Protective heterologous immunity against fatal ehrlichiosis and lack of protection following homologous challenge

Nagaraja R. Thirumalapura, Heather Stevenson-Lerner, David Walker, Nahed Ismail

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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 Ehrlichia-specific secondary gamma interferon (IFN-γ)-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-1α (IL-1α), 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 Ehrlichia-specific 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-γ-producing CD4+ and CD8+ effector memory type 1 T cells, which appear to be maintained in the presence of IgG antibodies and persistent infection.

Original languageEnglish
Pages (from-to)1920-1930
Number of pages11
JournalInfection and Immunity
Volume76
Issue number5
DOIs
StatePublished - May 2008

Fingerprint

Heterologous Immunity
Ehrlichiosis
Ehrlichia
Ixodes
T-Lymphocytes
Infection
Antibodies
Immunoglobulin G
Cytoprotection
Liver
Ticks
Granuloma
Interleukin-1
Interleukin-10
Interferon-gamma
Antibody Formation
Anti-Idiotypic Antibodies
Interleukin-6
Necrosis
Apoptosis

ASJC Scopus subject areas

  • Immunology

Cite this

Protective heterologous immunity against fatal ehrlichiosis and lack of protection following homologous challenge. / Thirumalapura, Nagaraja R.; Stevenson-Lerner, Heather; Walker, David; Ismail, Nahed.

In: Infection and Immunity, Vol. 76, No. 5, 05.2008, p. 1920-1930.

Research output: Contribution to journalArticle

@article{66883581e339480f9b1e5d82ace14258,
title = "Protective heterologous immunity against fatal ehrlichiosis and lack of protection following homologous challenge",
abstract = "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 Ehrlichia-specific secondary gamma interferon (IFN-γ)-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-1α (IL-1α), 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 Ehrlichia-specific 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-γ-producing CD4+ and CD8+ effector memory type 1 T cells, which appear to be maintained in the presence of IgG antibodies and persistent infection.",
author = "Thirumalapura, {Nagaraja R.} and Heather Stevenson-Lerner and David Walker and Nahed Ismail",
year = "2008",
month = "5",
doi = "10.1128/IAI.01293-07",
language = "English",
volume = "76",
pages = "1920--1930",
journal = "Infection and Immunity",
issn = "0019-9567",
publisher = "American Society for Microbiology",
number = "5",

}

TY - JOUR

T1 - Protective heterologous immunity against fatal ehrlichiosis and lack of protection following homologous challenge

AU - Thirumalapura, Nagaraja R.

AU - Stevenson-Lerner, Heather

AU - Walker, David

AU - Ismail, Nahed

PY - 2008/5

Y1 - 2008/5

N2 - 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 Ehrlichia-specific secondary gamma interferon (IFN-γ)-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-1α (IL-1α), 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 Ehrlichia-specific 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-γ-producing CD4+ and CD8+ effector memory type 1 T cells, which appear to be maintained in the presence of IgG antibodies and persistent infection.

AB - 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 Ehrlichia-specific secondary gamma interferon (IFN-γ)-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-1α (IL-1α), 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 Ehrlichia-specific 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-γ-producing CD4+ and CD8+ effector memory type 1 T cells, which appear to be maintained in the presence of IgG antibodies and persistent infection.

UR - http://www.scopus.com/inward/record.url?scp=42949166276&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=42949166276&partnerID=8YFLogxK

U2 - 10.1128/IAI.01293-07

DO - 10.1128/IAI.01293-07

M3 - Article

VL - 76

SP - 1920

EP - 1930

JO - Infection and Immunity

JF - Infection and Immunity

SN - 0019-9567

IS - 5

ER -