Modeling the measles paradox reveals the importance of cellular immunity in regulating viral clearance

Measles virus (MV) is a highly contagious member of the Morbillivirus genus that remains a major cause of childhood mortality worldwide. Although infection induces a strong MV-specific immune response that clears viral load and confers lifelong immunity, transient immunosuppression can also occur, l...

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Bibliographic Details
Published in:	PLoS pathogens Vol. 14; no. 12; p. e1007493
Main Authors:	Morris, Sinead E., Yates, Andrew J., de Swart, Rik L., de Vries, Rory D., Mina, Michael J., Nelson, Ashley N., Lin, Wen-Hsuan W., Kouyos, Roger D., Griffin, Diane E., Grenfell, Bryan T.
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 28.12.2018 Public Library of Science (PLoS)
Subjects:	Animals Biology and Life Sciences Canine distemper Cell activation Cell-mediated immunity Cellular immunity Children Colonization Computer simulation Cytotoxicity Dendritic cells Depletion Epidemiology Evolutionary biology Fitness HIV Hospitals Human immunodeficiency virus Immune clearance Immune response Immune system Immune Tolerance - immunology Immunity Immunity (cell-mediated) Immunity, Cellular - immunology Immunology Immunosuppression Infections Infectious diseases Lymphocytes Macaca mulatta Mathematical models Measles Measles - immunology Measles virus - immunology Medicine and Health Sciences Mice Models, Theoretical Morbillivirus Pathology Pediatrics Public health Virology Viruses New York Netherlands United States > US Switzerland Baltimore Maryland
ISSN:	1553-7374, 1553-7366, 1553-7374
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Summary:	Measles virus (MV) is a highly contagious member of the Morbillivirus genus that remains a major cause of childhood mortality worldwide. Although infection induces a strong MV-specific immune response that clears viral load and confers lifelong immunity, transient immunosuppression can also occur, leaving the host vulnerable to colonization from secondary pathogens. This apparent contradiction of viral clearance in the face of immunosuppression underlies what is often referred to as the 'measles paradox', and remains poorly understood. To explore the mechanistic basis underlying the measles paradox, and identify key factors driving viral clearance, we return to a previously published dataset of MV infection in rhesus macaques. These data include virological and immunological information that enable us to fit a mathematical model describing how the virus interacts with the host immune system. In particular, our model incorporates target cell depletion through infection of host immune cells-a hallmark of MV pathology that has been neglected from previous models. We find the model captures the data well, and that both target cell depletion and immune activation are required to explain the overall dynamics. Furthermore, by simulating conditions of increased target cell availability and suppressed cellular immunity, we show that the latter causes greater increases in viral load and delays to MV clearance. Overall, this signals a more dominant role for cellular immunity in resolving acute MV infection. Interestingly, we find contrasting dynamics dominated by target cell depletion when viral fitness is increased. This may have wider implications for animal morbilliviruses, such as canine distemper virus (CDV), that cause fatal target cell depletion in their natural hosts. To our knowledge this work represents the first fully calibrated within-host model of MV dynamics and, more broadly, provides a new platform from which to explore the complex mechanisms underlying Morbillivirus infection.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Current address: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA Current address: Department of Pediatrics and Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA The authors have declared that no competing interests exist.
ISSN:	1553-7374 1553-7366 1553-7374
DOI:	10.1371/journal.ppat.1007493