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 addition, there is a great need for host-directed adjuvant therapies in CNS infections, as permanent neurological deficits may develop despite timely institution of pathogen-directed treatments. In collaboration with the MHH Dept. of Neurology (M. Stangel) and the RCU Metabolomics and Mass Spectrometry (H. Bähre), we are therefore searching for cerebrospinal fluid small molecule (metabolite) biomarkers for risk stratification and early diagnosis of patients with suspected infections of the CNS, and for metabolic pathways involved in CNS cell damage. As a pilot project we selected 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 bacterial and other viral pathogens, especially chronic herpes viruses such as HSV-1. One strategic advantage of focusing on chronic herpesvirus infections is that there are excellent local opportunities to test the functional importance of any biomarker candidates by collaborating with scientists working on the biology of these pathogens.

Publications

Biomarkers for respiratory infections

We are focusing on pulmonary infections, especially influenza (the flu), community-acquired pneumonia, and tuberculosis (TB), as there is a great need for improved diagnosis and patient stratification in all of these, and they may also present with similar symptoms but require very different treatments. 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 biomarkers, particularly small noncoding RNAs because of their multifaceted regulatory functions. Metabolites constitute the other mainstay as they represent both beginning and end of many important biological regulatory circuits. The Krebs cycle metabolite itaconic acid is a recently recognized master regulator of innate immune cells and therefore promises to have particular biomarker potential. We have established an LC-MS/MS assay for the detection of itaconic acid and its isomers citraconic and mesaconic acid. In addition, in a collaboration with the Dept. of Structural Biology of the HZI we have solved the crystal structure of the enzyme responsible for itaconic acid synthesis, cis-aconitate decarboxylase (CAD, ACOD1; also known as immune response gene 1, Irg1). We are now beginning to assess the impact of naturally occurring variants (mutations) in itaconic acid synthesis upon human susceptibility for respiratory infections. 

Publications

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 that of a poor immune response to influenza vaccination. In this project we have therefore been collaborating with the CRC Core Facility (C. Schindler), the CRC Biobank (T. Illig), and the HZI Dept. of Vaccinology (C. Guzman) to identify biomarkers and individual risk factors for a poor immune response to influenza vaccination in individuals older than 65 years. We performed a pilot study (n=34) in 2014-15 and a main study (n=200) in 2015-16. 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.

Publications

Cerebrospinal biomarkers for early diagnosis and risk stratification of CNS infections

Suehs KW, Novoselova N, Kuhn M, Seegers L, Kaever V, Müller-Vahl K, Trebst C, Skripuletz T, Stangel M*, Pessler F*. *Equal contribution. Kynurenine is a cerebrospinal fluid biomarker for bacterial and viral CNS infections. J Infect Dis. 2019; 220:127-138.

Ratuszny D, Sühs KW, Novoselova N, Kuhn M, Kaever V, Skripuletz T, Pessler F*, Stangel M*. *Equal contribution. Identification of cerebrospinal fluid metabolites as biomarkers for enterovirus meningitis.  Int J Mol Sci. 2019; 20(2) 337. doi: 10.3390/ijms20020337.

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 signatures and biomarkers for CNS involvement in varicella zoster virus reactivation. Mass-spectrometric profiling of  cerebrospinal fluid reveals metabolite biomarkers for CNS involvement in varicella-zoster virus reactivation. J Neuroinflamm, 15:20.

Biomarkers for respiratory infections

Chen F*, Lukat P*, Iqbal A, … Blankenfeld W, Büssow K*, Pessler F*. *Equal contribution. Crystal structure of cis-aconitate decarboxylase reveals the impact of naturally occurring human mutations on itaconate synthesis.  Proc Nat Acad Sci USA. 2019 (doi: 10.1073/pnas.1908770116. ePub ahead of print).

Samir M, Vidal RO, Abdallah F, Capece V, Seehusen F, Geffers R, Hussein A, Ali AAH, Bonn S, Pessler F. Organ-specific small non-coding RNA responses in domestic (Sudani) ducks experimentally infected with highly pathogenic avian influenza virus (H5N1). RNA Biology (ePub ahead of print).

Ramli SR, Moreira G, Zantow J, Goris M, Nguyen VK, Novoselova N, Pessler F*, Hust M*. *Equal contribution. Discovery of Leptospira spp. seroreactive peptides using ORFeome Phage Display.  PLoS Negl Trop Dis. 2019; 13(1):e0007131.

Loof T, Sohail A, Bahgat MM, Tallam A, Arshad H, Akmatov MK, Pils MC, Heise U, Beineke A, Pessler F. Early lymphocyte loss and increased granulocyte/lymphocyte ratio predict systemic spread of Streptococcus pyogenes in a mouse model of acute skin infection. Front Cell Infect Microbiol. 2018; 8:101. doi.org/10.3389/fcimb.2018.00101.

Strehlitz A, Goldmann O, Pils M, Pessler F, Medina E. An interferon signature discriminates pneumococcal from staphylococcal pneumonia. Front Immunol 2018; 9:1424. |doi.org/10.3389/fimmu.2018.01424.

Preusse M., Schughart K, and Pessler F. Host genetic background strongly affects pulmonary miRNA expression before and during influenza A virus infection. Front Immunol 2017; 8:246 doi: 10.3389/fimmu.2017.00246.

de Araujo LS, Vaas LA, Ribeiro-Alves M, Geffers M, et al, … Pessler F.*, Saad MH*. *[equal contribution]. Transcriptomic biomarkers for tuberculosis: evaluation of DOCK9, EPHA4, and NPC2 mRNA expression in peripheral blood. Front Microbiol 2016; 7:1586.

Preusse M, Schughart K, Wilk E, Klawonn F, Pessler F. Hematological parameters in the early phase of influenza A virus infection in differentially susceptible inbred mouse strains. BMC Research Notes 2015; 8:225.

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

Akmatov MK, Jentsch L, Riese P, May M, Ahmed MW, Werner D, Rösel A, Prokein J, Bernemann I, Klopp N, Prochnow B, Illig T, Schindler C, Guzman, Pessler F. 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 Biomed Res Methodol 2017; 17:18. doi: 10.1186/s12874-017-0302-z

Akmatov MK, Riese P, May M, Jentsch L, Ahmed MW, Werner D, Rösel 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. Establishment of a cohort for deep phenotyping of the immune response to influenza vaccination among elderly individuals recruited from the general population. Human Vacc Immunother 2017; 10:1-10.

Akmatov MK, Riese P, Trittel S, May M, Prokein J, Illig T, Schindler C, Guzmán CA, Pessler F. 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 2019; 19(1) : 656.