CCR5 is essential for NK cell trafficking and host survival following Toxoplasma gondii infection
Imtiaz A Khan1, Seddon Y Thomas, Magali M Moretto
1Department of Microbiology, Immunology, and Parasitology, Louisiana State University Medical Center, New Orleans, Louisiana, USA. ikhan@lsuhsc.edu
Abstract:
The host response to intracellular pathogens requires the coordinated action of both the innate and acquired immune systems. Chemokines play a critical role in the trafficking of immune cells and transitioning an innate immune response into an acquired response. We analyzed the host response of mice deficient in the chemokine receptor CCR5 following infection with the intracellular protozoan parasite Toxoplasma gondii. We found that CCR5 controls recruitment of natural killer (NK) cells into infected tissues. Without this influx of NK cells, tissues from CCR5-deficient (CCR5-/-) mice were less able to generate an inflammatory response, had decreased chemokine and interferon gamma production, and had higher parasite burden. As a result, CCR5-/- mice were more susceptible to infection with T. gondii but were less susceptible to the immune-mediated tissue injury seen in certain inbred strains. Adoptive transfer of CCR5+/+ NK cells into CCR5-/- mice restored their ability to survive lethal T. gondii infection and demonstrated that CCR5 is required for NK cell homing into infected liver and spleen. This study establishes CCR5 as a critical receptor guiding NK cell trafficking in host defense.
Insights
Chemokine receptor CCR5 is vital for natural killer (NK) cell recruitment to combat Toxoplasma gondii infection. Its absence increases parasite burden but reduces immune-mediated tissue damage, highlighting CCR5
Area of Science:
- Immunology
- Infectious Diseases
- Cellular Biology
Background:
- Host defense against intracellular pathogens relies on integrated innate and adaptive immunity.
- Chemokines are crucial for immune cell migration and bridging innate to adaptive responses.
- The role of chemokine receptor CCR5 in host defense against intracellular parasites is not fully understood.
Purpose of the Study:
- To investigate the function of chemokine receptor CCR5 in the host response to Toxoplasma gondii infection.
- To determine the specific immune cells regulated by CCR5 during infection.
- To elucidate the impact of CCR5 deficiency on parasite control and host pathology.
Main Methods:
- Analysis of host response in CCR5-deficient (CCR5-/-) mice infected with Toxoplasma gondii.
- Assessment of immune cell infiltration, particularly natural killer (NK) cells, in infected tissues.
- Measurement of chemokine and cytokine production (e.g., interferon-gamma).
- Evaluation of parasite burden and host survival.
- Adoptive transfer experiments using NK cells.
Main Results:
- CCR5 deficiency impairs the recruitment of NK cells into T. gondii-infected tissues.
- CCR5-/- mice exhibit reduced inflammatory responses, lower chemokine and interferon-gamma levels, and increased parasite loads.
- Absence of CCR5 confers resistance to T. gondii-induced immune-mediated tissue injury but increases susceptibility to infection.
- Adoptive transfer of wild-type NK cells rescues survival in CCR5-/- mice, confirming CCR5's role in NK cell homing.
Conclusions:
- CCR5 is essential for guiding NK cell trafficking to infected liver and spleen during T. gondii infection.
- CCR5-mediated NK cell recruitment is critical for controlling parasite burden and host defense.
- CCR5 plays a dual role, promoting host defense while also contributing to immune-mediated pathology in certain contexts.
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