Spatiotemporal differences of early type I interferon response in acute and chronic viral infections

The main aim of this project was to uncover the spatiotemporal events influencing type I interferon (IFN-I) dynamics during the early phase of acute and chronic viral infections. Time-resolved spleen-transcriptome analysis of LCMV-infected mice revealed two waves of IFN-I expression in acute infection, while in chronically infected mice a single wave of IFN-I genes was induced. We identified CD169+ macrophages as the source of the second wave of IFN-I only during acute infection, and characterized its polyfunctional role involving (i) the induction of pro-inflammatory macrophages, and (ii) the expansion of virus-specific CD8 T cells. Importantly, the IFN-I-mediated antiviral CD8 T cell response resulted in the development of fibrosis in lymphatic tissue. In contrast, during chronic infection the early CD8 T cell-mediated depletion of CD169+ macrophages resulted in a lack of IFN-I production and the subsequent IFN-I-mediated-pro-inflammatory response. Overall, we demonstrated that the spatiotemporal regulation of IFN-I production in the early stages of infection is crucial for the induction of sequential immune events that lead to viral infection resolution.El objetivo principal de este proyecto fué analizar los eventos espacio-temporales que determinan la dinámica de la respuesta de interferón de tipo I (IFN-I) durante la fase inicial de las infecciones virales agudas o crónicas. El análisis de los transcriptomas de bazos de ratones infectados por LCMV reveló dos olas de expresión de IFN-I durante la infección aguda, en contraste con un único pico de expresión durante una infección crónica. Estudios posteriores permitierón demostrar que la segunda ola de producción de IFN-I durante una infección aguda está mediada por macrófagos CD169+, y que entre sus funciones se encuentran la inducción de (i) macrófagos proinflamatorios, y (ii) células T CD8 antivirales, las cuales son finalmente responsables de la aparición de fibrosis en tejido linfático. Por otro lado, durante una infección crónica los macrófagos CD169+ son eliminados por acción de las células CD8+, impidiendo así la producción de IFN-I y de la consiguiente respuesta proinflamatoria. En resumen, en este trabajo demostramos que la regulación espacio-temporal de la producción de IFN-I en las primeras etapas de una infección viral es determinante para la inducción de eventos inmunológicos secuenciales, que finalmente afectan el desarrollo de la misma

Predicting the kinetic coordination of immune response dynamics in SARS-CoV-2 infection: implications for disease pathogenesis

A calibrated mathematical model of antiviral immune response to SARS-CoV-2 infection is developed. The model considers the innate and antigen-specific responses to SARS-CoV-2 infection. Recently published data sets from human challenge studies with SARS-CoV-2 were used for parameter evaluation. The calibration of the mathematical model of SARS-CoV-2 infection is based on combining the parameter guesses from our earlier study of influenza A virus infection, some recent quantitative models of SARS-CoV-2 infection and clinical data-based parameter estimation of a subset of the model parameters. Hence, the calibrated mathematical model represents a theoretical exploration type of study, i.e., ‘in silico patient’ with mild-to-moderate severity phenotype, rather than a completely validated quantitative model of COVID-19 with respect to all its state-space variables. Understanding the regulation of multiple intertwined reaction components of the immune system is necessary for linking the kinetics of immune responses with the clinical phenotypes of COVID-19. Consideration of multiple immune reaction components in a single calibrated mathematical model allowed us to address some fundamental issues related to the pathogenesis of COVID-19, i.e., the sensitivity of the peak viral load to the parameters characterizing the antiviral specific response components, the kinetic coordination of the individual innate and adaptive immune responses, and the factors favoring a prolonged viral persistence. The model provides a tool for predicting the infectivity of patients, i.e., the amount of virus which is transmitted via droplets from the person infected with SARS-CoV-2, depending on the time of infection. The thresholds for variations of the innate and adaptive response parameters which lead to a prolonged persistence of SARS-CoV-2 due to the loss of a kinetic response synchrony/coordination between them were identified.The reported study was funded by RFBR according to the research projects number 20-04-60157 and 20-01-00352. AM is also supported by the Spanish Ministry of Science and Innovation grant no. PID2019-106323RB-I00 AEI//10.13039/501100011033 and the Unidad de Excelencia María de Maeztu (AEI CEX2018-000792-M)

Mathematical model predicting the kinetics of intracellular LCMV replication

The lymphocytic choriomeningitis virus (LCMV) is a non-cytopathic virus broadly used in fundamental immunology as a mouse model for acute and chronic virus infections. LCMV remains a cause of meningitis in humans, in particular the fatal LCMV infection in organ transplant recipients, which highlights the pathogenic potential and clinical significance of this neglected human pathogen. Paradoxically, the kinetics of the LCMV intracellular life cycle has not been investigated in detail. In this study, we formulate and calibrate a mathematical model predicting the kinetics of biochemical processes, including the transcription, translation, and degradation of molecular components of LCMV underlying its replication in infected cells. The model is used to study the sensitivity of the virus growth, providing a clear ranking of intracellular virus replication processes with respect to their contribution to net viral production. The stochastic formulation of the model enables the quantification of the variability characteristics in viral production, probability of productive infection and secretion of protein-deficient viral particles. As it is recognized that antiviral therapeutic options in human LCMV infection are currently limited, our results suggest potential targets for antiviral therapies. The model provides a currently missing building module for developing multi-scale mathematical models of LCMV infection in mice

Functional cure of a chronic virus infection by shifting the virus - host equilibrium state

The clinical handling of chronic virus infections remains a challenge. Here we describe recent progress in the understanding of virus - host interaction dynamics. Based on the systems biology concept of multi-stability and the prediction of multiplicative cooperativity between virus-specific cytotoxic T cells and neutralising antibodies, we argue for the requirements to engage multiple immune system components for functional cure strategies. Our arguments are derived from LCMV model system studies and are translated to HIV-1 infection.The authors are supported by the Russian Science Foundation (RSF grant no. 18-11-00171), the Russian Foundation of Basic Research (RFBR grant no. 20-01-00352), “la Caixa” Foundation under the project code HR17-00199, the Spanish Ministry of Science and Innovation grant no. PID2019-106323RB-I00 AEI//10.13039/501100011033, and “Unidad de Excelencia María de Maeztu”, funded by the MCIN and the AEI (DOI: 10.13039/501100011033) Ref: CEX2018-000792-M

Numbers game and immune geography as determinants of coronavirus pathogenicity

info:eu-repo/semantics/publishedVersio

XCR1+ DCs are critical for T cell-mediated immunotherapy of chronic viral infections

The contribution of cross-presenting XCR1+ dendritic cells (DCs) and SIRPα+ DCs in maintaining T cell function during exhaustion and immunotherapeutic interventions of chronic infections remains poorly characterized. Using the mouse model of chronic LCMV infection, we found that XCR1+ DCs are more resistant to infection and highly activated compared with SIRPα+ DCs. Exploiting XCR1+ DCs via Flt3L-mediated expansion or XCR1-targeted vaccination notably reinvigorates CD8+ T cells and improves virus control. Upon PD-L1 blockade, XCR1+ DCs are not required for the proliferative burst of progenitor exhausted CD8+ T (TPEX) cells but are indispensable to sustain the functionality of exhausted CD8+ T (TEX) cells. Combining anti-PD-L1 therapy with increased frequency of XCR1+ DCs improves functionality of TPEX and TEX subsets, while increase of SIRPα+ DCs dampened their proliferation. Together, this demonstrates that XCR1+ DCs are crucial for the success of checkpoint inhibitor-based therapies through differential activation of exhausted CD8+ T cell subsets.This work was supported by grants from the Spanish Ministry of Science and Innovation (grant No. PID2019-106323RB-I00 AEI//10.13039/501100011033), the “Unidad de Excelencia María de Maeztu” funded by the MCIN and the AEI (DOI: 10.13039/501100011033; Ref: CEX2018-000792-M), “la Caixa” Foundation (HR17-00199), the Russian Science Foundation (grant No. 18-11-00171), and the Research Council of Norway (grant No. 250884)

Systems analysis reveals complex biological processes during virus infection fate decisions

The processes and mechanisms of virus infection fate decisions that are the result of a dynamic virus-immune system interaction with either an efficient effector response and virus elimination or an alleviated immune response and chronic infection are poorly understood. Here, we characterized the host response to acute and chronic lymphocytic choriomeningitis virus (LCMV) infections by gene coexpression network analysis of time-resolved splenic transcriptomes. First, we found an early attenuation of inflammatory monocyte/macrophage prior to the onset of T cell exhaustion, and second, a critical role of the XCL1-XCR1 communication axis during the functional adaptation of the T cell response to the chronic infection state. These findings not only reveal an important feedback mechanism that couples T cell exhaustion with the maintenance of a lower level of effector T cell response but also suggest therapy options to better control virus levels during the chronic infection phase.This work was supported by a grant from the Spanish Ministry of Economy, Industry and Competitiveness and FEDER Grant No. SAF2016-75505-R (AEI/MINEICO/FEDER, UE), the Russian Science Foundation Grant 18-11-00171, the Uehara Memorial Foundation (to T.K.), Grant-in-Aid for Scientific Research B 17H04088 from the Japan Society for the Promotion of Science (JSPS), (to T.K.), and the grant of the National Bioinformatics Institute (INB), PRB2-ISCIII (PT13/0001/0044 to A.E.-C.)