Date Published: December 28, 2018
Publisher: Public Library of Science
Author(s): Sinead E. Morris, Andrew J. Yates, Rik L. de Swart, Rory D. de Vries, Michael J. Mina, Ashley N. Nelson, Wen-Hsuan W. Lin, Roger D. Kouyos, Diane E. Griffin, Bryan T. Grenfell, Neil M. Ferguson.
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.
Measles virus (MV) is highly contagious and remains one of the leading causes of child mortality worldwide, despite the existence of a safe and effective vaccine . In addition to its public health importance, MV is also a paradigm for understanding the dynamics of acute respiratory infections at broad epidemiological scales [2, 3]. However, at finer within-host scales, the kinetics of MV are less well understood. Unlike other common respiratory viruses such as influenza, MV does not initially infect epithelial cells of the respiratory tract . Instead, MV is unusual in that it preferentially targets host immune cells, in particular those expressing the CD150 (SLAMF1) receptor [5, 6]. This atypical target population includes dendritic cells of the innate immune system, and B and T lymphocytes of the adaptive system [6, 7], and thus creates a dynamical feedback whereby the cells responsible for mounting an effective immune response are also under viral predation.
In addition to its public health importance, MV is a paradigm for understanding the kinetics of acute immunizing infections at the epidemic scale [2, 3]. However, the dynamical underpinnings of MV immunity and immunosuppression are less well understood, in part due to a lack of integration between mathematical models and rich within-host data. We address this gap by developing a novel, data-rooted framework for modeling MV dynamics that incorporates predatory feedbacks between the virus and host immune cells. In general, we find that a model combining target cells and T cells best fits the data and is able to capture substantial variation in individual dynamics. By testing the relative impacts of T cell depletion and target cell addition on model predictions, we find that cellular immunity has a greater influence on viral clearance than target cell depletion. In addition to supporting the findings of previous experiments , this conclusion highlights the strength of MV-specific killer T cells in overcoming the direct effects of viral predation. More broadly, we find that the model can also reproduce dynamics dominated by target cell depletion (such as those observed for CDV) when viral growth rates are high or the strength of cellular immunity is low. Overall, our work provides a new quantitative platform from which to explore the complex dynamics of MV infection and test drivers of viral clearance across the Morbillivirus genus.