The protozoan parasite Plasmodium causes over 200 million cases of malaria each year, and 400,000 people die annually from this disease. Hence, the need for an efficacious and cost-effective vaccine to reduce disease burden. In order to design an efficacious vaccine, mechanisms to enhance humoral immunity to this infection are required. Here, we are focused on how the co-stimulatory molecule ICOS contributes to the humoral immune response to two murine species of Plasmodium. We demonstrate that the loss of ICOS signaling induces similar and unique outcomes in response to Plasmodium yoelii and Plasmodium chabaudi infection. For instance, persistent infection with P. chabaudi leads to higher and more frequent relapses in parasitemia in Icos-/- mice, resulting in waves of antibody production by B cells without germinal center (GC) formation. While GCs fail to form in Icos-/- mice after P. chabaudi infection, they are present in the spleen of Icos-/- mice after acute infection with P. yoelii. The ability of the GCs to form is not dependent on high antigen load, as treatment with atovaquone to lower peak parasitemia did not impede GC formation in Icos-/- mice. Furthermore, unlike primary infection with P. chabaudi, Icos-/- mice display a defect in their ability to control acute infection with P. yoelii compared to their wild-type counterparts. Lastly, T follicular helper cell expansion and GC formation is impaired in Icos-/- mice, but not wild-type mice, after re-challenge with P. yoelii and P. chabaudi, leading to defects in B-cell recall responses. Collectively, these studies provide further insight into the role of ICOS in promoting humoral immunity during primary and secondary infections
|Advisor:||Stumhofer, Jason S.|
|Commitee:||Voth, Dan, Dings, Ruud, Li, Lin-Xi, Weinkopff, Tiffany|
|School:||University of Arkansas for Medical Sciences|
|Department:||Microbiology and Immunology|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 81/10(E), Dissertation Abstracts International|
|Keywords:||Humoral immunity, ICOS, Plasmodium, T follicular helper|
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