Recovery of an Antiviral Antibody Response following Attrition Caused by Unrelated Infection

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 FcRIIB-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. Author Summary Antibody responses to infectious pathogens are critical in host survival, recovery and protection from reinfection; they also correlate with the success of vaccination. It is currently thought that antibody serum titers are maintained at protective levels over long periods of time by specialized long-lived antibody-secreting plasma cells residing in the bone marrow. Indeed, antibodies against the original virus can still be found in survivors of the 1918 Spanish Flu, more than 90 years ago. However, it is also becoming clear that subsequent infection with heterologous pathogens may cause attrition of previously established immunological memory, in order to accommodate new lymphocyte specificities in the finite space of the host. This phenomenon is seemingly at odds with long-term maintenance of immunological memory. We also 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. However, Influenza A virus-specific immunity does eventually recover in these animals with the replenishment of plasma cells by B cells over the course of several weeks. Thus, the reported mechanism reconciles attrition of immunological memory by heterologous infection and long-term stability, and places B cells, instead of their descendant plasma cells, at the center of humoral memory.