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 of infection-associated 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 to cause 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 controls herpesvirus infection. To this end, we study mouse models as well 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. The pathogenesis of virus-induced hepatitis is still 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 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 leucocytes. Furthermore, we are dissecting mechanisms how leucocytes are recruited to the infected CNS. 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 (H. Baehre) we have established a validated assay to measure concentrations of IA and its isomers citraconic and mesaconic acids in human biofluids in order to assess their value as biomarkers.

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. Because patients with autoinflammatory diseases show enhanced incidence and increased severity of common infections, we are studying an innovative anti-inflammatory strategy for local treatment of autoimmunity.

Publications

Chronic herpes virus infection

Tegtmeyer PK, Spanier J, Borst K, Becker J, Riedl A, Hirche C, Ghita L, Skerra J, Baumann K, Lienenklaus S, Doering M, Ruzsics Z, Kalinke U (2019) STING induces early IFN-β in the liver and constrains myeloid cell-mediated dissemination of murine cytomegalovirus. Nat Commun 10(1): 2830.

Chhatbar C, Detje CN, Grabski E, Borst K, Spanier J, Ghita L, Elliott DA, Jordão MJC, Mueller N, Sutton J, Prajeeth CK, Gudi V, Klein MA, Prinz M, Bradke F, Stangel M, Kalinke U (2018) Type I Interferon Receptor Signaling of Neurons and Astrocytes Regulates Microglia Activation during Viral Encephalitis. Cell Rep 25(1): 118-129.

Kuhn M, Sühs KW, Akmatov MK, Klawonn F, Wang J, Skripuletz T, Kaever V, Stangel M, Pessler F (2018) Mass-spectrometric profiling of cerebrospinal fluid reveals metabolite biomarkers for CNS involvement in varicella zoster virus reactivation. J Neuroinflammation 15(1): 20.

Borst K, Frenz T, Spanier J, Tegtmeyer PK, Chhatbar C, Skerra J, Ghita L, Namineni S, Lienenklaus S, Köster M, Heikenwaelder M, Sutter G, Kalinke U (2018) Type I interferon receptor signaling delays Kupffer cell replenishment during acute fulminant viral hepatitis. J Hepatol 68(4): 682-690.

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.

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.

Infektionsassoziierte Gewebeentzündungen

Hepatitis:

Koestner W, Spanier J, Klause T, Tegtmeyer PK, Becker J, Herder V, Borst K, Todt D, Lienenklaus S, Gerhauser I, Detje CN, Geffers R, Langereis MA, Vondran FWR, Yuan Q, van Kuppeveld FJM, Ott M, Staeheli P, Steinmann E, Baumgärtner W, Wacker F, Kalinke U (2018) Interferon-beta expression and type I interferon receptor signaling of hepatocytes prevent hepatic necrosis and virus dissemination in Coxsackievirus B3-infected mice. PLoS Pathog 14(8):e1007235. 

Borst K, Frenz T, Spanier J, Tegtmeyer PK, Chhatbar C, Skerra J, Ghita L, Namineni S, Lienenklaus S, Köster M, Heikenwaelder M, Sutter G, Kalinke U (2018) Type I interferon receptor signaling delays Kupffer cell replenishment during acute fulminant viral hepatitis. J Hepatol 68(4): 682-690.

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.

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.

Encephalitis: 

Chhatbar C, Detje CN, Grabski E, Borst K, Spanier J, Ghita L, Elliott DA, Costa Jordão MJ, Mueller N, Sutton S, Prajeeth CK, Gudi V, Klein MA, Prinz M, Bradke F, Stangel M, Kalinke U (2018) Type I interferon receptor signaling of neurons and astrocytes regulates microglia activation during viral encephalitis. Cell Rep 25(1): 118-129.

Kuhn M, Sühs KW, Akmatov MK, Klawonn F, Wang J, Skripuletz T, Kaever V, Stangel M, Pessler F (2018) Mass-spectrometric profiling of cerebrospinal fluid reveals metabolite biomarkers for CNS involvement in varicella zoster virus reactivation. J Neuroinflammation 15(1): 20. 

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.

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.

Innovative interventions

Durán V, Yasar H, Becker J, Thiyagarajan D, Loretz B, Kalinke U, Lehr CM (2019) Preferential uptake of chitosan-coated PLGA nanoparticles by primary human antigen presenting cells. Nanomedicine 21:102073.

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, 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.

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.

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.

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.

Biomarkers for infectious diseases

Akmatov MK, Riese P, Trittel S, May M, Prokein J, Illig T, Schindler C, Guzman CA, Pessler F (2019) Self-reported diabetes and herpes zoster are associated with a weak humoral response to the seasonal influenza A H1N1 vaccine antigen among the elderly. BMC Infect Dis 19(1): 656.

Suhs KW, Novoselova N, Kuhn M, Seegers L, Kaever V, Muller-Vahl K, Trebst C, Skripuletz T, Stangel M, Pessler F (2019) Kynurenine is a cerebrospinal fluid biomarker for bacterial and viral CNS infections. J Infect Dis 220(1): 127-138.

Ratuszny D, Suhs KW, Novoselova N, Kuhn M, Kaever V, Skripuletz T, Pessler F, Stangel M (2019) Identification of Cerebrospinal Fluid Metabolites as Biomarkers for Enterovirus Meningitis. Int J Mol Sci 20(2). pii: E337.

Kuhn M, Sühs KW, Akmatov MK, Klawonn F, Wang J, Skripuletz T, Kaever V, Stangel M, Pessler F (2018) Mass-spectrometric profiling of cerebrospinal fluid reveals metabolite biomarkers for CNS involvement in varicella zoster virus reactivation. J Neuroinflammation 15(1): 20.

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.