University of Heidelberg
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News

Oct. 6-7, 2017: 3rd Workshop on Virus Dynamics

Oct. 9-10, 2017: Hengstberger-Symposium on Systems Immunology & Vaccine Design

Research:

Why does our immune system work the way it works? How does it actually work? And what is the reason that our immune system fails to work sufficiently against some types of infectious pathogens?

In our group, we are combining mathematical models and experimental data to understand fundamental immunological and virological processes that occur within a host in response to infection with various pathogens. Thereby, we are particularly interested in the ability of the immune system to memorize previous infections, making it able to respond stronger and faster against subsequent infections with the same pathogen. Vaccines, one of the most important interventions in disease management and public health, use this immunological memory. However, especially in chronic infections, as e.g. caused by the human immunodeficiency virus (HIV) and hepatitis C virus (HCV), immunological memory seems to be impaired.

Below you find an enumeration of specific projects that we are currently working on to address open questions on the generation of immunological memory, and specific aspects of the infection dynamics of different pathogens, such as HCV, Malaria, Ebola and influenza virus.  

(1.) Viral spread

Spatial infection patterns and viral dynamics

Several aspects of the Hepatitis C virus (HCV) infection dynamics are still unknown. For example, does the virus propagate by cell-to-cell transmission or mostly via diffusion of viral particles? And how many cells get infected within the human liver during infection? In several projects we are using mathematical models and computational simulations to determine how viral replication and transmission dynamics, as well as local immune responses shape the spatial distribution of infected cells. Comparing these models to experimental and clinical data, we are trying to determine how HCV spreads during chronic infection.

In a similar project, together with Oliver Fackler (University Hospital Heidelberg) and Ulrich Schwarz (BioQuant-Center) in the context of the SFB1129, we are analyzing the kinetics and contribution of cell-to-cell transmission to HIV-1 infection. To this end, we combine mathematical models with experimental data on HIV-1 spread within complex 3D in vitro cultures.

 

Graw F, Martin DN, Perelson AS, Uprichard SL, Dahari H: Quantification of Hepatitis C virus cell-to-cell spread by using a stochastic modeling approach. J Virol 2015, 89:6551-6561

Graw F, Balagopal A, Kandathil AJ, Ray SC, Thomas DL, Ribeiro RM, Perelson AS Inferring viral dynamics in chronically HCV infected patients from the spatial distribution of infected hepatocytes. PLoS Comp Biol 2014, 10(11):e1003934

Kandathil AJ, Graw F, Quinn J, Hwang HS, Torbenson M, Perelson AS, Ray SC, Thomas DL, Ribeiro RM, Balagopal A: Use of laser capture microdissection to map HCV-positive hepatocytes in human liver. Gastroenterology 2013, 145:1404-1413

 

(2.) MCMV

Memory CD8+ T cell development in MCMV infection

Cytomegalovirus (CMV), a beta-herpesvirus that establishes life-long persistence in healthy individuals, received some attention as a potential vaccine vector against persistent infections. The specific CD8+ T cell response against this virus can be distinguished into two type of cell populations: (i) non-inflationary CD8+ T cells which are comparable in kinetic, function and phenotype to CD8+ T cells that develop during acute resolved infections, and (ii) inflationary CD8+ T cells which increase in number after resolution of acute infection and eventually stabilize at high frequencies with life-long persistence, a phenomenon which is called "memory inflation".

In this project, we are studying inflationary and non-inflationary CD8+ T cell popluations in response to murine CMV (MCMV) infection. We aim at describing and quantifying the dynamics and interaction of different subsets of memory cells to determine how inflationary CD8+ T cells are generated and maintained. This project is done in close collaboration with Roland Regoes and Annette Oxenius at the ETH Zurich.

 

(3.) Malaria

Parasite dynamics and Malaria pathogenesis

Malaria is one of the most serious tropical diseases with an estimated 210 million cases and ~660,000 deaths in 2010. Some strains of malarial parasites are known to cause more serious disease outcomes than other strains, i.e., leading to cerebral malaria and death. Thereby, parasite specificity for particular red blood cells (RBC) seems to play a key role in disease development. In this joined project with the group of Ann-Kristin Mueller from the University Hospital Heidelberg, we develop a mathematical model for blood stage malaria infection and immune dynamics, thereby accounting for RBC age structure and disease induced anaemia. Combining the model 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. The project is funded by the FRONTIER-initiative and the MWK Baden-W├╝rttemberg, RiSC-initiative.

Optimising vaccination regimens agains Malaria infection

In a second joined project with the group of Ann-Kristin Mueller, we aim to determine optimal malaria vaccination regimens that rely on the use of attenuated parasites. Based on data showing the influence of varying dosage, timing and frequencies during prime-boost vaccination regimes in mice, we use mathematical models to describe and quantify the dynamics of memory T cell generation in various organs. This project is also funded by the FRONTIER-initiative and the MWK Baden-W├╝rttemberg, RiSC-initiative.

Contact: E-Mail (Last update: 11/10/2017)