Infection and immunity

Principal Investigator

Jukka Alinikula

Adjunct Professor of Immunobiology, University Lecturer

Institute of Biomedicine, Unit of Infection and Immunity, University of Turku

Contact: jukka.alinikula@utu.fi I Orcid

Description of Research

We investigate how efficient B-cell-mediated immunity is generated, focusing on the mechanisms that enable high-affinity antibody production. While most cells minimize somatic mutations to avoid genome instability and tumorigenesis, immunoglobulin genes in developing B cells undergo extensive mutagenesis through processes such as somatic hypermutation (SHM). Incorrect targeting of the mutation machinery can severely compromise genome integrity and is associated with several forms of cancer, particularly lymphoma. Our research explores the molecular mechanisms that direct SHM specifically to immunoglobulin genes, as well as the factors leading to off-target mutations elsewhere in the genome, including proto-oncogenes.

Current topics

- Mechanisms targeting SHM to immunoglobulin genes

- Off-target SHM mutations in non-immunoglobulin genes and their role in cancer

Research group members

Senior Researchers: Anni Soikkeli

PhD students: Alina Tarsalainen, Katriina Eskelinen

Other students: Pauliina Laine

Recent key publications

1. Šenigl F, Soikkeli AI, Prost S, Schatz DG, Slavková M, Hejnar J, Jukka Alinikula (2024). The SV40 virus enhancer functions as a somatic hypermutation-targeting element with potential tumorigenic activity. Tumour Virus Research 8:200293, doi.org/10.1016/j.tvr.2024.200293
2. Rinne V, Gröndahl-Yli-Hannuksela K, Fair-Mäkelä R, Salmi M, Rantakari P, Lönnberg T, Jukka Alinikula, Pietikäinen A, Hytönen J. (2024) Single-cell transcriptome analysis of the early immune response in the lymph nodes of Borrelia burgdorferi-infected mice. Microbes and Infection. doi: 10.1016/j.micinf.2024.105424
3. Soikkeli Anni, Minna Kyläniemi, Harri Sihto and Jukka Alinikula (2022). Oncogenic Merkel cell polyomavirus T antigen truncating mutations are mediated by APOBEC3 activity in Merkel cell carcinoma, Cancer Research Communications. 2(11):1344-1354.
4. Tarsalainen Alina, Yaakov Maman, Fei-Long Meng, Minna K. Kyläniemi, Anni Soikkeli, Paulina Budzyńska, Jessica J. McDonald, Filip Šenigl, Frederic W. Alt, David G. Schatz and Jukka Alinikula (2022). Ig Enhancers Increase RNA Polymerase II Stalling at Somatic Hypermutation Target Sequences. Journal of Immunology, 208(1):143-154.
5. Dinesh Ravi K., Benjamin Barnhill, Anoj Ilanges, Lizhen Wu, Daniel A. Michelson, Filip Senigl, Jukka Alinikula, Jeffrey Shabanowitz, Donald F. Hunt, and David G. Schatz (2020). Transcription factor binding at immunoglobulin enhancers is linked to somatic hypermutation targeting. European Journal of Immunology, 50(3):380-395

Principal Investigator

Principal Investigator

Eeva-Liisa Eskelinen

Professor in Medical Cell Biology

Contact: eeva-liisa.eskelinen@utu.fi I Orcid profile

Description of Research

Eskelinen group investigates the small GTPase RAB24, which belongs to the RAB protein family. RAB proteins are monomeric GTPases that regulate intracellular membrane traffic. The group showed earlier that RAB24 functions at a late stage or the lysosome-mediated catabolic process called autophagy. In line with these findings, RAB24 has been shown to support neuronal survival. Further, published data indicate that RAB24 facilitates the malignant phenotype of liver cancer and enhances liver fat accumulation. However, the molecules that regulate and execute RAB24 functions are fully unknown.

Current topics

• Molecular mechanisms of RAB24 in neuronal and hepatic cells

• Expression of RAB24 protein in various human cancers and in mouse tissues during postnatal development

• Eeva-Liisa Eskelinen also leads the Electron Microscopy Laboratory at the Institute of Biomedicine.

Research group's website

Kirsi Gröndahl-Yli-Hannuksela, Adjunct Professor, University Lecturer

Contact: kagron@utu.fi

Description of research

The overall goal of our research is to understand the differences and similarities between bacterial populations during carriage stage and disease with the focus on beta haemolytic streptococci. Beta haemolytic streptococci and especially group A (GAS, Streptococcus pyogenes) and group B (GBS, S. agalactiae) are important human pathogens with a broad range of disease types. Currently the research focus is on pregnant women, asymptomatic carriage of GAS and GBS during pregnancy and possible association of carriage with delivery complication. The overall health of mothers as well as newborns is investigated in association with bacterial carriage stage. Bacterial populations and microbiota during pregnancy are investigated with several molecular techniques.

Current topics

• Carriage and household transmission of beta haemolytic streptococci during pregnancy
• Microbiota composition at the time of delivery
• National and local disease burden and aetiology of puerperal infections

Research group members

• Doctoral researchers: recruitment pending
• Technician: Ann-Sofie Wierda (part-time)

Recent key publications

1. Lönnqvist E, Gröndahl-Yli-Hannuksela K, Loimaranta V, Vuopio J. Low rate of asymptomatic carriage and salivary immunoglobulin A response to Group A Streptococci in the healthy adult population in Finland. In press 2022 Medical Microbiology and Immunology
2. Gröndahl-Yli-Hannuksela K, Beres SB, Hyyryläinen HL, Kallonen K, Musser JM and Vuopio J. Genetic evolution of invasive emm28 Streptococcus pyogenes strains and significant association with puerperal infections in young women, Finland. Clinical Microbiology and Infection 2020 Mar;27(3):420-427.
3. Vilhonen J, Vuopio J, Vahlberg T, Gröndahl-Yli-Hannuksela K, Rantakokko-Jalava K and Oksi J. Group A streptococcal bacteremias in Southwest Finland 2007-2018: epidemiology and role of infectious diseases consultation in antibiotic treatment selection. 2020. European Journal of Clinical Microbiology and Infectious Diseases, 2020 Jul;39(7):1339-1348.
4. Musser JM, Beres SB, Zhu L, Olsen RJ, Vuopio J, Hyyryläinen HL, Gröndahl-Yli- Hannuksela K, Kristinsson KG, Darenbergh J, Henriques-Normarki B, Hoffmann S,  Caugant D, Smith AJ, Lindsayn D, Boragineo D, and Palzkill T. Reduced in vitro susceptibility of Streptococcus pyogenes to beta-lactam antibiotics associated with mutations in the pbp2x gene is geographically widespread. J. Clin. Microbiol. 2020, 25;58(4):e01993-19
5. Kachroo P, Eraso JM, Beres SB, Olsen RJ, Zhu L, Nasser W, Bernard PE, Cantu CC, Saavedra MO, Arredondo MJ, Strope B, Do H, Kumaraswami M, Vuopio J, Gröndahl-Yli-Hannuksela K,  Kristinsson KG, Gottfredsson M, Pesonen M, Pensar J, Davenport ER, Clark AG, Corander J, Caugant DA, Gaini S, Magnussen MD, Kubiak SL, Nguyen HAT, Long SW, Porter AR, DeLeo FR, and Musser JM. Integrated Analysis of Population Genomics, Transcriptomics and Virulence Provides Novel Insights into Serotype M28 Streptococcus pyogenes Pathogenesis. Nature Genetics, 2019, Mar;51(3):548-559.

Links

• Utu reseach profile

Antti Hakanen

Heli Harvala, 

Description of research

Current topics

Blood safety related research:

• Understanding occult HBV infection and developing better biomarkers for blood donation screening
• Emerging infections as blood safety treat – with special focus on rat hepatitis E virus, Usutu virus and TBEV
• Microbiological risks following the introduction of individualized blood donor assessment with special focus on syphilis and PrEP use
• Is syphilis a blood safety risk, or simply a marker of risk?
• Considerations for bacterial screening of blood donations
• Impact of parvovirus B19 to blood donation and recipient safety

ENTEROVIRUS related research:

• Comparison of enterovirus data reported to the WHO Regional Office for Europe via the acute flaccid paralysis (AFP), additional enterovirus and environmental surveillance system along with that collected by the European Non-Polio Enterovirus Network (ENPEN) [Collaborative study with WHO Europe]
• Severe neonatal hepatitis associated with echovirus 11 infection: retrospective clinical, epidemiological and genetic investigations in Europe, 2018-2023 [Collaborative study with ECDC]

Group's website: https://sites.utu.fi/harvalagroup/en/research/

Principal Investigator

Qiushui He, Professor of Molecular Microbiology

Qiushui.he@utu.fi I Utu research profile I Orcid profile

Description of Research

The research projects of this group focus on respiratory bacterial pathogens (Bordetella pertussis and Corynebacterium diphtheriae), vaccine immunology and genetic susceptibility to infectious diseases. We study 1) cell-mediated and humoral immune responses after acellular pertussis vaccines and natural infections; 2) impact of innate immune gene polymorphisms on nasopharyngeal bacterial colonization, respiratory infections and asthma development in children; 3) molecular surveillance of Bordetella pertussis and Corynebacterium diphtheria; and 4) Development of novel point of care tests for bacterial infections including pertussis. The research group has served as Finnish Reference Laboratory for Diphtheria and Pertussis since 2001 and as European Reference Laboratory for Public Health in the field of Diphtheria and Pertussis (EURL-PH-DIPE) since 2025. 

Current topics

Research group members

Recent key publications

Links

• Research group's website: under construction

Maija Hollmen, PhD, Adjunct Professor of Tumor Immunology

Contact: maijal@utu.fi

Description of Research

Overcoming tumor-related immunosuppression presents a significant obstacle to successful cancer treatment. To activate the host’s anti-tumor immunity, our research exploits macrophage reprogramming as an alternative approach to stimulate CD8 T-cell mediated tumor cell killing. 

Current topics

• Mechanisms regulating macrophage function in the tumor microenvironment
• Macrophage-derived extracellular vesicles in the regulation of T-cell activation
• Macrophage targeted immunotherapy

Research group members

• PhD students: Miro Viitala, Jenna Rannikko, Sina Tadayon
• Other students: Nesrin Mohamed
• Technicians: Mari Parsama

Recent key publications

1. Viitala M, Virtakoivu R, Tadayon S, Rannikko J, Jalkanen S, Hollmén M. Immunotherapeutic. Blockage of Macrophage Clever-1 Reactivates the CD8+ T Cell Response Against Immunosuppressive Tumors. Clin Can Res 2019, 25:3289-3303.
2. Hollmén M, Karaman S, Schwager S, Lisibach A, Christiansen AJ, Maksimow M, Varga Z, Jalkanen S, Detmar M. G-CSF regulates macrophage phenotype and associates with poor overall survival in human triple-negative breast cancer. Oncoimmunology 2015, 5: e1115177.
3. Hollmén M, Roudnicky F, Karaman S, Detmar M. Characterization of macrophage - cancer cell crosstalk in estrogen receptor positive and triple-negative breast cancer. Scientific Reports 2015, 5:9188.
4. Takeda A, Hollmén M, Dermadi D, Pan J, Francis Brulois K, Kaukonen R, Lönnberg T, Boström P, Koskivuo I, Irjala H, Miyasaka M, Salmi M, Butcher EC, Jalkanen S. Single-cell survey of human lymphatics unveils marked endothelial cell heterogeneity and mechanisms of homing for neutrophils. Immunity 2019, pii: S1074-7613(19)30297-3.
5. Tadayon S, Dunkel J,Takeda A, Halle O, Karikoski M, Gerke H, Rantakari P, Virtakoivu R, Pabst O, Salmi M, Hollmén M *, Jalkanen S*. Clever-1 contributes to lymphocyte entry into the spleen via the red pulp. Science Immunology 2019 Vol. 4, Issue 33, eaat0297. *equal contribution

Links

• Research group's website
• Utu research profile
• Orcid profile

Veijo Hukkanen

Pentti Huovinen

Principal Investigator

Description of Research

Current topics

Research group members

Recent key publications

Links

Arno Hänninen

Principal Investigator

Sirpa Jalkanen, MD, PhD, Professor of Immunology, Academician

sirpa.jalkanen@utu.fi I UTU research I Orcid I Linkedin

Description of Research

The overall goal of our research is to elucidate the mechanisms regulating the traffic of leukocytes and cancer cells in the body. Harmful leukocyte migration into the joints in rheumatoid arthritis and into the pancreas in diabetes are examples of diseases where leukocytes cause extensive destruction. These inflammatory diseases can be cured by inhibiting leukocyte trafficking. Also, metastasising malignant cells often use the same mechanisms as leukocytes when extravasating from blood to different organs or migrating via the lymphatics into distant sites. The results obtained can be utilized when new types of drugs are developed to treat harmful inflammations and cancer.

Current topics

• In cancer: How cancer modifies lymphatics for promoting its spread
• In inflammation: Does the polymorphism in interferon-beta receptor affect the outcome of viral infections

Links

• Research group's website

   

Ilkka Julkunen

Principal Investigator

Laura Kakkola, PhD, Adjunct Professor in Virology, Laboratory Manager, Biosafety Officer

laura.kakkola@utu.fi I Orcid profile

Description of Research

Our research focuses to understand what are the key molecular changes required in the zoonotic viruses for the crossing of species barriers (i.e. spillover) and the changes that enable the virus to adapt to humans. Specifically we are interested in virus-host interactions, how viruses interfere with the innate immune responses, and could these events be utilized in vaccine, antiviral drug or diagnostic test development. 

Current topics

• Crossing species barriers - molecular mechanisms of infectious disease emergence.

• Innate immune responses in virus infections. 

Research group members

• Senior researchers: Pekka Kolehmainen

• PhD students: Beda Anttila, Milja Belik, Hira Khan, Rickard Lundberg, Ulla Mikkonen, Rauno Naves (together with Professor Olli Ritvos, University of Helsinki), Arttu Reinholm, Sanna Tervo (together with professor Harvala), Jessica Tikkala (together with professor Hytönen)

• Technicians: Terhi Laakso 

Recent key publications

Santosh Lamichhane

Description of Research

The focus of our group is to explore microbially derived small molecules (i.e., metabolites) in the gut and their influence on human health. By integrating advanced laboratory techniques such as metabolomics, 3D cell culture, and microbial monocultures with computational analysis, we investigate the chemical interactions between gut microbes and their impact on the host. Our group also utilizes a reverse metabolomics approach—a big data discovery framework that leverages public data repositories to identify phenotype-relevant information from MS/MS-based metabolomics data.

Current topics:

We are investigating the relationship between gut microbiota, lipids, and their clinical effects (islet cell autoimmunity progression) in early childhood. Our work includes microbial monoculture studies to explore emerging microbial metabolites, such as microbial-conjugated bile acids and conjugated lipids. We are also developing a CaCo2-HT29–based 3D culture model to investigate host–microbe–metabolite interactions.

Research group members

• Ifrat Tamanna, Doctoral Researcher, TuDMM
• Abdul Qadeer, Master thesis student, Systems Biology

Alumni

• Fanny Borg, Master trainee, Abo Academy
• Ritu Dagar, Master trainee, UTU

Selected publications

Mannochio-Russo, H., V. Charron-Lamoureux, M. van Faassen, S. Lamichhane, W. D. Gonçalves Nunes, V. Deleray, A. V. Ayala, Y. Tanaka, A. Patan, K. Vittali, P. Rajkumar, Y. El Abiead, H. N. Zhao, P. W. P. Gomes, I. Mohanty, C. Lee, A. Sund, M. Sharma, Y. Liu, D. Pattynama, G. T. Walker, G. J. Norton, L. Khatib, M. S. Andalibi, C. X. Wang, R. J. Ellis, D. J. Moore, J. E. Iudicello, D. Franklin, Jr., S. Letendre, L. Chin, C. Walker, S. Renwick, J. Zemlin, M. J. Meehan, X. Song, D. Kasper, Z. Burcham, J. J. Kim, S. Kadakia, M. Raffatellu, L. Bode, H. Chu, K. Zengler, M. Wang, D. Siegel, R. Knight and P. C. Dorrestein "The microbiome diversifies long- to short-chain fatty acid-derived N-acyl lipids." Cell.

Charron-Lamoureux, V., H. Mannochio-Russo, S. Lamichhane, S. Xing, A. Patan, P. W. Portal Gomes, P. Rajkumar, V. Deleray, A. M. Caraballo-Rodríguez, K. V. Chua, L. S. Lee, Z. Liu, J. Ching, M. Wang and P. C. Dorrestein (2025). "A guide to reverse metabolomics—a framework for big data discovery strategy." Nature Protocols.

Isokääntä, H., L. Pinto da Silva, N. Karu, T. Kallonen, A.-K. Aatsinki, T. Hankemeier, L. Schimmel, E. Diaz, T. Hyötyläinen, P. C. Dorrestein, R. Knight, M. Orešič, R. Kaddurah-Daouk, A. M. Dickens and S. Lamichhane (2024). "Comparative Metabolomics and Microbiome Analysis of Ethanol versus OMNImet/gene•GUT Fecal Stabilization." Analytical Chemistry 96(22): 8893-8904.

Lamichhane, S., P. Sen, A. M. Dickens, M. A. Alves, T. Härkönen, J. Honkanen, T. Vatanen, R. J. Xavier, T. Hyötyläinen, M. Knip and M. Orešič (2022). "Dysregulation of secondary bile acid metabolism precedes islet autoimmunity and type 1 diabetes." Cell Reports Medicine 3(10).

Johanna Lempainen, MD, Adjunct Professor, Pediatrician

Contact: johanna.lempainen@utu.fi

Description of Research

Our research focuses on the pathogenesis of type 1 diabetes. In particular, we investigate the genetic background of T1D, risk gene effects on various disease phases, and heterogeneity of the disease pathogenesis. We mainly perform genetic analyses, but also search for alterations in gene regulation and immune activation leading to autoimmunity. We aim to combine genetic and environmental data during the autoimmunity to identify interactions and disease pathway specific effects.

Current topics

• Genetics of type 1 diabetes
• Heterogeneity of type 1 diabetes pathogenesis
• Immune alterations in early childhood

Research group members

• Senior researchers: Antti-Pekka Laine, Minna Kiviniemi, Jorma Ilonen
• PhD students: Mari-Liis Mikk, Milla Valta, Sirpa Pahkuri
• Technicians: Mia-Maria Karlsson, Terhi Laakso, Piia Nurmi, Anne Suominen

Recent key publications

1. Ilonen J, Lempainen J, Hammais A, Laine A-P, Härkönen T, Toppari J, Veijola R, Knip M, the Finnish Pediatric Diabetes Register. Primary islet autoantibody at initial seroconversion and autoantibodies at diagnosis of type 1 diabetes as markers of disease heterogeneity. Pediatr Diabetes 2018;19(2):284-292
2. Bauer W, Veijola R, Lempainen J, Kiviniemi M, Härkönen T, Toppari J, Knip M, Gyenesei A, Ilonen J. Age at seroconversion, HLA genotype and specificity of autoantibodies in progression of islet autoimmunity in childhood. J Clin Endocrinol Metab 2019;104:4521-4530
3. Ilonen J, Lempainen J, Veijola R. The heterogeneous pathogenesis of type 1 diabetes mellitus. Nat Rev Endocrinol 2019 15(11):635-650
4. Valta M, Gazali AM, Viisanen T, Ihantola EL, Ekman I, Toppari J, Knip M, Veijola R, Ilonen J, Lempainen J, Kinnunen T. Type 1 diabetes linked PTPN22 gene polymorphism is associated with the frequency of circulating regulatory T cells. Eur J Immunol 2020;50(4):581-588
5. Mikk ML, Pfeiffer S, Kiviniemi M, Laine AP, Lempainen J, Härkönen T, Toppari J, Veijola R, Knip M, Ilonen J; Finnish Pediatric Diabetes Register. HLA-DR-DQ haplotypes and specificity of the initial autoantibody in islet specific autoimmunity. Pediatr Diabetes, Online ahead of print 

Links

• Utu research profile
• Orcid profile

Description of Research

Our group focuses on the mechanisms of early B cell activation. Upon activation by various pathogens, B cells mount highly specific antibody responses as well as immunological memory. We are particularly interested in the initial triggering of B cells by the recognition of specific antigens via the B cell receptor (BCR). The cellular responses following antigenic trigger involve formation of an immune synapse, and antigen uptake and processing for further presentation to T cells. To gain deeper insights into these cellular processes, we combine advanced microscopy and proteomics with in vivo mouse models and clinical samples. Our research aims for better understanding of the adaptive immune responses both in health and disease, and to facilitate more efficient harnessing of lymphocytes in the immunological therapies of the future. 

Current topics

• Mechanisms of early B cell activation and the formation of the immune synapse

• B cell antigen processing for peptide-MHCII presentation.

• Cell biology of the B cell responses to viruses and presentation of viral antigens (part of the Yellow4FLAVI EU consortium).  

Research group's website

Alexander Mildner, Associate Professor

Contact: Alexander.mildner@utu.fi

Description of Research

Tissue resident macrophages are long-lived cells that are distributed throughout the body and migrate into the tissue during embryogenesis. They are specialized in ingesting and processing dead cells, debris and foreign materials, and in the recruitment of other immune cells – like monocytes – to sites of injury in response to inflammatory signals. Monocytes, on the other hand, represent short-lived cells that can be found in the peripheral circulation. Traditionally, it was assumed that monocytes represent an intermediate stage, linking mononuclear phagocyte precursors in the bone marrow with terminally differentiated tissue resident macrophages. However, this concept seems to hold true only for certain tissues. In most of the cases, embryo-derived tissue macrophages are endowed with an intrinsic self-renewal program to maintain homeostasis, while monocyte descendants are devoid of this capacity. Instead, monocytes are highly plastic cells and can differentiate – depending on the cellular context – into various cell types with fundamental different functions like effector monocytes, monocyte-derived dendritic cells and monocyte-derived macrophages.

The transcription factor C/EBPβ is expressed in cells of the myeloid lineage, especially in monocytes, macrophages and dendritic cells. Recently, we applied epigenetic approaches to identify C/EBPβ as one of the main regulators of monocyte and Alveolar macrophage development under physiological conditions. Deficiency of C/EBPβ in mice let to a complete absence of Ly6C- monocytes due to impaired induction of the monocytic survival factor Nr4a1. In Alveolar macrophages, C/EBPβ controlled the expression of a lipid catabolic program.

We are currently investigating the differentiation of myeloid cells under steady state as well as pathological conditions such as autoimmunity in various tissues using epigenetic approaches including ATACseq, ChIPseq and high resolution immune profiling like scRNA-Seq. The central goal of our laboratory is to identify new factors that are involved in the differentiation of monocytes and macrophages under pathological conditions. We hope to manipulate the fate and activation status of macrophages and thereby beneficially influence disease progression.

Current topics

• Monocytes differentiation and function during neuroinflammation
• Microglia heterogeneity
• Tissue-specific function of macrophages

Research group members

• PhD students: Besmir Hyseni, Ae Parena
• PostDoc: Luis Crisostomo

Recent publications

1. Lyras EM, Zimmermann K, Wagner LK, Dörr D, Klose CSN, Fischer C, Jung S, Yona S, Hovav AH, Stenzel W, Dommerich S, Conrad T, Leutz A, Mildner A. Tongue immune compartment analysis reveals spatial macrophage heterogeneity. Elife. 2022 Jun 24;11:e77490. doi: 10.7554/eLife.77490. https://pubmed.ncbi.nlm.nih.gov/35749158/
2. Giladi A*, Wagner LK*, Li H, Dörr D, Medaglia C, Paul F, Shemer A, Jung S, Yona S, Mack M, Leutz A, Amit I*, Mildner A* (2020): Cxcl10+ monocytes define a pathogenic subset in the central nervous system during autoimmune neuroinflammation. Nat Immunol. 21(5):525-534. https://pubmed.ncbi.nlm.nih.gov/32313246/
3. Guilliams M*, Mildner A*, Yona S* (2018): Developmental and Functional Heterogeneity of Monocytes. Immunity. 16;49(4):595-613. https://pubmed.ncbi.nlm.nih.gov/30332628/
4. Mildner A*, Schönheit J*, Giladi A, David E, Lara-Astiaso D, Lorenzo-Vivas E, Paul F, Chappell-Maor L, Priller J, Leutz A, Amit I, Jung S (2017): Genomic Characterization of Murine Monocytes Reveals C/EBPβ Transcription Factor Dependence of Ly6C- Cells. Immunity. 46(5):849-862.e7. https://pubmed.ncbi.nlm.nih.gov/28514690/

Links

Utu research profile

Orcid profile

Researchgate

Cecilia Söderberg-Nauclér MD, PhD, Professor of Immunology

Contact: cecilia.naucler@utu.fi

Description of the research

I have a long-standing interest in pathogenesis studies of human cytomegalovirus (HCMV). This virus is considered harmless for healthy individuals but may cause severe disease in immunocompromised patients such as organ and stem cell transplant patients and AIDS patients. It is also the most common congenital infection and may cause birth defects, of which the most common are hearing loss and mental retardation. Emerging evidence also imply a role of this virus in inflammatory diseases and cancer. 

HCMV establishes a latent/persistent life-long infection after a primary infection. 70-90% of adults have been infected with and are carriers of this virus. The virus resides in a latent state mainly in myeloid lineage cells in the bone marrow and reactivation occurs when these cells differentiate into inflammatory macrophages or dendritic cells in various tissues. Infected cells further promote inflammation via enhanced expression of 5-LO and COX-2 and induced production of inflammatory cytokines and chemokines. HCMV is often found to be activated in inflamed tissue specimens obtained from patients with inflammatory diseases such as SLE, rheumatoid arthritis, inflammatory bowel disease, cardiovascular diseases and aortic aneurysms, while rarely detected in healthy tissues. Thereby, there is a close relationship between this virus and inflammation, but it is today unclear how important HCMV is in promoting clinical disease activity and progression of these diseases. 

HCMV is also commonly found to be active in tumors of different origin; HCMV proteins and nucleic acids are found in >90% of glioblastoma, neuroblastoma, medulloblastoma, breast, colon, prostate and ovarian cancer. Both primary tumors as well as metastases are virus positive, while healthy tissues surrounding tumors and metastases are virus negative. New evidence imply that perhaps only certain HCMV strains may be associated with cancer, and hence potentially be oncogenic. We are currently studying the effect of anti-HCMV therapy in glioblastoma patients in a randomized trial, VIGAS2. Retrospective analyses of so far treated patients (139 patients) indicate substantial prolonged survival time in patients receiving anti-viral therapy. These observations imply a potential role of this virus in cancer.

Activation of immune cells depend on alterations in cellular metabolism; i.e the Warburg effect, which is also essential for cancer cells to grow. Although the metabolic alterations to the Warburg effect is essential for inflammation and cancer, it is not known how cells switch from normal metabolism to the Warburg effect. HCMV establishes the Warburg effect in infected cells, which appears to be essential for reactivation of latent HCMV and virus production. We have used HCMV as a tool to try to understand the underlying mechanisms of the Warburg effect in immune cells and cancer cells. We made unexpected insights into how cells with a normal metabolism switch to the Warburg effect, which allowed us to identify metabolic inhibitors that we are now testing how they affect immune cell activation and cancer cell growth. 

The long-term goal of our projects is to further understand how cellular metabolism control immune activation, cancer cell growth, and the life cycle of HCMV that appears to be closely involved in these diseases. We hope that this will allow us to find new treatment strategies for many of our common diseases. Our research is carried out at Turku University and Karolinska Institutet.

Current topics

• Defining key common metabolic mechanisms governing macrophage differentiation, T cell activation and cancer cell growth; i.e the underlying mechanism of the Warburg effect
• Defining how metabolic alterations change cellular fate and induce HCMV reactivation via epigenetic mechanisms
• Defining genetic variants that affect immune functions and confer immune control of viral and bacterial infections
• To assess whether anti-viral therapy to HCMV can improve the prognosis for glioblastoma patients (clinical multicentral randomized clinical trial, VIGAS2, 220 patients)

Research group members

University of Turku:

• PhD students: Hatem Abou-Guendia, Iqra Anam Khwaja, Mohammed Pirouzfar, Shaghayegh Hansanpour
• Post doc: Päivi Ylä-Anttila

Karolinska Institutet:

• PhD students : Mattia Russel Pantalone, Xinling Xu, Inti Peredo Harvey, Nerea Martin Almazan
• Post docs: Jennifer Gorwood, Kristen Schroeder, Tong Liu, Koon Chu Yaiw
• Associate professors: Afsar Rahbar, Piotr Religa
• Senior researcher: Giuseppe Stragliotto, neurooncologist
• Medical student: Cedric Bratt

Recent key publications

Cell Death and Differentiation

Joanna Maria Merchut-Maya, Jiri Bartek Jr., Jirina Bartkova, Mattia Russel Pantalone, Panagiotis Galanos, MyungHee Lee, Huanhuan L. Cui, Afsar Rahbar, Patrick J. Shilling, Christian Beltoft Brøchner, Helle Broholm, Apolinar Maya-Mendoza,  Cecilia Söderberg-Naucler* and Jiri Bartek*Cytomegalovirus hijacks host stress response fueling genome instability *Shared senior authorship, 2022 Feb 22. doi: 10.1038/s41418-022-00953-w. 

EbioMedicine

Söderberg-Nauclér C New mechanistic insights of the pathogenicity of high-risk cytomegalovirus (CMV) strains derived from breast cancer: Hope for new cancer therapy options. 2022 Jun 13;81:104103. doi: 10.1016/j.ebiom.2022.104103. 

Cancers

Peredo-Harvey I, Rahbar A, Söderberg-Nauclér C. Presence of the human Cytomegalovirus in Glioblastomas- a Systematic Review  2021 Oct 9;13(20):5051. doi: 10.3390/cancers13205051.PMID: 34680198 

Clinical Cancer Research

Stragliotto G, Pantalone MR, Rahbar A, Bartek J, Söderberg-Naucler C. Valganciclovir as add-on to standard therapy in glioblastoma patients. 2020. Clin Cancer Res. 2020 Aug 1;26(15):4031-4039. 

Lancet

King C, Einhorn L, Brusselaers N, Carlsson M, Einhorn S, Elgh F, Frisén J, Gustafsson Å, Hanson S, Hanson C, Hedner T, Isaksson O, Jansson A, Lundkvist Å, Lötvall J, Lundback B, Olsen B, Söderberg-Nauclér C, Wahlin A, Steineck G, Vahlne A. COVID-19-a very visible pandemic. 2020 Aug 8;396(10248):e15.

Journal of Cancer Research and Clinical Oncology

Costa H, Touma J, Davoudi B, Benard M, Sauer T, Geisler J, Vetvik K, Rahbar A, Söderberg-Naucler C. Human cytomegalovirus infection is correlated with enhanced cyclooxygenase-2 and 5-lipoxygenase protein expression in breast cancer. 2019;145(8):2083-95. 

Translational Oncology

Radestad AF, Estekizadeh A, Cui HL, Kostopoulou ON, Davoudi B, Hirschberg AL, Carlson J, Rahbar A, Söderberg-Naucler C. Impact of Human Cytomegalovirus Infection and its Immune Response on Survival of Patients with Ovarian Cancer. 2018;11(6):1292-300. 

Cell Reports

Low H, Mukhamedova N, Cui HL, McSharry BP, Avdic S, Hoang A, Ditiatkovski M, Liu Y, Fu Y, Meikle PJ, Blomberg M, Polyzos KA, Miller WE, Religa P, Bukrinsky M, Söderberg-Naucler C, Slobedman B, Sviridov D. Cytomegalovirus Restructures Lipid Rafts via a US28/CDC42-Mediated Pathway, Enhancing Cholesterol Efflux from Host Cells. 2016;16(1):186-200.

Cell Host Microbe

Söderberg-Naucler C. CMV and NK Cells: An Unhealthy Tryst? 2016;19(3):277-9.

Cell Death Differentiation

Fornara O, Bartek J, Jr., Rahbar A, Odeberg J, Khan Z, Peredo I, Hamerlik P, Bartek J, Stragliotto G, Landazuri N, Söderberg-Naucler C. Cytomegalovirus infection induces a stem cell phenotype in human primary glioblastoma cells: prognostic significance and biological impact. 2016;23(2):261-9.

Oncoimmunology

Rahbar A, Cederarv M, Wolmer-Solberg N, Tammik C, Stragliotto G, Peredo I, Fornara O, Xu X, Dzabic M, Taher C, Skarman P, Söderberg-Naucler C. Enhanced neutrophil activity is associated with shorter time to tumor progression in glioblastoma patients. 2016;5(2):e1075693.

Oncoimmunology

Rahbar A, Peredo I, Solberg NW, Taher C, Dzabic M, Xu X, Skarman P, Fornara O, Tammik C, Yaiw K, Wilhelmi V, Assinger A, Stragliotto G, Söderberg-Naucler C. Discordant humoral and cellular immune responses to Cytomegalovirus (CMV) in glioblastoma patients whose tumors are positive for CMV. 2015;4(2):e982391.

Oncoimmunology.

Fornara O, Odeberg J, Wolmer Solberg N, Tammik C, Skarman P, Peredo I, Stragliotto G, Rahbar A, Söderberg-Naucler C. Poor survival in glioblastoma patients is associated with early signs of immunosenescence in the CD4 T-cell compartment after surgery. 2015;4(9):e1036211.

Links

• Utu research profile
• Orcid profile

Arto Pulliainen, PhD, University lecturer

Contact: arto.pulliainen@utu.fi

Description of Research

Turku Cellular Microbiology Laboratory (TCML) studies molecular mechanisms of the bacterial pathogen-host cell interaction. We aim to understand how host cell signaling is regulated in bacterial infection to orchestrate pathogen clearance, and how pathogen utilizes protein secretion systems and their effector proteins to counterattack this host anti-bacterial response. We utilize animal experimentation, cell culture models and a range of biochemical and biophysical methods of protein chemistry to understand bacterial infection at the molecular level. Our ultimate goal is to gain molecular knowledge allowing development of new and targeted therapeutic solutions to bacterial infections, and potentially also to other inflammatory disorders.

Current topics

• ADP-ribosylation signaling in gastrointestinal tract infections
• Mammalian ADP-ribosylating PARP enzymes
• Bacterial  ADP-ribosylating toxins  
• Bacterial toxin-targeted drug modalities

Research group members

• Senior researchers: Rita Azevedo, Anbu Poosakkannu
• PhD students: Moona Miettinen, Madhukar Vedantham
• Other students: Olli Laaksoaho, Vili Niinikoski, Arttu Laisi, Antti Kaatiala,  Alaa Benkherouf
• Technicians: Mika Savisalo

Recent key publications

1. Paramonov, V.M., Sahlgren, C., Rivero-Müller, A., and Pulliainen, A.T. (2020) iGIST - a kinetic bioassay for pertussis toxin based on its effect on inhibitory GPCR signaling. ACS Sensors (in press)
2. Eskonen, V., Tong-Ochoa, N., Mattsson, L., Miettinen, M., Lastusaari, M., Pulliainen, A.T., Kopra, K., and Härmä H. (2020) Single-peptide TR-FRET detection platform for cysteine-specific post-translational modifications. Analytical Chemistry 92:13202-13210.
3. Ashok, Y., Miettinen, M, De Oliveira, D.K.H., Tamirat, M.Z., Näreoja, K., Tiwari, A., Hottiger, M.O., Johnson, M.S., Lehtiö, L. and Pulliainen, A.T. (2020) Discovery of compounds inhibiting the ADP-ribosyltransferase activity of pertussis toxin. ACS Infectious Diseases 6:588-602. (in the special issue of Chemical Microbiology)
4. Kopra, K., Vuorinen, E., Abreu-Blanco, M., Wang, Q., Eskonen, V., Gillette, W., Pulliainen, A.T., Holderfield, M., and Härmä H. (2020) Homogeneous dual-parametric coupled assay for simultaneous nucleotide exchange and KRAS/RAF-RBD interaction monitoring. Analytical Chemistry 92:4971-4979.
5. Miettinen, M., Vedantham, M., and Pulliainen, A.T. (2019) Host poly(ADP-ribose) polymerases (PARPs) in acute and chronic bacterial infections. Microbes and Infection 21:423-431. (invited review)

Links

• Research group's website
• Utu research profile
• Orcid profile

Pia Rantakari, Adjunct Professor of Physiology, Senior Research Fellow

Contact: pia.rantakari@utu.fi

Description of Research

Our research emphasis is on endothelium's involvement in fetal leukocyte cell migration and the outcome of impaired embryonic leukocyte migration in adult tissue homeostasis. We are particularly interested in the tissue-resident macrophages and whether diverse developmental origin among resident macrophages relates to macrophages' postnatal functions. We use single-cell genomics with single-cell proteomics combined with various sophisticated in vivo mouse models to answer our research question.

Current topics

• The function of the endothelium and molecular steps underlying the leukocyte migration during embryogenesis
• Understanding how the ontogeny relates to the function of macrophages under homeostatic conditions or in diseases
• Cross-talk of Immune and endocrine system

Research group members

• Senior researchers: Heli Jokela, Heidi Gerke
• PhD students: Emmi lokka, Ines Felix, Laura Lintukorpi, Elias Mokkala
• Other students: Venla Ojasalo, Joonas Karhula, Elina Laine
• Technicians: Laura Grönfors, Etta-Liisa Väänänen

Recent key publications

1. Lokka E, Lintukorpi L, Cisneros-Montalvo S, Mäkelä A-T, Tyystjärvi S, Ojasalo O, Gerke H, Toppari J, Rantakari P# and Salmi M# Generation, localization and functions of macrophages during the maturation of testis. Nature Communications 2020. PMID:32873797.
2. Jokela H, Lokka E, Kiviranta M, Tyystjärvi S, Gerke H, Elima K, Salmi M# and Rantakari P#. Fetal –derived macrophages persist and sequentially maturate in ovaries after birth. Eur J Immunol. 2020. PMID:32459864.
3. Jäppinen N, Felix I, Lokka E, Tyystjärvi S, Pynttäri A, Lahtela T, Gerke H, Elima K, Rantakari P, Salmi M. Fetal-derived macrophages dominate in adult mammary glands. Nature Communications 2019. PMID:30655530.
4. Rantakari P, Jäppinen N, Lokka E, Mokkala E, Gerke H, Peuhu E, Ivaska J, Elima K, Auvinen K, Salmi M. Fetal liver endothelium regulates the seeding of tissue-resident macrophages. Nature 2016. PMID:27732581.
5. Rantakari P, Patten DA, Valtonen J, Karikoski M, Gerke H, Dawes H, Laurila J, Ohlmeier S, Elima K, Hübscher SG, Weston CJ, Jalkanen S, Adams DH, Salmi M, Shetty S. Stabilin-1 expression defines a subset of macrophages that mediate tissue homeostasis and prevent fibrosis in chronic liver injury. Proc Natl Acad Sci U S A. 2016. PMID:27474165.

Links

• Research group's website
• Utu research profile
• Orcid profile

Principal Investigator

Marko Salmi, MD, PhD, Professor of Immunology

marko.salmi@utu.fi I Utu research profile I Orcid profile

Description of Research

Leukocyte migration from the blood and lymph into tissues and transport of antigens into secondary lymphoid organs are critical for the generation of normal immune responses. Dysregulation of these dynamic processes contribute to the pathogenesis of all inflammatory diseases and several other diseases, such as cancer. We study the molecular mechanisms and functional implications of antigen and leukocyte traffic in the body. We are interested in defining the routes and mechanisms by which antigens enter the lymph node parenchyma via the lymphatic vasculature. We elucidate the role of stromal cells of draining lymph nodes in antigen handling. We also study the effects of tissue niche on the plasticity and functions of macrophages and other myeloid cells.  Moreover, we analyze therapeutic potential of the new leukocyte trafficking molecules we have identified on blood and lymphatic vessels (e.g. vascular adhesion protein-1 (VAP-1), CD73, stabilin-1, plasmalemma vesicle associated protein (Plvap)) in inflammation and cancer.  As a separate line of research, we study the value of leukocyte and endothelial cell subsets and soluble inflammatory mediators (e.g., cytokines) as biomarkers of disease in population and patient cohorts.

Current topics

• delivery of lymph-borne antigens into draining lymph nodes
• effects of immunization on lymph node stromal cells
• role of cell origin and tissue niche in differentiation of myeloid leukocytes
• immunological biomarkers of inflammation and cancer

Research group's website

Description of Research

Akira Takeda, Academy Research Fellow

Contact: akitak@utu.fi

Description of research

Although immune cells play a critical role in human diseases such as infection and cancer, structural cells including endothelial and stromal cells are also crucial for maintaining the function of the immune cells. Recent single-cell technologies showed multiple heterogenous subsets in structural cells that have not been considered before. The aim of our group is (1) to find unrecognized heterogeneous structural cell subsets in human organs including lymphoid organs and tumors using single-cell technologies, and (2) to find the new molecular mechanism between heterogeneous structural cells and immune cells in health and disease.

Current topics

• Heterogeneity of human dendritic cells and their functions
• Blood and lymphatic endothelial cell heterogeneity in the tumor microenvironment
• Lymphatics in human spleen

Research group members

• PhD student: Diana Lehotina
• Research assistant: Sadaf Fazeli

Recent selected publications

1. Takeda A, Hollmén M, Dermadi D, Pan J, Brulois KF, Kaukonen R, Lönnberg T, Boström P, Koskivuo I, Irjala H, Miyasaka M, Salmi M, Butcher EC, Jalkanen S: “Single-Cell Survey of Human Lymphatics Unveils Marked Endothelial Cell Heterogeneity and Mechanisms of Homing for Neutrophils.” Immunity 51: 561-572, 2019.
2. Takeda A, Kobayashi D, Aoi K, Sasaki N, Sugiura Y, Igarashi H, Tohya K, Inoue A, Hata E, Akahoshi N, Hayasaka H, Kikuta J, Scandella E, Ludewig B, Ishii S, Aoki J, Suematsu M, Ishii M, Takeda K, Jalkanen S, Miyasaka M, Umemoto E: “Fibroblastic reticular cell-derived lysophosphatidic acid regulates confined intranodal T-cell motility.” eLIFE 5: e10561, 2016.
3. Takeda A, Hossain MS, Rantakari P, Simmons S, Sasaki N, Salmi M, Jalkanen S, Miyasaka M: “Thymocytes in Lyve1-CRE/S1pr1f/f mice accumulate in the thymus due to cell-intrinsic loss of sphingosine-1-phosphate receptor expression.” Frontiers in Immunology, 7, 2016.
4. Xiang M, Grosso RA, Takeda A, Pan J, Bekkhus T, Brulois K, Dermadi D, Nording S, Vanlandewijck M, Jalkanen S, Ulvmar MH#, Butcher EC# (#equally contributed senior authors): “A single-cell transcriptional roadmap of the mouse and human lymph node lymphatic vasculature.” Frontiers in Cardiovascular Medicine 7, 2020.
5. Takeda A, Jalkanen S: “Single-cell transcriptomics of human lymph node stroma.” STAR Protocols, 2020. doi: 10.1016/j.xpro.2020.100021

Links

• Utu research profile
• Research group's website
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Sisko Tauriainen

Matti Waris