Protective immunity against Nippostrongylus brasiliensis requires antigen presentation by IL-4Rα responsive B cells

Includes bibliographical references.Nippostrongylus brasiliensis is a parasitic nematode infection that affects rodents. B-cells have been shown to play an important role in immunity to many different infections by antibody production and T-cell activation. But B-cell function in the protective TH2 response against N. brasiliensis infection is an area of immunity that is currently not well defined. Recently, it has been shown that B-cells are essential to the resolution of a Heligomosomoides polygyrus infection, another parasitic helminth. Our aim in this study was to investigate any role that B-cells may play in response to a secondary N. brasiliensis infection by analysing the differences in immunity of wild-type and B-cell-specific IL-4Rα knockout mice after a N. brasiliensis re-infection

Preconception maternal exposure to Nippostrongylus brasiliensis transfers protection against Nb to her offspring

In early life the immature immune system has a reduced ability to control infection. This susceptibility is offset by transfer of protective immune components from the mother. Helminth infections are widespread and can have a long lasting influence on host immunity. Children of mothers exposed to helminth infections may display T cell sensitization to endemic helminth infections and associations have been made between maternal helminth infection and altered immune responses to childhood diseases and vaccinations. This shows that helminth-modified maternal immunity may imprint on early offspring immune development in-utero or through breast milk in the form of transfer of, for example, antibodies, cytokines and lymphocytes. Our study shows that, in mice, maternal infection with the helminth Nippostrongylus brasiliensis is not only associated with a passive transfer of antigen specific antibody(IgG1) but also inherently alters offspring immunity, increasing offspring cytokine production, alveolar macrophages, lung neutrophils and B cell population development and proliferation. Pups born to N. brasiliensis exposed mothers also had increased populations of lung and spleen CD4+ cells and higher subpopulations of central memory and effector CD4+ cells compared to pups born to naive mothers

Il4ra-independent vaginal eosinophil accumulation following helminth infection exacerbates epithelial ulcerative pathology of HSV-2 infection

How helminths influence the pathogenesis of sexually transmitted viral infections is not comprehensively understood. Here, we show that an acute helminth infection (Nippostrongylus brasiliensis [Nb]) induced a type 2 immune profile in the female genital tract (FGT). This leads to heightened epithelial ulceration and pathology in subsequent herpes simplex virus (HSV)-2 infection. This was IL-5-dependent but IL-4 receptor alpha (Il4ra) independent, associated with increased FGT eosinophils, raised vaginal IL-33, and enhanced epithelial necrosis. Vaginal eosinophil accumulation was promoted by IL-33 induction following targeted vaginal epithelium damage from a papain challenge. Inhibition of IL-33 protected against Nb-exacerbated HSV-2 pathology. Eosinophil depletion reduced IL-33 release and HSV-2 ulceration in Nb-infected mice. These findings demonstrate that Nb-initiated FGT eosinophil recruitment promotes an eosinophil, IL-33, and IL-5 inflammatory circuit that enhances vaginal epithelial necrosis and pathology following HSV-2 infection. These findings identify a mechanistic framework as to how helminth infections can exacerbate viral-induced vaginal pathology

Acetonyl Peroxy and Hydro Peroxy Self- and Cross-Reactions: Kinetics, Mechanism, and Chaperone Enhancement from the Perspective of the Hydroxyl Radical Product

Pulsed laser photolysis coupled with infrared (IR) wavelength modulation spectroscopy and ultraviolet (UV) absorption spectroscopy was used to study the kinetics and branching fractions for the acetonyl peroxy (CH₃C(O)CH₂O₂) self-reaction and its reaction with hydro peroxy (HO₂) at a temperature of 298 K and pressure of 100 Torr. Near-IR and mid-IR lasers simultaneously monitored HO₂ and hydroxyl, OH, respectively, while UV absorption measurements monitored the CH₃C(O)CH₂O₂ concentrations. The overall rate constant for the reaction between CH₃C(O)CH₂O₂ and HO₂ was found to be (5.5 ± 0.5) × 10⁻¹² cm³ molecule⁻¹ s⁻¹, and the branching fraction for OH yield from this reaction was directly measured as 0.30 ± 0.04. The CH₃C(O)CH₂O₂ self-reaction rate constant was measured to be (4.8 ± 0.8) × 10⁻¹² cm³ molecule⁻¹ s⁻¹, and the branching fraction for alkoxy formation was inferred from secondary chemistry as 0.33 ± 0.13. An increase in the rate of the HO₂ self-reaction was also observed as a function of acetone (CH₃C(O)CH₃) concentration which is interpreted as a chaperone effect, resulting from hydrogen-bond complexation between HO₂ and CH₃C(O)CH₃. The chaperone enhancement coefficient for CH₃C(O)CH₃ was determined to be k_A″ = (4.0 ± 0.2) × 10⁻²⁹ cm⁶ molecule⁻² s⁻¹, and the equilibrium constant for HO₂·CH₃C(O)CH₃ complex formation was found to be K_c(R14) = (2.0 ± 0.89) × 10⁻¹⁸ cm³ molecule⁻¹; from these values, the rate constant for the HO₂ + HO₂·CH₃C(O)CH₃ reaction was estimated to be (2 ± 1) × 10⁻¹¹ cm³ molecule⁻¹ s⁻¹. Results from UV absorption cross-section measurements of CH₃C(O)CH₂O₂ and prompt OH radical yields arising from possible oxidation of the CH₃C(O)CH₃-derived alkyl radical are also discussed. Using theoretical methods, no likely pathways for the observed prompt OH radical formation have been found and the prompt OH radical yields thus remain unexplained

Acetonyl Peroxy and Hydro Peroxy Self- and Cross- Reactions: Kinetics, Mechanism, and Chaperone Enhancement from the Perspective of the Hydroxyl Radical Product

Pulsed laser photolysis coupled with infrared (IR) wavelength modulation spectroscopy and ultraviolet (UV) absorption spectroscopy was used to study the kinetics and branching fractions for the acetonyl peroxy (CH₃C(O)CH₂O₂) self-reaction and its reaction with hydro peroxy (HO₂) at a temperature of 298 K and pressure of 100 Torr. Near-IR and mid-IR lasers simultaneously monitored HO₂ and hydroxyl, OH, respectively, while UV absorption measurements monitored the CH₃C(O)CH₂O₂ concentrations. The overall rate constant for the reaction between CH₃C(O)CH₂O₂ and HO₂ was found to be (5.5 ± 0.5) × 10⁻¹² cm³ molecule⁻¹ s⁻¹ and the branching fraction for OH yield from this reaction was directly measured as 0.30 ± 0.04. The CH₃C(O)CH₂O₂ self-reaction rate constant was measured to be (4.8 ± 0.8) × 10⁻¹² cm³ molecule⁻¹ s⁻¹ and the branching fraction for alkoxy formation was inferred from secondary chemistry as 0.33 ± 0.13. An increase in the rate of the HO₂ self-reaction was also observed as a function of acetone (CH₃C(O)CH₃) concentration which is interpreted as a chaperone effect resulting from hydrogen-bond complexation between HO₂ and CH₃C(O)CH₃. The chaperone enhancement coefficient for CH₃C(O)CH₃ was determined to be k”A = (4.0 ± 0.2) x 10⁻²⁹ cm⁶ molecule⁻² s⁻¹ and the equilibrium constant for HO₂•CH₃C(O)CH₃ complex formation was found to be K_c(R15) = (2.0 ± 0.89) × 10⁻¹⁸ cm³ molecule⁻¹; from these values the rate constant for the HO₂ + HO₂•CH₃C(O)CH₃ reaction was estimated to be (2 ± 1) × 10⁻¹¹ cm³ molecule⁻¹ s⁻¹. Results from UV absorption cross-section measurements of CH₃C(O)CH₂O₂ and prompt OH radical yields arising from possible oxidation of the CH₃C(O)CH₃-derived alkyl radical are also discussed. Using theoretical methods, no likely pathways for the observed prompt OH radical formation have been found and thus remains unexplained

Pre-conception maternal helminth infection transfers via nursing long-lasting cellular immunity against helminths to offspring

Maternal immune transfer is the most significant source of protection from early-life infection, but whether maternal transfer of immunity by nursing permanently alters offspring immunity is poorly understood. Here, we identify maternal immune imprinting of offspring nursed by mothers who had a pre-conception helminth infection. Nursing of pups by helminth-exposed mothers transferred protective cellular immunity to these offspring against helminth infection. Enhanced control of infection was not dependent on maternal antibody. Protection associated with systemic development of protective type 2 immunity in T helper 2 (TH2) impaired IL-4R-/- offspring. This maternally acquired immunity was maintained into maturity and required transfer (via nursing) to the offspring of maternally derived TH2-competent CD4 T cells. Our data therefore reveal that maternal exposure to a globally prevalent source of infection before pregnancy provides long-term nursing-acquired immune benefits to offspring mediated by maternally derived pathogen-experienced lymphocytes. © 2019 by the Authors

Surfactant Protein-D is essential for immunity to Helminth Infection

Author Summary Infections by parasitic worms are very common, and controlling them is a major medical and veterinary challenge. Very few drugs exist to treat them, and the parasites can develop resistance to these. In order to find new ways to control worm infections, understanding how our immune system responds to them is essential. Many important parasitic worm infections move through the host lung. In this study we show that a major secreted protein in the lung, Surfactant Protein D (SP-D), is essential for immunity to a parasitic worm infection. We found that this protein binds to worm larvae in the lung to help the immune system kill them. Infecting mice that do not express SP-D with worms demonstrates SP-D is important in this immune response. These mice are unable to launch an effective anti-worm immune response and have many more worms in their intestine compared to mice that do express SP-D. We also show that if we increase SP-D levels in the lung the mouse has better immunity to worms. Together this shows for the first time that SP-D is very important for immunity to worm infections

The M3 muscarinic receptor Is required for optimal adaptive immunity to Helminth and bacterial infection

Innate immunity is regulated by cholinergic signalling through nicotinic acetylcholine receptors. We show here that signalling through the M3 muscarinic acetylcholine receptor (M3R) plays an important role in adaptive immunity to both Nippostrongylus brasiliensis and Salmonella enterica serovar Typhimurium, as M3R-/- mice were impaired in their ability to resolve infection with either pathogen. CD4 T cell activation and cytokine production were reduced in M3R-/- mice. Immunity to secondary infection with N. brasiliensis was severely impaired, with reduced cytokine responses in M3R-/- mice accompanied by lower numbers of mucus-producing goblet cells and alternatively activated macrophages in the lungs. Ex vivo lymphocyte stimulation of cells from intact BALB/c mice infected with N. brasiliensis and S. typhimurium with muscarinic agonists resulted in enhanced production of IL-13 and IFN-γ respectively, which was blocked by an M3R-selective antagonist. Our data therefore indicate that cholinergic signalling via the M3R is essential for optimal Th1 and Th2 adaptive immunity to infection

Improving pregnancy outcomes in humans through studies in sheep

Experimental studies that are relevant to human pregnancy rely on the selection of appropriate animal models as an important element in experimental design. Consideration of the strengths and weaknesses of any animal model of human disease is fundamental to effective and meaningful translation of preclinical research. Studies in sheep have made significant contributions to our understanding of the normal and abnormal development of the fetus. As a model of human pregnancy, studies in sheep have enabled scientists and clinicians to answer questions about the etiology and treatment of poor maternal, placental, and fetal health and to provide an evidence base for translation of interventions to the clinic. The aim of this review is to highlight the advances in perinatal human medicine that have been achieved following translation of research using the pregnant sheep and fetus