Abstract
The delay in parasite-specific B cell development leaves people in malaria endemic areas vulnerable to repeated Plasmodium infections. Here, we investigated the role of transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), a molecule involved in the generation of antigen-specific antibody secreting cells, in host response to non-lethal Plasmodium yoelii infection. We found that TACI deficiency not only resulted in higher peak parasitemia levels in P. yoelii challenged mice, but also led to a delay in parasite clearance and anti-P. yoelii Merozoite Surface Protein 1(C-terminal 19-kDa fragment [rMSP-119]) protein and anti-rMSP-119 and anti-P. yoelii IgG antibody development. There was also a delay in the generation of splenic high affinity antibody secreting cells that recognize rMSP-119 protein as compared to wild-type mice. Interestingly, coinciding with the delay in parasite clearance there was a delay in the resolution of T follicular helper (TFH) cell and germinal center (GC) B cell responses in TACI -/- mice. The persistence of TFH and GC B cells is likely a result of enhanced interaction between TFH and GC B cells because inducible costimulator ligand (ICOSL) expression was significantly higher on TACI -/- GC B cells than wild-type cells. The difference in the kinetics of GC reaction appeared to also impact the emergence of plasma cells (PC) because there was a delay in the generation of TACI -/- mice PC. Nevertheless, following the recovery from P. yoelii infection, TACI -/- and wild-type mice were both protected from a rechallenge infection. Establishment of protective B cell response was responsible for the resolution of parasitemia because B cells purified from recovered TACI -/- or wild-type mice were equally protective when introduced to naïve wild-type mice prior to P. yoelii challenge. Thus, despite the increased susceptibility of TACI -/- mice to P. yoelii infection and a delay in the development of protective antibody levels, TACI -/- mice are able to clear the infection and resist rechallenge infection.
Highlights
Children under the age of 5 years [1], especially those who are less than 1 year of age, are highly vulnerable to Plasmodium infections [2]
Parasitemia levels were significantly higher in TACI -/- mice starting at day 11 post-P. yoelii infection when compared to the wild-type mice
Elicited protective humoral immunity was likely responsible for the clearance of Plasmodium in TACI -/- mice because the delayed clearance of P. yoelii coincided with the late emergence of anti-malaria antibodies, and B cells transferred from P. yoelii immune TACI -/- mice afforded protection in naïve wildtype mice, and TACI -/- mice rechallenged with P. yoelii resisted infection
Summary
Children under the age of 5 years [1], especially those who are less than 1 year of age, are highly vulnerable to Plasmodium infections [2]. Shortcomings of immunological response that can control Plasmodium parasites have been attributed to the diversity of the malarial antigens, the rapid disappearance of antimalarial antibodies and an insufficient long-lived plasma cell (PC) pool [4]. While immunization of TACI -/- mice with a T cell dependent antigen elicited reduced antibody responses and short lived PC as compared to wild-type mice [11], TACI -/- mice controlled Citrobacter rodentium infection better than the wild-type mice most likely because of an increase in antibody secreting cells and development of high affinity antibodies directed against C. rodentium [12]. Measurement of elevated circulating BAFF and increased BAFF-R on B cells in humans experimentally challenged with Plasmodium falciparum suggest an involvement of these molecules in host response to malaria [13, 14]. Whether TACI participates in BAFFinduced host responses during malaria infection has not been explored
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