Control theory helps to resolve the measles paradox

Abstract

Measles virus (MV) is a highly contagious respiratory morbillivirus that results in many disabilities and deaths. A crucial challenge in studying MV infection is to understand the so-called ‘measles paradox’—the progression of the infection to severe immunosuppression before clearance of acute viremia, which is also observed in canine distemper virus (CDV) infection. However, a lack of models that match in vivo data has restricted our understanding of this complex and counter-intuitive phenomenon. Recently, progress was made in the development of a model that fits data from acute measles infection in rhesus macaques. This progress motivates our investigations to gain additional insights from this model into the control mechanisms underlying the paradox. In this paper, we investigated analytical conditions determining the control and robustness of viral clearance for MV and CDV, to untangle complex feedback mechanisms underlying the dynamics of acute infections in their natural hosts. We applied control theory to this model to help resolve the measles paradox. We showed that immunosuppression is important to control and clear the virus. We also showed under which conditions T-cell killing becomes the primary mechanism for immunosuppression and viral clearance. Furthermore, we characterized robustness properties of T-cell immunity to explain similarities and differences in the control of MV and CDV. Together, our results are consistent with experimental data, advance understanding of control mechanisms of viral clearance across morbilliviruses, and will help inform the development of effective treatments. Further the analysis methods and results have the potential to advance understanding of immune system responses to a range of viral infections such as COVID-19.

Measles Infection Dose Responses: Insights from Mathematical Modeling

“…When MV infection dose increases for TCID 50 , the peak viremia remains almost constant at about 3.3 per PBMCs, supporting the notion that cellular immunity plays the role of a predictable and robust control mechanism to achieve clearance of acute viremia (Anelone et al. 2021 ) (see Fig. 1 a, b).…”

“… 2018 ), and delivers analytical conditions under which T-cell killing becomes the primary mechanism for immunosuppression and viral clearance. The results in Morris et al ( 2012 ; 2018 ; 2021 ) are in line with experimental findings supporting that T-cell-mediated immunity controls infectious viral load during acute MV infection (Permar et al. 2003 , 2004 ).…”

“… 2018 ; Anelone et al. 2021 ). Our work predicts that variations of MV infection doses lead to similar changes in timings rather than magnitudes for both acute viremia and lymphocyte dynamics (Figs.…”

“… 2018 ; Anelone et al. 2021 ), we formulated the alternative model parameterization (B) by setting , to cancel the lysis of lymphocytes by MV, and to test T cell killing as the only mechanism for lymphocyte depletion and viral clearance.…”

“… 2018 ). The work in Anelone et al ( 2021 ) applied control theory to analyze on the model in (Morris et al. 2018 ), and delivers analytical conditions under which T-cell killing becomes the primary mechanism for immunosuppression and viral clearance.…”