Projects Biomarkers for Infectious Diseases

Projects Biomarkers for Infectious Diseases

Cerebrospinal fluid biomarkers for early diagnosis and risk stratification of CNS infections

Infections of the CNS can often not be differentiated well from non-infectious inflammatory diseases, and pathogen detection is variably efficient, depending on the assay, the pathogen and the time of lumbar puncture with respect to the onset of infection. In collaboration with the MHH Dept. of Neurology (T. Skripuletz, K.-W. Sühs), we are analyzing cerebrospinal fluid samples to identify small molecule (metabolite) biomarkers for risk stratification and early diagnosis of patients with suspected infections of the CNS. A second goal is to identify metabolic pathways that are involved in CNS cell damage during infections. We initially studied reactivation of chickenpox virus (varicella-zoster virus, VZV), as this disease may span the spectrum from mild segmental zoster (shingles) to a life-threatening encephalitis. We have expanded this project to herpes simplex viruses (HSV), enteroviruses, coronaviruses, and to bacterial CNS infections. Our current focus is on identifying biomarkers for long COVID and for the clinically important discrimination between viral CNS infections and autoimmune neuroinflammation.  



Functional Biomarkers for respiratory infections

We are focusing on pulmonary infections, especially influenza, COVID-19, community-acquired pneumonia, and tuberculosis (TB), as there is a great need for improved diagnosis, patient stratification, and treatment. Our studies on TB have been possible through a collaboration with the Instituto Oswaldo Cruz in Rio de Janeiro. One focus of biomarker profiling is on RNA biomarkersbecause of their multifaceted regulatory functions. Metabolites constitute the other mainstay as they represent both beginning and end of many important biological regulatory circuits. The endogenous isomers itaconic, mesaconic and citraconic acid have potent immunomodulatory, cytoprotective, and antiviral properties. In a collaboration with the Dept. of Structural Biology of the HZI solved the crystal structure of the enzyme responsible for itaconic acid synthesis, cis-aconitate decarboxylase (ACOD1; Irg1). We are currently assessing these three isomers and related molecules as adjunct treatments for severe viral infections and are evaluating inhibitors of ACOD1 as interventions to counteract immune exhaustion in viral and bacterial infections.    



Predictive biomarkers for a poor immune response to influenza vaccination in elderly individuals

Elderly individuals have the highest risk of severe influenza infection, but –tragically- also the highest risk of a poor immune response to influenza vaccination. Together with the CRC Core Facility (C. Schindler), the CRC Biobank (T. Illig), and the HZI Dept. of Vaccinology (C. Guzman) we have been searching for biomarkers and individual risk factors for a poor immune response to influenza vaccination in individuals older than 65 years. In the years 2014-16, we performed a pilot study (n=34) and a main study (n=200) with participants from Hannover Region. The resulting dual data set now allows biostatistical identification and initial validation of biomarker candidates. Thus far, we have identified two cytokines (IL-8 and IL-18) whose plasma concentrations, in both studies, are lower in the vaccine-nonresponders than in the responders. These results are particularly interesting because they suggest that low concentrations of these molecules could serve as warning signals for a poor vaccine response, but also that raising their levels in individuals with low levels (for instance by injection with the vaccine) may improve the vaccine response.


Cerebrospinal biomarkers for early diagnosis and risk stratification of CNS infections

Al-Mekhlafi A, Sühs K-W, Schuchardt S, Kuhn M, Müller-Vahl K, Trebst C, Skripuletz T, Klawonn F, Stangel M*, Pessler F*. *Equal contribution. Elevated free phosphatidylcholine levels in cerebrospinal fluid distinguish bacterial from viral CNS infections. Cells 2021; 10, 1115.

de Araujo LS, Pessler K, Suhs KW, Novoselova N, Klawonn F, Kuhn M, Kaever V, Muller-Vahl K, Trebst C, Skripuletz T, Stangel M*, Pessler F* (2020) Phosphatidylcholine PC ae C44:6 in cerebrospinal fluid is a sensitive biomarker for bacterial meningitis. J Transl Med 18(1): 9. *equal contribution

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. *equal contribution

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) *equal contribution

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 Neuroinflamm 15 (1): 20.



Biomarkers for respiratory infections

Waqas FH, Shehata M, Elgaher WAM, Lacour A, Kurmasheva N, Begnini F, Kiib AE, Dahlmann J, Chen C, Poulsen T, Merkert S, Martin U, Olmer R, Olagnier D, Hirsch AKH, Pleschka S, Pessler F. 2023 NRF2 activators inhibit influenza A virus replication by interfering with nucleo-cytoplasmic export of viral RNPs in an NRF2-independent manner. PLoS Pathog; 19(7):e1011506.

Arshad H, Siokis K, Franke R, Habib A, et al., Pessler F. Reprogramming of amino acid metabolism differs between community-acquired pneumonia and infection-associated exacerbation of chronic obstructive pulmonary disease. Cells 2022; 11, 2283. Doi: 10.3390/cells11152283

Waqas FSH, Sohail A, Nguyen AHA, et al., Pessler F. 2022 ISG15 deficiency features a complex cellular phenotype that responds to treatment with itaconate and derivatives. Clin Transl Med 12:e931. doi: 10.1002/ctm2.931. 

Chen F, Elgaher WAM, Winterhoff M, Büssow K, et al., Pessler F. Citraconate inhibits ACOD1 (IRG1) catalysis, reduces interferon responses and oxidative stress, and modulates inflammation and cell metabolism. Nature Metabolism 2022;

Sohail S, Iqbal AA, Sahini N, Chen F, et al., Pessler, F. Itaconate and derivatives reduce interferon responses and inflammation in influenza A virus infection. PLoS Pathog 2022; 18(1):e1010219.

Helmholtz Association; Pre4D Fund (2022-2023)
AMPRO – Aging and Metabolic Programming (2018-2021)
BMBF; COVID-Protect (coordinator) (2020-2022)
iMed, the Helmholtz Association‘s Cross Programme Inititiative on Personalised Medicine (2014-2020)


Predictive biomarkers for a poor immune response to influenza vaccination in elderly individuals

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. 

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.