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CR3-dependent resistance to acute Toxoplasma gondii infection in mice
L L Johnson1, G W Gibson, P C Sayles
1Trudeau Institute, Inc., Saranac Lake, New York 12983, USA.
Abstract:
Studies were performed to determine whether resistance to acute Toxoplasma gondii infection in mice depends on a mechanism involving CR3, the type 3 complement receptor. Nineteen of 22 mice (86%) given multiple injections of the anti-CR3 monoclonal antibody, 5C6, prior to and after intraperitoneal inoculation of cysts of the ordinarily mildly virulent ME49 strain of T. gondii died within 8 to 12 days, whereas control antibody-treated mice survived. All (five of five) anti-CR3-treated BALB/c mice infected via the natural peroral route died within 8 days of infection. Flow cytometric analysis of cells recovered from peritoneal lavages of anti-CR3-treated T. gondii-infected mice revealed that the percentage of Thy-1+ CD4- CD8- cells was reduced to about 50% of that of control antibody-treated mice and to about 20% of the number of such cells in controls. The numbers of macrophages, polymorphonuclear leukocytes, and lymphocytes recovered from the peritoneal cavities of T. gondii-infected mice were all reduced in anti-CR3-treated mice to about 40% of those of controls. In addition, anti-CR3-treated mice had less than 25% of the induced NK cell activity of the controls, and gamma interferon was reduced to undetectable levels. Thus, the rapid death of anti-CR3-treated mice was probably caused by impaired preimmune defenses. Histological examination of anti-CR3-treated T. gondii-infected mice revealed extensive liver pathology compared with that of infected mice given a control antibody or uninfected mice given anti-CR3. The inflammation, degeneration, and necrosis in most of the anti-CR3-treated mice were severe enough to account for the observed mortalities.
Insights
Blocking the type 3 complement receptor (CR3) severely impairs mice's innate immune defenses against Toxoplasma gondii infection, leading to high mortality and severe liver pathology. This highlights CR3's crucial role in controlling acute parasitic infections.
Area of Science:
- Immunology
- Parasitology
- Infectious Diseases
Background:
- Toxoplasma gondii is a common parasite causing opportunistic infections.
- The role of complement receptor 3 (CR3) in innate immunity against T. gondii is not fully understood.
Purpose of the Study:
- To investigate the role of CR3 in resistance to acute Toxoplasma gondii infection in mice.
Main Methods:
- Mice were treated with anti-CR3 monoclonal antibody (5C6) or control antibody.
- Mice were infected with T. gondii via intraperitoneal or peroral routes.
- Flow cytometry, cell counts, NK cell activity assays, and histological examinations were performed.
Main Results:
- Anti-CR3 treatment led to 86% mortality in intraperitoneally infected mice and 100% mortality in perorally infected mice.
- CR3 blockade significantly reduced immune cell populations (Thy-1+ CD4- CD8- cells, macrophages, leukocytes, lymphocytes) and NK cell activity.
- Histological analysis revealed severe liver pathology, including inflammation, degeneration, and necrosis, in anti-CR3 treated mice.
Conclusions:
- CR3 is essential for effective innate immune responses against acute T. gondii infection.
- Impairment of CR3 function compromises the host's ability to control parasitic invasion, leading to severe disease and mortality.
- Targeting CR3 may represent a potential therapeutic strategy for toxoplasmosis.