Measles Immune Suppression: Lessons from the Macaque Model

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Abstract
Measles remains a significant childhood disease, and is associated with a transient immune suppression. Paradoxically, measles virus (MV) infection also induces robust MV-specific immune responses. Current hypotheses for the mechanism underlying measles immune suppression focus on functional impairment of lymphocytes or antigen-presenting cells, caused by infection with or exposure to MV. We have generated stable recombinant MVs that express enhanced green fluorescent protein, and remain virulent in non-human primates. By performing a comprehensive study of virological, immunological, hematological and histopathological observations made in animals euthanized at different time points after MV infection, we developed a model explaining measles immune suppression which fits with the “measles paradox”. Here we show that MV preferentially infects CD45RA− memory T-lymphocytes and follicular B-lymphocytes, resulting in high infection levels in these populations. After the peak of viremia MV-infected lymphocytes were cleared within days, followed by immune activation and lymph node enlargement. During this period tuberculin-specific T-lymphocyte responses disappeared, whilst strong MV-specific T-lymphocyte responses emerged. Histopathological analysis of lymphoid tissues showed lymphocyte depletion in the B- and T-cell areas in the absence of apoptotic cells, paralleled by infiltration of T-lymphocytes into B-cell follicles and reappearance of proliferating cells. Our findings indicate an immune-mediated clearance of MV-infected CD45RA− memory T-lymphocytes and follicular B-lymphocytes, which causes temporary immunological amnesia. The rapid oligoclonal expansion of MV-specific lymphocytes and bystander cells masks this depletion, explaining the short duration of measles lymphopenia yet long duration of immune suppression. Measles is associated with a transient immune suppression, resulting in increased susceptibility to opportunistic infections. Indeed, the main causes of measles mortality are secondary infections in the respiratory and digestive tract. Although measles is associated with lymphopenia, depletion of lymphocytes has often been dismissed as a cause of immune suppression. Lymphocyte counts rapidly return to normal after clearance of the virus, while immune suppression lasts several weeks to months. Many studies have focused on suppression of lymphocyte proliferation as an in vitro correlate of immune suppression. However, experimental infections of non-human primates show that in vivo lymphocyte proliferation is not impaired after measles. Instead, we hypothesize that massive expansion of MV-specific and bystander lymphocytes masks the fact that pre-existing memory lymphocytes have been depleted. We conclude that measles virus infection wipes out immunological memory, leaving individuals susceptible to opportunistic infectious agents that would normally be controlled by the immune system.