Influence of tissue-structures on the spread of HIV-1

In this project we investigate how different environmental conditions influence the kinetics and contribution of cell-to-cell transmission to HIV-1 infection. By combining time-lapse microscopy data and time-course infection data for the spread of HIV-1 within 3D in vitro cultures, we developed a spatially explicit individual cell-based mathematical model that is able to recapitulate the observed infection dynamics. Based on this cellular Potts model, we are able to link single-cell characteristics to cell population dynamics, and to determine and quantify aspects of the viral transmission process that cannot be obtained experimentally so far. The project is part of a large collaboration of experimentalists, biophysicists, image analysts and mathematical modellers within the context of the DFG-funded SFB1129.

Participants: Peter Kumberger, Jana Fehr, Paola Carrillo-Bustamante; Andrea Imle, Oliver Fackler (Univ. Hospital HD), Ulrich Schwarz (BioQuant HD), Karl Rohr (DKFZ/IPMB), Fred Hamprecht (IWR)

Publications: Imle et al., Nat Comm 2019; Ahmed et al. Cells 2020

Parasite dynamics and Malaria pathogenesis

Specificity of malaria parasites for particular red blood cells (RBC) seems to play a key role in disease progression and the development of cerebral malaria. Combining mathematical models that describe blood stage infection dynamics with experimental data of different murine malaria strains, we aim at providing a systematic and quantitative analysis of how parasite specificity for RBC influences the spread of infection and disease development. The results are an important prerequisite for determining the precise mechanisms that lead to the observed neuropathology within the brain during malaria infection.

Participants: Neha Thakre; Priyanka Fernandes, Ann-Kristin Mueller (Univ. Hospital HD)

Publication: Thakre et al., Front Microbiol 2018

Quantifying HCV cell-to-cell spread in vitro

To determine the contribution of cell-to-cell transmission for the spread of HCV in vitro, we develop mathematical methods for analyzing HCV foci spread assays. Using image analysis tools and an individual cell-based model combining intracellular viral replication and intercellular viral spread, we are able disentangle the contribution of cell-free and cell-to-cell transmission to viral spread. These analyses provide a better understanding on how individual processes shape infection patterns and lead to the development of improved methods for quantifying viral spread based on single-cell infection data.  

Participants: Peter Kumberger; Susan L. Uprichard, Karina Durso-Cain, Harel Dahari (Loyola Univ. Chicago); Karl Rohr (DKFZ/IPMB)

Publications: Kumberger et al., Viruses 2018, Durso-Cain et al., Viruses 2021

Resources: https://github.com/GrawLab/HCVspread

Antiviral efficacy of Ribavirin against Lassa virus infection

The broad spectrum antiviral ribavirin is the only approved treatment against Lassa virus (LASV) infection but its efficacy is largely suboptimal and its mechanism of action remains unknown. As was observed in other viral diseases, the efficacy of ribavirin when given in monotherapy is low but could be potentiated by using combinations with other antivirals. Here, we use an interdisciplinary approach combining mathematical models and experimental data in mice treated with ribavirin alone or in combination with the drug favipiravir to explore different putative mechanisms of action for ribavirin. Our approach contributes towards understanding the mechanisms by which ribavirin mediates its antiviral effectiveness, which has important implications for the design of novel therapeutic strategies against LASV, and potentially other hemorrhagic fever viruses, such as Ebola.

Participants: Paola Carrillo-Bustamante; Jeremie Guedj, Tram Nguyen (INSERMS, Paris); Lisa Oestereich, Stephan Günther (BNI, Hamburg)

Publications: Carrillo-Bustamante et al., Scientific Reports 2017