Theresa Graalmann

• Dr. med.Dr. rer. nat.
• Junior group leader at TWINCORE Center for Experimental and Clinical Infection Research

Objectives Systemic sclerosis (SSc) and Sjögren’s disease (SjD) are characterized by systemic inflammation. Although for both entities lymphocyte involvement is reported, the contribution of T cell responses to lung manifestation of SSc and SjD remains elusive. Therefore, we aimed for systematically investigating T cell responses in blood and lungs...

Background: Sarcoidosis is a disease of unknown etiology characterized by the formation of immune cell accumulation (granuloma) in the lung and other tissues. Chronic sarcoidosis may lead to pulmonary fibrosis. Aim: To unravel cellular niches within pulmonary granuloma of chronic sarcoidosis patients using spatial transcriptomics. Methods: Spatial...

Objective Systemic sclerosis (SSc) is a severe rheumatic disease causing fibrotic tissue rearrangement. Aberrant toll‐like receptor (TLR) 8 transcripts in plasmacytoid dendritic cells (pDCs) were recently linked to SSc pathogenesis, which is at least partially mediated by increased type I interferon (IFN‐I) responses. Here, we addressed the functio...

Objective The signal transducer and activator of transcription 3 (STAT3) gain-of-function (GOF) syndrome (STAT3-GOF) is an inborn error of immunity (IEI) characterized by diverse manifestations of immune dysregulation that necessitate systemic immunomodulatory treatment. The blockade of the interleukin-6 receptor and/or the inhibition of the Janus...

Background Human tapasin deficiency was reported to cause an autosomal recessive inborn error of immunity (IEI), characterized by substantially reduced cell surface expression of major histocompatibility complex class I (MHC-I). Objective To evaluate the immunological and the clinical consequences of tapasin deficiency. Methods A novel homozygous v...

COVID‐19 induces re‐circulating long‐lived memory B cells (MBC) that, upon re‐encounter with the pathogen, are induced to mount immunoglobulin responses. During convalescence, antibodies are subjected to affinity maturation, which enhances the antibody binding strength and generates new specificities that neutralize virus variants. Here, we perform...

Memory B cells (MBC) are an important element of the long-lived immunological memory and they provide a diverse pool of B cell receptors that are utilized rapidly under conditions of re-infection. In a recent publication, Mohn et al. monitored spike- and RBD-specific MBC in individuals who recovered from infection with SARS-CoV-2. The authors concl...

Prolidase deficiency (PD) is a rare autosomal recessive inborn error of immunity caused by biallelic homozygous or compound heterozygous loss-of-function mutations in PEPD, the gene that encodes prolidase. PD typically manifests with variable dysmorphic features, chronic cutaneous ulcers, recurrent infections and autoimmune features, including syst...

SARS-CoV-2 Omicron XBB subvariants efficiently evade immunity from prior infection or vaccination, requiring vaccine adaptation. Here, we analyzed immunogenicity of an adapted vaccine, BNT162b2 Omicron XBB.1.5, which is currently used for booster vaccination. Booster vaccination significantly increased anti-Spike IgG, accompanied by expansion of cr...

During the COVID-19 pandemic, numerous new SARS-CoV-2 variants of concern (VOC) evolved, many of which escape from antibody responses. Vaccination of COVID-19 convalescent individuals induces antibody responses of superior quantity and quality, which may even neutralize new VOC. We analyzed memory B cells (MBC) from convalescent donors and studied...

Here, we described the case of a B cell-deficient patient after CD19 CAR-T cell therapy for refractory B cell Non-Hodgkin Lymphoma with protracted coronavirus disease 2019 (COVID-19). For weeks, this patient only inefficiently contained the virus while convalescent plasma transfusion correlated with virus clearance. Interestingly, following convale...

Objectives The monoclonal anti-CD20 antibody rituximab is frequently applied in the treatment of lymphoma as well as autoimmune diseases and confers efficient depletion of recirculating B cells. Correspondingly, B cell-depleted patients barely mount de novo antibody responses during infections or vaccinations. Therefore, efficient immune responses...

Antibiotic treatment of tuberculosis (TB) is complex, lengthy, and can be associated with various adverse effects. As a result, patient compliance often is poor, thus further enhancing the risk of selecting multi-drug resistant bacteria. Macrophage mannose receptor (MMR)-positive alveolar macrophages (AM) constitute a niche in which Mycobacterium t...

Abstract Background Serology testing is explored for epidemiological research and to inform individuals after suspected infection. During the coronavirus disease 2019 (COVID-19) pandemic, frontline healthcare professionals (HCP) may be at particular risk for infection. No longitudinal data on functional seroconversion in HCP in regions with low COV...

Background: Serology testing is explored for epidemiological research and to inform individuals after suspected infection. During the COVID-19 pandemic, frontline healthcare professionals (HCP) may be at particular risk for infection. No longitudinal data on functional seroconversion in HCP in regions with low COVID-19 prevalence and low pre-test p...

Acute lower respiratory tract infections (ALRI) caused by respiratory syncytial virus (RSV) are associated with a severe disease burden among infants and elderly patients. Treatment options are limited. While numerous drug candidates with different viral targets are under development, the utility of RSV entry inhibitors is challenged by a low resis...

IFN-γ is an enigmatic cytokine that shows direct anti-viral effects, confers upregulation of MHC-II and other components relevant for antigen presentation, and that adjusts the composition and balance of complex cytokine responses. It is produced during immune responses by innate as well as adaptive immune cells and can critically affect the course...

Background Antibody-mediated targeting of regulatory T cell receptors such as CTLA-4 enhances antitumor immune responses against several cancer entities including malignant melanoma. Yet, therapeutic success in patients remains variable underscoring the need for novel combinatorial approaches. Methods Here we established a vaccination strategy tha...

Background and aim: Virus-induced fulminant hepatitis is a major cause of acute liver failure. During acute viral hepatitis the impact of type I interferon (IFN-I) on myeloid cells, including liver-resident Kupffer cells (KC), is only partially understood. Here we dissected the impact of locally induced IFN-I responses on myeloid cell function and...

Quiescent long-term hematopoietic stem cells (LT-HSCs) are efficiently activated by type I interferon (IFN-I). However, this effect remains poorly investigated in the context of IFN-I-inducing virus infections. Here we report that both vesicular stomatitis virus (VSV) and murine cytomegalovirus (MCMV) infection induce LT-HSC activation that substan...

Most viruses developed mechanisms that inhibit the induction or the function of type I interferon (IFN-I). Vaccinia virus (VACV), a large DNA-encoded poxvirus, encodes several IFN-I evasins, including the viral IFN-I receptor B18. Nevertheless, here we found that VACV infection still induced local IFN-I responses in secondary lymphoid organs, which...

Targeted drug delivery systems hold promise for selective provision of active compounds to distinct tissues or cell subsets. Thus, locally enhanced drug concentrations are obtained that would confer improved efficacy. As a consequence adverse effects should be diminished, as innocent bystander cells are less affected. Currently, several controlled...

Viruses express a wide range of immune evasion proteins to modulate host immunity. The DNA-encoded poxvirus vaccinia virus (VACV) carries IFN-I inhibitors of which the viral IFN-I receptor B18 binds to the surface of host cells to compete with the endogenous host IFN-I receptor. Upon VACV infection WT mice survive infection with mild signs of disea...

Unlabelled: In healthy individuals, the functional immune system effectively confines human cytomegalovirus (CMV) replication, while viral immune evasion and persistence preclude sterile immunity. Mouse CMV (MCMV) is a well-established model to study the delicate CMV-host balance. Effective control of MCMV infection depends on the induction of pro...

Upon treatment with vesicular stomatitis virus (VSV) particles, plasmacytoid dendritic cells (pDC) are triggered to mount substantial type I IFN responses, whereas myeloid DC (mDC) are only minor producers. Interestingly, bone marrow-derived (BM-)mDC were more vulnerable to infection with enhanced GFP (eGFP)-expressing VSV (VSVeGFP) than BM-pDC. BM...

Vaccination is highly effective in preventing various infectious diseases, whereas the constant threat of new emerging pathogens necessitates the development of innovative vaccination principles that also confer rapid protection in a case of emergency. Although increasing evidence points to T cell immunity playing a critical role in vaccination aga...

Intranasal immunization with MVA induces peribronchiolar and perivascular infiltrate of leukocytes in the lung. Histopathological examination of lungs from C57BL/6 mice after intranasal (i.n.) inoculation with mock vaccine (top panel) or 108 PFU MVA (lower panel). At 48 hours after inoculation inflated lungs were fixed with 4% formalin and embedded...

Intranasal immunization with MVA induces peribronchiolar and perivascular infiltrate of leukocytes in the lung. Histopathological examination of lungs from C57BL/6 mice after intranasal (i.n.) inoculation with mock vaccine (top panel) or 108 PFU MVA (lower panel). At 48 hours after inoculation inflated lungs were fixed with 4% formalin and embedded...

Rapid infiltration of innate immune cells after i. n. immunization with MVA. The bronchoalveolar lavage (BAL) data are representative of two independent experiments. Mice (n = 3) were immunized with either mock vaccine (PBS) (○) or MVA (1×108 PFU) (•) and BAL performed at the indicated time points. (A) Pooled BAL cells were analyzed by FACS to dete...

Rapid activation of innate immune responses after i. n. immunization with MVA. The bronchoalveolar lavage (BAL) data are representative of two independent experiments. Mice (n = 3) were immunized with either mock vaccine (PBS) (□) or MVA (1×108 PFU) (▪) and BAL performed at the indicated time points. (A) Pooled BAL fluids were analyzed for interfer...

Heat-inactivated MVA vaccine does not protect from morbidity and mortality following ECTV challenge. (A) C57BL/6 mice were i.m. immunized with MVA (108 PFU) (n = 5) or heat-inactivated MVA (corresponding to 108 PFU) (n = 5) two days before 3×LD50 ECTV challenge. Mock-challenged (▪) (n = 3) and mock-vaccinated (▴) (n = 5) mice served as controls. In...

B8R gene products are expressed at equal levels by MVA and conventional VACV strain Elstree/Lister. (A) Schematic representation of the B8R coding sequences (CDS) in the genomes of VACV Elstree/Lister (CDS 257) and MVA (CDS 176). The gene products are depicted by grey arrows and the sites of truncations within the MVA B8 protein are shown by white...

Efficient depletion of NK cells, CD8+, and CD4+ T cells at the time point of immunization. Mice were depleted of CD4+ T cells, CD8+ T cells, and NK cells by intraperitoneal (i.p.) administration of mouse monoclonal antibodies. Spleen cells were stained for different cell surface markers and analyzed by FACS. The percentage of (A) NK cells (CD3−, NK...

Protective immunization is independent of the presence of B cells. B cell-deficient JHT mice were i.n. immunized with MVA (○) two days before 3×LD50 ECTV challenge. Mock-challenged (▪) and mock-vaccinated (▴) mice served as controls. In all experiments weight loss of individual mice was monitored daily (n = 2 to 3 per group). +indicate the individu...

C57BL/6 mice and B cell-deficient JHT mice mount comparable VACV specific T cell responses. At 7 days after MVA immunization spleen cells from individual C57BL/6 (wt) (n = 6) mice or B-cell deficient JHT mice (n = 5) were stimulated with VACV specific peptide B8R20–27 and subsequently CD8+ CD62Llow T cells were analyzed by intracellular cytokine st...

Virus-induced expansion of CD8(+) T cells may be promoted by type I IFN receptor (IFNAR)-triggering of T cells, depending on the pathogen tested. We studied modified vaccinia virus Ankara (MVA), a promising vaccine vector candidate, which was derived from conventional vaccinia virus (VACV) by more than 570 consecutive in vitro passages. In adoptive...

Transgenic mice are highly valuable tools for biological research as they allow cell type-specific expression of functionally instrumental genes. In this protocol, the generation of bacterial artificial chromosome (BAC) transgenic constructs is described. We give an overview of different transgenic inserts, such as fluorescent proteins (alone or in...

Type I interferon (IFN-α/β) induction upon viral infection contributes to the early antiviral host defense and ensures survival until the onset of adaptive immunity. Many viral infections lead to an acute, transient IFN expression which peaks a few hours after infection and reverts to initial levels after 24 to 36 h. Robust IFN expression often is...

Production of type I interferons (IFN-I, mainly IFNalpha and IFNbeta) is a hallmark of innate immune responses to all classes of pathogens. When viral infection spreads to lymphoid organs, the majority of systemic IFN-I is produced by a specialized "interferon-producing cell" (IPC) that has been shown to belong to the lineage of plasmacytoid dendri...

A–C) Splenocytes were isolated from C57BL/6, IFNAR1fl/fl-LysMCre, and IFNAR1−/− mice and CD11b+ cells were enriched by magnetic activated cell sorting (MACS). CD11b-enriched cell fraction was stained for CD11c and IFNAR1 and percentages of CD11c+IFNAR+ and CD11c+IFNAR− cells were determined by flow cytometry. D–F) CD11b-enriched splenocytes were st...

A) C57BL/6 wt or TLR9−/− mice were injected i.p. with 5×106L. monocytogenes or PBS as a control. After 24 h of infection, mice were killed and spleens isolated. Protein was extracted from spleens of three infected mice per genotype (1–3) or from mice injected with PBS (−), and Western blot for the indicated proteins was performed. STAT1 and STAT2 a...

Supplementary Materials and Methods (0.03 MB DOC)

A) Mice of the indicated genotypes were injected i.p. with 5×106L. monocytogenes or PBS as a control. After 24 h of infection, mice were killed and spleens isolated. Protein was extracted from spleens of four infected mice per genotype (1–4) or from mice injected with PBS (−), and Western blot for the indicated proteins was performed. STAT1 and STA...

Groups of 9 C57BL/6 wt or IFNAR1−/− mice were infected with 5×106L. monocytogenes. After 24 h of infection, mice were killed and the L. monocytogenes titre was determined in the liver and spleen and presented as CFU. Data were log transformed to achieve approximate normality. Linear models with genotype as fixed effect were fitted using SPSS. No si...

Poxviruses such as virulent vaccinia virus (VACV) strain Western Reserve encode a broad range of immune modulators that interfere with host responses to infection. Upon more than 570 in vitro passages in chicken embryo fibroblasts (CEF), chorioallantois VACV Ankara (CVA) accumulated mutations that resulted in highly attenuated modified vaccinia vir...