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Published on: January 2, 2013
Model of severe malaria in young mice suggests unique response of CD4 T cells
Margaret R Smith1, Komi Gbedande2, Corey M Johnson1
1Department of Biology, College of Arts and Sciences, Appalachian State University, Boone, North Carolina, USA.
Insights
Researchers developed a young mouse model for severe malaria, revealing neurological symptoms and slower T helper 1 cell development in pups. This model aids understanding of pediatric malaria pathogenesis.
Area of Science:
- Immunology
- Infectious Diseases
- Pathogenesis Research
Background:
- Severe malaria disproportionately affects young children, yet a suitable rodent model for studying disease pathogenesis is lacking.
- Limited data exists on the adaptive immune system's intermediate stage in murine neonates, particularly regarding T helper cell responses.
- Understanding pediatric malaria requires a model that reflects developmental immune differences.
Purpose of the Study:
- To establish and characterize a novel mouse model of severe malaria in young mice (pups).
- To investigate the pathogenesis of Plasmodium chabaudi infection in a developmentally relevant preclinical model.
- To compare immune responses, specifically CD4+ T cell differentiation and function, between infected pups and adults.
Main Methods:
- Infection of 15-day-old mice (pups) with Plasmodium chabaudi.
- Monitoring parasite growth, mortality rates, and growth rates in pups versus adult mice.
- Utilizing behavioral assays to assess neurological symptoms.
- Analyzing CD4+ T cell activation, differentiation (Teff), and transcription factor expression (T-bet) via flow cytometry.
Main Results:
- The young mouse model exhibited a 60% mortality rate, similar parasite growth to adults, and reduced growth in survivors.
- Neurological symptoms were observed in infected pups, distinct from adult responses.
- CD4+ T cells in pups showed activation and differentiation into effector T cells (Teff), but with fewer terminally differentiated cells compared to adults.
- Pup Teff cells expressed higher levels of T-bet despite lower overall activation.
Conclusions:
- The developed mouse model effectively mimics aspects of severe pediatric malaria, including mortality and neurological manifestations.
- Murine neonates mount a functional, albeit slower developing, T helper 1 (Th1) cell response during Plasmodium infection.
- This model provides a valuable tool for dissecting the unique immunological challenges and pathogenesis of severe malaria in young children.
Abstract:
Severe malaria occurs most in young children but is poorly understood due to the absence of a developmentally-equivalent rodent model to study the pathogenesis of the disease. Though functional and quantitative deficiencies in innate response and a biased T helper 1 (Th1) response are reported in newborn pups, there is little information available about this intermediate stage of the adaptive immune system in murine neonates. To fill this gap in knowledge, we have developed a mouse model of severe malaria in young mice using 15-day old mice (pups) infected with Plasmodium chabaudi. We observe similar parasite growth pattern in pups and adults, with a 60% mortality and a decrease in the growth rate of the surviving young mice. Using a battery of behavioral assays, we observed neurological symptoms in pups that do not occur in infected wildtype adults. CD4+ T cells were activated and differentiated to an effector T cell (Teff) phenotype in both adult and pups. However, there were relatively fewer and less terminally differentiated pup CD4+ Teff than adult Teff. Interestingly, despite less activation, the pup Teff expressed higher T-bet than adults' cells. These data suggest that Th1 cells are functional in pups during Plasmodium infection but develop slowly.
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