Abstract
The homeostatic mechanisms that regulate the maintenance of immunological memory to the multiple pathogen encounters over time are unknown. We found that a single malaria episode caused significant dysregulation of pre-established Influenza A virus-specific long-lived plasma cells (LLPCs) resulting in the loss of Influenza A virus-specific Abs and increased susceptibility to Influenza A virus re-infection. This loss of LLPCs involved an FcγRIIB-dependent mechanism, leading to their apoptosis. However, given enough time following malaria, the LLPC pool and humoral immunity to Influenza A virus were eventually restored. Supporting a role for continuous conversion of Influenza A virus-specific B into LLPCs in the restoration of Influenza A virus immunity, B cell depletion experiments also demonstrated a similar requirement for the long-term maintenance of serum Influenza A virus-specific Abs in an intact LLPC compartment. These findings show that, in addition to their established role in the anamnestic response to reinfection, the B cell pool continues to be a major contributor to the maintenance of long-term humoral immunity following primary Influenza A virus infection, and to the recovery from attrition following heterologous infection. These data have implications for understanding the longevity of protective efficacy of vaccinations in countries where continuous infections are endemic.
Highlights
Infection or vaccination usually induces high levels of antigenspecific antibodies (Abs) in the systemic circulation and mucosal surfaces
We show that a single episode of malaria, caused by infection by Plasmodium chabaudi, leads to the loss of preexisting plasma cells, serum antibodies and protective immunity against Influenza A virus
BALB/c mice were first infected with Puerto Rico/8/34 (PR8) and the kinetics of Ab induction, specific serum Ab concentrations and specific plasma cells and memory B cells (MBCs) were quantified at various time points after infection
Summary
Infection or vaccination usually induces high levels of antigenspecific antibodies (Abs) in the systemic circulation and mucosal surfaces. Virus-neutralizing Abs have been detected in humans over 90 years after Influenza A virus infection [2] and in mice over 250 days after lymphocytic choriomeningitis virus (LCMV) infection [3] The establishment of these long-term Ab responses relies on the maintenance of antigen-specific memory B cells (MBCs) and long-lived plasma cells (LLPCs). MBCs and LLPCs occupy distinct anatomical locations in the spleen and bone marrow, respectively, which are thought to be of finite size and under homeostatic control [4]. One consequence of such regulation is that new antigenic challenges, with complex pathogens that generate large populations of MBCs and LLPCs, would affect the maintenance of Ab responses to previously encountered antigens
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