Research foci Experimental Infection Research

Chronic herpes virus infection

Infections with herpesviruses, which are latently present in 60-100% of the world population, constitute a major but still underestimated threat. Notably, human cytomegalovirus (HCMV) infections are the most common cause for infection-related abortions and disabilities such as mental retardation and hearing loss in newborn children. Other herpesviruses, such as herpes simplex virus (HSV) and varicella zoster virus (VZV), which are commonly known for causing cold sores and chickenpox, respectively, can also trigger detrimental encephalitis. We focus on the analysis of signaling platforms underlying the sensing of herpes viruses to better understand how the immune system recognizes and subsequently protects against herpesvirus infections. To this end, we deploy mouse models to gain a better understanding of the overall conditions in the body. Furthermore, a major emphasis is laid on the analysis of virus-host interactions in primary human cells. Finally, we closely collaborate with the clinics to identify biomarkers from specimen that report on viral encephalitis.

Publications

Infection-associated tissue inflammation

During many virus infections mostly one or few organs are mainly affected. The overall tolerogenic environment within different organs, such as the liver and the central nervous system (CNS) facilitate pathogen propagation in such organs. We focus on chronic and acute viral hepatitis and viral encephalitis. Unfortunately, pathogenesis of virus-induced hepatitis is not well understood and immunological therapies aiming at re-adjustment of immunological processes are not available. Virus infection of the central nervous system causes high morbidity and mortality. Due to a major lack of the understanding of molecular mechanisms of anti-viral protection within the CNS, currently efficacious therapies are very limited. For acute viral hepatitis and viral encephalitis, we aim at better understanding what roles tissue-resident myeloid cells, i.e., Kupffer cells in the liver and microglia in the CNS, play during infection and how they interact with infiltrating myeloid cells. By molecular profiling CSF from patients with CNS infections, we are trying to infer about immune response/host response mechanisms and end-organ damage in neuroinfections. We are also investigating the role of the small molecule itaconic  acid (an intermediate of the TCA cycle that is specifically induced in myeloid cells upon activation) in modulating inflammatory responses during infections. In collaboration with the MHH (V. Kaever) we have established the world-wide first reliable assay to measure IA levels in human plasma in order to assess its value as a biomarker.

Publications

Innovative interventions

We developed innovative test systems based on primary human immune cells and mouse models that are currently used for pre-clinical testing of new therapeutic monoclonal antibodies, as well as a new RNA-based adjuvant. In the context of the Helmholtz Cross Program Initiative iMed a new vaccination study has been initiated to better understand the molecular basis of HBV vaccination non-responsiveness. Also new formulations of approved drugs are being tested currently. Because autoimmune patients show enhanced incidence and increased severity of common infectious diseases, we are studying an innovative anti-inflammatory strategy for local treatment of autoimmunity.

Publications

Biomarkers for infectious diseases

Biomarkers are molecular (e.g., C-reactive protein) or non-molecular (e.g., fever) parameters that can be host or pathogen-derived and can be used to measure biological or pathological processes or the response to treatment. By molecular and cellular profiling of human biosamples such as blood, tissues, cerebrospinal fluid we aim to identify more accurate markers that will improve individualized treatment and prevention of infectious diseases. Areas of research focus include host biomarkers for CNS infections (including by chronic herpes viruses) and predictive markers for an inadequate vaccine response, currently focusing on influenza vaccination of elderly individuals.

Publications

Chronic herpes virus infection

Hirche C, Frenz T, Haas SF, Doring M, Borst K, Tegtmeyer PK, Brizic I, Jordan S, Keyser K, Chhatbar C, Pronk E, Lin S, Messerle M, Jonjic S, Falk CS, Trumpp A, Essers MAG, Kalinke U (2017) Systemic Virus Infections Differentially Modulate Cell Cycle State and Functionality of Long-Term Hematopoietic Stem Cells In Vivo. Cell Rep 19(11): 2345-2356.

Doring M, Lessin I, Frenz T, Spanier J, Kessler A, Tegtmeyer P, Dag F, Thiel N, Trilling M, Lienenklaus S, Weiss S, Scheu S, Messerle M, Cicin-Sain L, Hengel H, Kalinke U (2014) M27 expressed by cytomegalovirus counteracts effective type I interferon induction of myeloid cells but not of plasmacytoid dendritic cells. J Virol 88(23): 13638-13650.

Spanier J, Lienenklaus S, Paijo J, Kessler A, Borst K, Heindorf S, Baker DP, Kroger A, Weiss S, Detje CN, Staeheli P, Kalinke U (2014) Concomitant TLR/RLH signaling of radioresistant and radiosensitive cells is essential for protection against vesicular stomatitis virus infection. J Immunol 193(6): 3045-3054.

Paijo J, Doring M, Spanier J, Grabski E, Nooruzzaman M, Schmidt T, Witte G, Messerle M, Hornung V, Kaever V, Kalinke U (2016) cGAS Senses Human Cytomegalovirus and Induces Type I Interferon Responses in Human Monocyte-Derived Cells. PLoS Pathog 12(4): e1005546.

Infection-associated tissue inflammation

Grabski E, Wappler I, Pfaender S, Steinmann E, Haid S, Dzionek A, Pietschmann T, Kalinke U (2015) Efficient virus assembly, but not infectivity, determines the magnitude of hepatitis C virus-induced interferon alpha responses of plasmacytoid dendritic cells. J Virol 89(6): 3200-3208.

Pfaender S, Grabski E, Detje CN, Riebesehl N, Lienenklaus S, Steinmann E, Kalinke U, Pietschmann T (2016) Hepatitis C Virus Stimulates Murine CD8alpha-Like Dendritic Cells to Produce Type I Interferon in a TRIF-Dependent Manner. PLoS Pathog 12(7): e1005736.

Detje CN, Meyer T, Schmidt H, Kreuz D, Rose JK, Bechmann I, Prinz M, Kalinke U (2009) Local type I IFN receptor signaling protects against virus spread within the central nervous system. J Immunol 182(4): 2297-2304.

Detje CN, Lienenklaus S, Chhatbar C, Spanier J, Prajeeth CK, Soldner C, Tovey MG, Schluter D, Weiss S, Stangel M, Kalinke U (2015) Upon intranasal vesicular stomatitis virus infection, astrocytes in the olfactory bulb are important interferon Beta producers that protect from lethal encephalitis. J Virol 89(5): 2731-2738.

Kuhn M, Sühs KW, Akmatov MK, Klawonn F, Wang J, Skripuletz T, Kaever V, Stangel M, Pessler F. Cerebrospinal fluid metabolites as biomarkers for CNS involvement in varicella-zoster virus reactivation. Frontiers Cell Infect Microbiol (in revision)

Innovative interventions

Vogel S, Grabski E, Buschjager D, Klawonn F, Doring M, Wang J, Fletcher E, Bechmann I, Witte T, Durisin M, Schraven B, Mangsbo SM, Schonfeld K, Czeloth N, Kalinke U (2015) Antibody induced CD4 down-modulation of T cells is site-specifically mediated by CD64(+) cells. Sci Rep 5: 18308.

Bartholomaeus P, Semmler LY, Bukur T, Boisguerin V, Romer PS, Tabares P, Chuvpilo S, Tyrsin DY, Matskevich A, Hengel H, Castle J, Hunig T, Kalinke U (2014) Cell contact-dependent priming and Fc interaction with CD32+ immune cells contribute to the TGN1412-triggered cytokine response. J Immunol 192(5): 2091-2098.

Ziegler A, Soldner C, Lienenklaus S, Spanier J, Trittel S, Riese P, Kramps T, Weiss S, Heidenreich R, Jasny E, Guzman CA, Kallen KJ, Fotin-Mleczek M, Kalinke U (2017) A New RNA-Based Adjuvant Enhances Virus-Specific Vaccine Responses by Locally Triggering TLR- and RLH-Dependent Effects. J Immunol 198(4): 1595-1605.

Frenz T, Grabski E, Duran V, Hozsa C, Stepczynska A, Furch M, Gieseler RK, Kalinke U (2015) Antigen presenting cell-selective drug delivery by glycan-decorated nanocarriers. Eur J Pharm Biopharm 95(Pt A): 13-17.

Frenz T, Grabski E, Buschjager D, Vaas LA, Burgdorf N, Schmidt RE, Witte T, Kalinke U (2016) CD4(+) T cells in patients with chronic inflammatory rheumatic disorders show distinct levels of exhaustion. J Allergy Clin Immunol 138(2): 586-589 e510.

Biomarkers for infectious diseases

Kuhn M, Sühs KW, Akmatov MK, Klawonn F, Wang J, Skripuletz T, Kaever V, Stangel M, Pessler F. Cerebrospinal fluid metabolites as biomarkers for CNS involvement in varicella-zoster virus reactivation. Frontiers Cell Infect Microbiol (in revision)

Akmatov MK, Jentsch L, Riese P, May M, Ahmed MW, Werner D, Rosel A, Prokein J, Bernemann I, Klopp N, Prochnow B, Illig T, Schindler C, Guzman CA, Pessler F (2017) Motivations for (non)participation in population-based health studies among the elderly - comparison of participants and nonparticipants of a prospective study on influenza vaccination. BMC Med Res Methodol 17(1): 18.

Akmatov MK, Riese P, May M, Jentsch L, Ahmed MW, Werner D, Rosel A, Tyler M, Pessler K, Prokein J, Bernemann I, Klopp N, Prochnow B, Trittel S, Tallam A, Illig T, Schindler C, Guzman CA, Pessler F (2017) Establishment of a cohort for deep phenotyping of the immune response to influenza vaccination among elderly individuals recruited from the general population. Hum Vaccin Immunother 13(7): 1630-1639.