Incomplete genetic reconstitution of B cell pools contributes to prolonged immunosuppression after measles

Abstract

Measles causes immunosuppression by restricting naïve B cell diversity and eliminating previously established B memory cells. Measles infection prunes back B cell memory Measles virus is a highly infectious lymphotropic virus associated with an extended period of immunosuppression after resolution of acute viremia. Petrova et al. sequenced the immunoglobulin gene repertoire of naïve and memory B cells in paired pre- and post-measles infection blood samples from unvaccinated children. Memory B cell clones present before infection were depleted in post-measles samples even after lymphocyte counts had recovered, a change not seen in controls given a flu vaccination. The naïve B cell repertoire exhibited multiple perturbations after measles infection, including a profound skew toward clones with immature features in ~10% of the cohort. The B cell repertoire changes documented in this study provide a molecular explanation for the durable “immune amnesia” observed after measles infection in unvaccinated populations. Measles is a disease caused by the highly infectious measles virus (MeV) that results in both viremia and lymphopenia. Lymphocyte counts recover shortly after the disappearance of measles-associated rash, but immunosuppression can persist for months to years after infection, resulting in increased incidence of secondary infections. Animal models and in vitro studies have proposed various immunological factors underlying this prolonged immune impairment, but the precise mechanisms operating in humans are unknown. Using B cell receptor (BCR) sequencing of human peripheral blood lymphocytes before and after MeV infection, we identified two immunological consequences from measles underlying immunosuppression: (i) incomplete reconstitution of the naïve B cell pool leading to immunological immaturity and (ii) compromised immune memory to previously encountered pathogens due to depletion of previously expanded B memory clones. Using a surrogate model of measles in ferrets, we investigated the clinical consequences of morbillivirus infection and demonstrated a depletion of vaccine-acquired immunity to influenza virus, leading to a compromised immune recall response and increased disease severity after secondary influenza virus challenge. Our results show that MeV infection causes changes in naïve and memory B lymphocyte diversity that persist after the resolution of clinical disease and thus contribute to compromised immunity to previous infections or vaccinations. This work highlights the importance of MeV vaccination not only for the control of measles but also for the maintenance of herd immunity to other pathogens, which can be compromised after MeV infection.