Natalie E Nieuwenhuizen

University of Wuerzburg | JMU · Institute of Hygiene and Microbiology

Several case reports show allergy and anaphylactic reactions to the fish parasite Anisakis in the domestic and occupational setting. Further research is needed on the prevalence and mechanisms of disease. To determine the prevalence of Anisakis sensitization and related symptoms among workers in 2 fish-processing factories, and to use gene-deficien...

In BALB/c mice, susceptibility to infection with the intracellular parasite Leishmania major is driven largely by the development of T helper 2 (Th2) responses and the production of interleukin (IL)-4 and IL-13, which share a common receptor subunit, the IL-4 receptor alpha chain (IL-4Rα). While IL-4 is the main inducer of Th2 responses, paradoxica...

Unlabelled: The current tuberculosis (TB) vaccine, Mycobacterium bovis Bacillus Calmette-Guérin (BCG), provides insufficient protection against pulmonary TB. Previously, we generated a listeriolysin-expressing recombinant BCG strain, which to date has successfully completed phase I and phase IIa clinical trials. In an attempt to further improve ef...

Activin A strongly influences immune responses; yet, few studies have examined its role in infectious diseases. We measured serum activin A levels in two independent tuberculosis (TB) patient cohorts and in patients with pneumonia and sarcoidosis. Serum activin A levels were increased in TB patients compared to healthy controls, including those wit...

Tuberculosis (TB), caused by the intracellular bacterium Mycobacterium tuberculosis (Mtb), remains a major health threat. A live, attenuated mycobacterium known as Bacille Calmette–Guérin (BCG), derived from the causative agent of cattle TB, Mycobacterium bovis, has been in clinical use as a vaccine for 90 years. The current incidence of TB demonst...

A more effective vaccine against tuberculosis than Bacille Calmette-Guérin (BCG) is urgently needed. BCG derived recombinant VPM1002 has been found to be more efficacious and safer than the parental strain in mice models. Newer candidates, such as VPM1002 Δpdx1 (PDX) and VPM1002 ΔnuoG (NUOG), were generated to further improve the safety profile or...

Tuberculous granulomas are highly dynamic structures reflecting the complex host–mycobacterium interactions. The objective of this study was to compare granuloma development at the site of vaccination with BCG and its recombinant derivatives in goats. To characterize the host response, epithelioid cells, multinucleated giant cells (MNGC), T cell su...

Tuberculosis (TB), caused by the bacillus Mycobacterium tuberculosis (Mtb), remains a leading cause of death by infectious disease, overshadowed only recently by the COVID-19 pandemic [...]

Mycobacterium tuberculosis (Mtb) represents a major burden to global health, and refined vaccines are needed. Replication-deficient lymphocytic choriomeningitis virus (rLCMV)-based vaccine vectors against cytomegalovirus have proven safe for human use and elicited robust T cell responses in a large proportion of vaccine recipients. Here, we develop...

BCG – the only available vaccine against tuberculosis (TB) - was first given to babies 100 years ago in 1921. While it is effective against TB meningitis and disseminated TB, its efficacy against pulmonary TB is variable, notably in adults and adolescents. TB remains one of the world’s leading health problems, with a higher prevalence among men. Ma...

Cellular stress has been associated with inflammation, yet precise underlying mechanisms remain elusive. In this study, various unrelated stress inducers were employed to screen for sensors linking altered cellular homeostasis and inflammation. We identified the intracellular pattern recognition receptors NOD1/2, which sense bacterial peptidoglycan...

Leishmaniasis is a vector-borne disease caused by Leishmania parasites. Macrophages are considered the primary parasite host cell, but dendritic cells (DCs) play a critical role in initiating adaptive immunity and controlling Leishmania infection. Accordingly, our previous study in CD11ccreIL-4Rα−/lox mice, which have impaired IL-4 receptor alpha (...

Many pathogens, ranging from viruses to multicellular parasites, promote expansion of MDSCs, which are myeloid cells that exhibit immunosuppressive features. The roles of MDSCs in infection depend on the class and virulence mechanisms of the pathogen, the stage of the disease, and the pathology associated with the infection. This work compiles evid...

Development of IL-4 receptor alpha (IL-4Rα)-dependent cellular immunity regulates host protection against acute schistosomiasis. In this study, we investigated the importance of IL-4Rα-expressing CD11c+ cells in driving the development of optimal cellular responses to Schistosoma mansoni infection by using CD11ccreIL-4Rα−/lox BALB/c mice, which lac...

Schistosomiasis (bilharzia) is a parasitic helminth disease that can cause severe inflammatory pathology leading to organ damage in humans. Failure of the host to regulate egg-driven granulomatous inflammation causes host morbidity during chronic infection with Schistosoma mansoni. Although the importance of B cells in regulating pathology during c...

The skin microenvironment at the site of infection plays a role in the early events that determine protective T helper 1/type 1 immune responses during cutaneous leishmaniasis (CL) infection. During CL in non-healing BALB/c mice, early Interleukin (IL)-4 can instruct dendritic cells for protective Th1 immunity. Additionally, keratinocytes, which ar...

Background Cellulose is an insoluble plant polysaccharide produced from soft‐wood pulp. Although chronic respiratory effects associated with high cellulose‐based dust levels have been previously described, occupational asthma has not. A 37 year old machine operator in a sanitary pad production factory presented with new‐onset work‐related asthma sy...

The precise mechanisms leading to development of T helper type (Th)2-driven allergic responses are unknown. We aimed to determine how IL-4 receptor alpha (IL-4Rα) signaling on CD11c+ cells influences allergen-induced Th2 responses in mice. CD11ccreIL-4Rα-/l°x mice, deficient in IL-4Rα on dendritic cells and alveolar macrophages, were compared to IL...

Mass spectrometry (MS)-based immunopeptidomics investigates the repertoire of peptides presented at the cell surface by major histocompatibility complex (MHC) molecules. The broad clinical relevance of MHC-associated peptides, e.g. in precision medicine, provides a strong rationale for the large-scale generation of immunopeptidomic datasets and rec...

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a global threat. The only approved vaccine against TB, Mycobacterium bovis bacillus Calmette–Guérin (BCG), provides insufficient protection and, being a live vaccine, can cause disseminated disease in immunocompromised individuals. Previously, we found that intradermal cDNA tatt...

The only licensed vaccine against tuberculosis (TB), bacille Calmette–Guérin (BCG), protects against severe extrapulmonary forms of TB but is virtually ineffective against the most prevalent form of the disease, pulmonary TB. BCG was genetically modified at the Max Planck Institute for Infection Biology to improve its immunogenicity by replacing th...

Bacille Calmette-Guérin (BCG), the only tuberculosis (TB) vaccine in clinical practice, has limitations in efficacy, immunogenicity and safety. Much current TB vaccine research focuses on engineering live mycobacteria to interfere with phagosome biology and host intracellular pathways including apoptosis and autophagy, with candidates such as BCG Δ...

Mass spectrometry (MS)-based immunopeptidomics investigates the repertoire of peptides presented at the cell surface by major histocompatibility complex (MHC) molecules. The broad clinical relevance of MHC-associated peptides, e.g. in precision medicine, provides a strong rationale for the large-scale generation of immunopeptidomic datasets and rec...

Anisakis species are marine nematodes which can cause zoonotic infection in humans if consumed in raw, pickled or undercooked fish and seafood. Infection with Anisakis is associated with abdominal pain, nausea and diarrhoea, and can lead to massive infiltration of eosinophils and formation of granulomas in the gastrointestinal tract if the larvae a...

Immune responses in spleens after vaccination with BCG, BCG ΔureC::hly, and BCG ΔureC::hly ΔnuoG. (A to F) Frequencies of T follicular helper (TFH) cells (A), germinal center (GC) B cells (B), CD4+ central memory T (TCM) cells (C), effector memory T (TEM) cells (D), CD8+ TCM cells (E), and TEM cells (F) at 21 days postvaccination. Two experiments;...

Upregulation of inflammasome-associated genes IL-1β, IL-18, and Ifi204 and Gbps at day 3 was validated by RT-PCR. RNA from lymph nodes of mice vaccinated with BCG, BCG ΔureC::hly, and BCG ΔureC::hly ΔnuoG was reverse transcribed to cDNA, and PCRs were performed on a Step One Plus real-time PCR machine. Analysis was performed using the comparative C...

Genes significantly upregulated (P < 0.05) at least 2-fold compared to naive control only in BCG ΔureC::hly ΔnuoG-vaccinated mice. Venn diagrams were plotted in GeneSpring to analyze overlap of genes significantly upregulated (P < 0.05) at least 2-fold compared to naive control in groups vaccinated with different strains of BCG, at 1, 3, and 7 days...

GO enrichment analysis of genes identified as significantly upregulated (P < 0.05) at least 2-fold compared to naive controls only in BCG ΔureC::hly ΔnuoG-vaccinated mice. GeneSpring was used to perform GO analysis on genes significantly upregulated compared to naive controls in BCG ΔureC::hly ΔnuoG mice only, as identified by Venn diagrams. At day...

Lists of genes in the heat map gene clusters labeled R1 to R8. A heat map was generated in GeneSpring from genes significantly differentially regulated (P < 0.05) compared to naive controls, and lists were compiled of gene clusters. Long noncoding RNAs are not included. Confirmed or potential gene/protein functions were obtained from the Mouse Gene...

Differential gene expression after vaccination with BCG, BCG ΔureC::hly, and BCG ΔureC::hly ΔnuoG. (A) Microarray analysis demonstrates that vaccination of mice with BCG ΔureC::hly and particularly BCG ΔureC::hly ΔnuoG drives earlier and stronger immune responses in the lymph nodes compared to BCG SSI. Number of entities significantly differentiall...

Differential expression of IFN-inducible GTPases 7 days after vaccination with BCG, BCG ΔureC::hly, and BCG ΔureC::hly ΔnuoG. Draining lymph nodes were collected at day 7 postvaccination, and gene expression was analyzed by whole-genome mouse microarray. Microarray data were analyzed using GeneSpring 12.6 GX (Agilent Technologies), with quality con...

Primers for RT-PCR.

Dissemination and survival of BCG and recombinant derivatives in mice. Animals were subcutaneously vaccinated with 106 CFU of BCG SSI, BCG ΔureC::hly, or BCG ΔureC::hly ΔnuoG (Fig. 3A). The dissemination of live vaccines was determined by plating organ homogenates on agar at designated time points. When bacterial counts were expected to be low, the...

Background: TH2 cells and their cytokines are associated with allergic asthma in human subjects and with mouse models of allergic airway disease. IL-4 signaling through the IL-4 receptor α (IL-4Rα) chain on CD4(+) T cells leads to TH2 cell differentiation in vitro, implying that IL-4Rα-responsive CD4(+) T cells are critical for the induction of al...

Background A meta-analysis of published data was conducted to investigate the overall risks of hypertension and QTc prolongation in patients with advanced non-small cell lung cancer (NSCLC) who were receiving vandetanib. Methods A computerized search through electronic databases, including PubMed and Embase (until Dec 2014), was performed to obtain...

Gastro-allergic anisakiasis (GAA) and Anisakis sensitization associated chronic urticaria (CU+) are diseases which differ in their IgE and IgG4 responses against both crude extract and specific allergens. Anisakis and Ascaris are closely related nematodes that usually cause problems with specificity in immunodiagnostics. In this study we measured I...

Background: The recombinant BCG ΔureC::hly (rBCG) vaccine candidate induces improved protection against tuberculosis over parental BCG (pBCG) in preclinical studies and has successfully completed a phase 2a clinical trial. However, the mechanisms responsible for the superior vaccine efficacy of rBCG are still incompletely understood. Here, we inve...

The food-borne parasite Anisakis is an important hidden food allergen. Anisakis is a parasitic nematode which has a third-stage larval form that infects mainly fish, and ingestion of contaminated seafood can result in severe allergic reactions. Symptoms experienced due to exposure to this parasite include gastrointestinal disorders, urticaria, derm...

In this study, B cell function in protective TH2 immunity against N. brasiliensis infection was investigated. Protection against secondary infection depended on IL-4Rα and IL-13; but not IL-4. Protection did not associate with parasite specific antibody responses. Re-infection of B cell-specific IL-4Rα(-/-) mice resulted in increased worm burdens c...

Nematode secreted haemoglobins have unusually high affinity for oxygen and possess nitric oxide deoxygenase, and catalase activity thought to be important in protection against host immune responses to infection. In this study, we generated a monoclonal antibody (48Eg) against haemoglobin of the nematode Anisakis pegreffii, and aimed to characteriz...

Anisakis is a parasitic nematode which infects fish and marine invertebrates, including crustaceans and molluscs. Ingestion of contaminated seafood can cause acute gastrointestinal diseases. Infection can be accompanied by severe allergic reactions such as urticaria, angioedema and anaphylaxis. Diagnosis of allergy due to Anisakis currently relies...

Background: Allergic asthma is a T(H)2-promoted hyperreactivity with an immediate, IgE, and mast cell-dependent response followed by eosinophil-dominated inflammation and airway obstruction. Objective: Because costimulation by CD28 is essential for T(H)2 but not T(H)1 responses, we investigated the effect of selective interference with this path...

Prevention of tissue damages at the site of Leishmania major inoculation can be achieved if the BALB/c mice are systemically given L. major antigen (LmAg)-loaded bone marrow-derived dendritic cells (DC) that had been exposed to CpG-containing oligodeoxynucleotides (CpG ODN). As previous studies allowed establishing that interleukin-4 (IL-4) is invo...

Markers of alternatively activated macrophages (AAMs) are upregulated in the lungs of asthmatic patients and in mice with allergic airway disease. AAMs are thought to contribute to the pathogenesis of allergic airway disease by virtue of their decreased NO production and increased production of proline and polyamines, which are important in the syn...

Induction of colitis in mice by administration of oxazolone is mediated by T-helper (Th) 2 cells and has features of human ulcerative colitis. We investigated whether activation of interleukin (IL)-4Rα on T and B cells determines their effector functions and mediates oxazolone-induced colitis. We studied induction of colitis with oxazolone in wild-...

Aerosolized fish proteins are an important cause of allergic airway reactions in both the domestic and the occupational environment. The aim of this study was to investigate inhalant fish-induced allergy in a mouse model and compare immune responses generated by raw and heat-treated fish extracts as well as natural and recombinant forms of the majo...

Asthma is a chronic inflammatory disease of the lungs, characterized by increased sensitivity to bronchoconstriction associated with infiltration of immune cells, mucus hypersecretion and structural remodelling of the airways. In South Africa, the indigenous plant Siphonochilus aethiopicus, is used by traditional health practitioners to treat colds...

Three spice mill workers developed work-related allergy and asthma after prolonged exposure to high levels (>10 mg/m(3)) of inhalable spice dust. Patterns of sensitization to a variety of spices and putative allergens were identified. Work-related allergy and asthma were assessed on history, clinical evaluation, pulmonary function and fractional ex...

Infection with the fish parasite Anisakis following exposure to contaminated fish can lead to allergic reactions in humans. The present study examined the immunological mechanisms underlying the development of allergic airway inflammation in mice after different routes of sensitization to Anisakis. Wild-type and interleukin-4 receptor alpha (IL-4Rα...

SUMMARY Anisakis is a parasitic nematode which infects fish and can cause gastrointestinal disease if accidental- ly ingested. Infection can be accompanied by severe allergic reactions such as urticaria, angio-oedema and anaphylaxis. Furthermore, workers involved in fish processing can develop occupational allergy to Anisakis, including asthma, rhi...

Anisakis is a parasitic nematode which infects fish and can cause gastrointestinal disease if accidentally ingested. Infection can be accompanied by severe allergic reactions such as urticaria, angio-oedema and anaphylaxis. Furthermore, workers involved in fish processing can develop occupational allergy to Anisakis, including asthma, rhinoconjunct...

Exposure to antigens of the fish parasite Anisakis is associated with the development of protein contact dermatitis in seafood-processing workers. Understanding the basic mechanisms controlling allergic sensitization through the skin is critical for designing therapies that will prevent the progression of allergic disease. To investigate the roles...

IL-4Ralpha-mediated STAT6 activation serves an essential role in various animal models of allergy and asthma at both the sensitization and effector phases. IL-4 and IL-13 signaling via the IL-4Ralpha chain exacerbates murine anaphylaxis, but the cell-specific requirements for IL-4Ralpha expression are unclear. The purpose of this study was to eluci...

Infections with pinworms are common in rodent animal facilities. In this study, we show the consequence of an outbreak in a transgenic barrier facility of infection by Syphacia obvelata, a murine pinworm gastrointestinal nematode. Immune responses were defined in experimental infection studies with BALB/c mice. Infection with S. obvelata induced a...

Food allergy is defined as an adverse immunologic reaction to allergens present in food and is associated with symptoms ranging from gastrointestinal discomfort to anaphylactic shock and death. The increase in prevalence and potential fatality of disease has led to increased efforts to find effective therapies and prophylaxis. While specific immuno...