immunity to ehrlichiae mediated by antibodies, Fc receptors, MHC class II, and IFN-␥ and suggest novel anti-ehrlichial mechanisms involving MHC class I and CTL (1,3,5,8,14,21,22,26,44,50).…”

Section: Discussionsupporting

confidence: 73%

Mechanisms of Immunity toEhrlichia muris: a Model of Monocytotropic Ehrlichiosis

Feng

Walker

2004

Infect Immun

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Ehrlichia species can cause life-threatening infections or chronic persistent infections. Mechanisms of protective immunity were examined in an Ehrlichia muris mouse model of monocytotropic ehrlichiosis. C57BL/6 mice possessed strong genetic resistance to E. muris of an undetermined mechanism. CD8 T lymphocytes were particularly important, as revealed by 81% fatalities for E. muris-infected, major histocompatibility complex class I gene knockout mice compared with no deaths for wild-type C3H mice. Moreover, 80% of C3H mice depleted of CD8 and CD4 cells died of E. muris infection compared with only 44% of CD4 cell-depleted mice. CD8 T lymphocytes were demonstrated for the first time in an Ehrlichia infection to exhibit cytotoxic T-lymphocyte activity against Ehrlichia-infected target cells. Both gamma interferon and tumor necrosis factor were shown to play synergistic roles in protective immunity in vivo for the first time, as demonstrated by 75% fatalities when both cytokines were neutralized compared with minimal mortality when they were depleted separately. Passive transfer of antibodies, but not Fab fragments, to E. muris protected C3H/SCID mice against lethal infection. The mechanism of increased susceptibility (22% lethality) of C57BL/6 major histocompatibility complex class II gene knockout mice and CD4 cell-depleted C3H mice (i.e., through a gamma interferon or antibody mechanism), as well as the more important role of CD8 T lymphocytes (in the form of cytotoxic T-lymphocyte activity and/or gamma interferon production), remains to be elucidated. Protective immunity against monocytotropic E. muris is mediated by a combination of CD8 and CD4 T lymphocytes, gamma interferon, tumor necrosis factor alpha, and antibodies.

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Section: Discussionsupporting

confidence: 73%

Mechanisms of Immunity toEhrlichia muris: a Model of Monocytotropic Ehrlichiosis

Feng

Walker

2004

Infect Immun

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“…(iii) There is not a substantial difference in the time it takes to clear an infection in CD4D mice after one or two injections of bacteria, even in the presence of a strong CTL response at 6 days after a second experimental challenge. Our observations are also consistent with the data presented by Byrom et al (7). They found that ␤ 2 M knockout mice, deficient for CD8 ϩ T cells, were less susceptible to E. ruminantium infection than were healthy or MHCII knockout mice and suggested that the presence of CTLs may be detrimental in the face of infection.…”

Section: Cd4supporting

confidence: 82%

“…Additional experiments will be needed to determine the importance of these processes during E. chaffeensis infection. The lack of an IgG antibody response in MHCII knockout mice is consistent with our previous work (20) and that with E. ruminantium (7) and the concept that helper T cells are required for isotype switching (21). Moreover, it is not surprising that helper T cells not only activate macrophages to mediate bacterial clearance (20) but also contribute to the more robust antibody responses seen in the wild-type mice after a second injection of the bacteria in our study.…”

Section: Vol 72 2004supporting

confidence: 78%

Delayed Clearance of Ehrlichia chaffeensis Infection in CD4 ⁺ T-Cell Knockout Mice†

Ganta¹,

Cheng²,

Wilkerson³

et al. 2004

Infect Immun

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Human monocytic ehrlichiosis is an emerging tick-borne disease caused by the rickettsia Ehrlichia chaffeensis. To examine the role of helper T cells in host resistance to this macrophage-tropic bacterium, we assessed E. chaffeensis infections in three mouse strains with differing functional levels of helper T cells. Human monocytic ehrlichiosis, an emerging tick-borne disease with influenza-like symptoms, is caused by the macrophage/monocyte-tropic intracellular rickettsial agent Ehrlichia chaffeensis (11,19,30). E. chaffeensis also infects a wide range of vertebrate hosts which include white-tailed deer, dogs, goats, and coyotes (4,12,13,15,25,26). Human monocytic ehrlichiosis can cause a severe, potentially fatal illness in immunocompromised and elderly people with symptoms such as prolonged fever, renal failure, respiratory distress, seizures, and coma (33, 34).Tick-transmitted Rickettsiales members, including E. chaffeensis, persist in their vertebrate hosts for long periods despite the active host immune response (1,16,36,49). The relationship between E. chaffeensis and its targeted host cells, macrophages and monocytes, is critical because contrary to their natural function these cells fail to clear E. chaffeensis, allowing it to establish persistence by undefined evasion mechanisms. Studies of the murine host have been valuable in mapping the contributions of the host response to E. chaffeensis infections (20,41,46,47). Immunocompetent mice clear E. chaffeensis infection within 16 days (20,46), while the absence of macrophage activation results in a prolonged infection that can last over a month (20,41 MATERIALS AND METHODSMice. (i) C57BL/6J (B6) mice. B6 mice were obtained from the Jackson Laboratory (Bar Harbor, Maine) or from the breeding colony at Kansas State University (KSU). The B6 mouse breeding colony at KSU has been maintained by brother-sister matings for approximately 10 years.(ii) B6.129-Abb tm1 N5F20 (C2D) mice. The C2D mouse strain lacks MHCII. It has been backcrossed to the B6 mouse background and has been brother-sister mated for over 20 generations over the last 9 years at KSU. These mice do not express MHCII and lack CD4 ϩ T cells (Fig. 1) due to natural and manipulated mutagenesis (21). We established that these mice are unable to clear E. chaffeensis after infection (20).(iii) B6.129S6-Cd4 tm1Knw (CD4D) mice. CD4D mice were obtained from the Jackson Laboratory. These mice have a targeted disruption in the CD4 gene. We have confirmed the lack of CD4 ϩ T cells in these mice by flow cytometry (Fig. 1). All mice used in this study at the time of experimental infection were between 8 and 12 weeks old and were of mixed sexes. They were maintained ad libitum on standard lab chow with autoclaved water. Gene-deficient mice were routinely genotyped as described previously to confirm their genetic backgrounds (22,48).E. chaffeensis mouse infections. The E. chaffeensis Arkansas isolate was cultivated in the canine macrophage cell line DH82 as described previously (9). The mouse infections were p...

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“…In support of our results, a previous study showed that CD8 ϩ T cell knockout mice were less susceptible than wild-type or CD4 ϩ T cell knockout mice to infection with Ehrlichia ruminantum (another tick-transmitted Ehrlichia strain that is very closely related to other monocytotropic Ehrlichia, including IOE). In this study 50% of the CD8 ϩ T cell knockout mice survived infection, whereas the other half died after a prolonged period (33).…”

Section: Discussionmentioning

confidence: 99%

Overproduction of TNF-α by CD8+ Type 1 Cells and Down-Regulation of IFN-γ Production by CD4+ Th1 Cells Contribute to Toxic Shock-Like Syndrome in an Animal Model of Fatal Monocytotropic Ehrlichiosis

Ismail¹,

Soong

McBride

et al. 2004

The Journal of Immunology

114

233

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Human monocytotropic ehrlichiosis (HME) is an emerging, life-threatening, infectious disease caused by Ehrlichia chaffeensis, an obligate intracellular bacterium that lacks cell wall LPS. We have previously developed an animal model of severe HME using a strain of Ehrlichia isolated from Ixodes ovatus ticks (IOE). To understand the basis of susceptibility to severe monocytotropic ehrlichiosis, we compared low and high doses of the highly virulent IOE strain and the less virulent Ehrlichia muris strain that are closely related to E. chaffeensis in C57BL/6 mice. Lethal infections caused by high or low doses of IOE were accompanied by extensive liver damage, extremely elevated levels of TNF-α in the serum, high frequency of Ehrlichia-specific, TNF-α-producing CD8+ T cells in the spleen, decreased Ehrlicha-specific CD4+ T cell proliferation, low IL-12 levels in the spleen, and a 40-fold decrease in the number of IFN-γ-producing CD4+ Th1 cells. All groups contained negligible numbers of IL-4-producing cells in the spleen. Transfer of Ehrlichia-specific polyclonal Abs and IFN-γ-producing Ehrlichia-specific CD4+ and CD8+ type 1 cells protected naive mice against lethal IOE challenge. Interestingly, infection with high dose E. muris provided protection against rechallenge with a lethal dose of IOE. Cross-protection was associated with substantial expansion of IFN-γ-producing CD4+ and CD8+ cells, but not TNF-α-producing CD8+ T cells, a high titer of IgG2a, and a low serum level of TNF-α. In conclusion, uncontrolled TNF-α production by CD8+ T cells together with a weak CD4+ Th1 cell response are associated with immunopathology and failure to clear IOE in the fatal model of HME.

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CD8+ T cell knockout mice are less susceptible to Cowdria ruminantium infection than athymic, CD4+ T cell knockout, and normal C57BL/6 mice

Cited by 27 publications

References 45 publications

Mechanisms of Immunity toEhrlichia muris: a Model of Monocytotropic Ehrlichiosis

Mechanisms of Immunity toEhrlichia muris: a Model of Monocytotropic Ehrlichiosis

Delayed Clearance of Ehrlichia chaffeensis Infection in CD4 ⁺ T-Cell Knockout Mice†

Overproduction of TNF-α by CD8+ Type 1 Cells and Down-Regulation of IFN-γ Production by CD4+ Th1 Cells Contribute to Toxic Shock-Like Syndrome in an Animal Model of Fatal Monocytotropic Ehrlichiosis

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CD8+ T cell knockout mice are less susceptible to Cowdria ruminantium infection than athymic, CD4+ T cell knockout, and normal C57BL/6 mice

Cited by 27 publications

References 45 publications

Mechanisms of Immunity toEhrlichia muris: a Model of Monocytotropic Ehrlichiosis

Mechanisms of Immunity toEhrlichia muris: a Model of Monocytotropic Ehrlichiosis

Delayed Clearance of Ehrlichia chaffeensis Infection in CD4 + T-Cell Knockout Mice†

Overproduction of TNF-α by CD8+ Type 1 Cells and Down-Regulation of IFN-γ Production by CD4+ Th1 Cells Contribute to Toxic Shock-Like Syndrome in an Animal Model of Fatal Monocytotropic Ehrlichiosis

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Delayed Clearance of Ehrlichia chaffeensis Infection in CD4 ⁺ T-Cell Knockout Mice†