Broad and potent neutralizing human antibodies to tick-borne flaviviruses protect mice from disease

Tick-borne encephalitis virus (TBEV) is an emerging human pathogen that causes potentially fatal disease with no specific treatment. Mouse monoclonal antibodies are protective against TBEV, but little is known about the human antibody response to infection. Here, we report on the human neutralizing antibody response to TBEV in a cohort of infected and vaccinated individuals. Expanded clones of memory B cells expressed closely related anti-envelope domain III (EDIII) antibodies in both groups of volunteers. However, the most potent neutralizing antibodies, with IC₅₀s below 1 ng/ml, were found only in individuals who recovered from natural infection. These antibodies also neutralized other tick-borne flaviviruses, including Langat, louping ill, Omsk hemorrhagic fever, Kyasanur forest disease, and Powassan viruses. Structural analysis revealed a conserved epitope near the lateral ridge of EDIII adjoining the EDI–EDIII hinge region. Prophylactic or early therapeutic antibody administration was effective at low doses in mice that were lethally infected with TBEV.     

IL-10 Restrains IL-17 to Limit Lung Pathology Characteristics following Pulmonary Infection with Francisella tularensis Live Vaccine Strain

IL-10 production during intracellular bacterial infections is generally thought to be detrimental because of its role in suppressing protective T-helper cell 1 (Th1) responses. Francisella tularensis is a facultative intracellular bacterium that activates both Th1 and Th17 protective immune responses. Herein, we report that IL-10–deficient mice (Il10^−/−), despite having increased Th1 and Th17 responses, exhibit increased mortality after pulmonary infection with F. tularensis live vaccine strain. We demonstrate that the increased mortality observed in Il10^−/−-infected mice is due to exacerbated IL-17 production that causes increased neutrophil recruitment and associated lung pathology. Thus, although IL-17 is required for protective immunity against pulmonary infection with F. tularensis live vaccine strain, its production is tightly regulated by IL-10 to generate efficient induction of protective immunity without mediating pathology. These data suggest a critical role for IL-10 in maintaining the delicate balance between host immunity and pathology during pulmonary infection with F. tularensis live vaccine strain.Francisella tularensis, a facultative intracellular bacterium, because of its infectious nature and the severe disease caused by low doses of airborne bacteria, has been classified as a category A select bioterrorism agent.¹ Infection in humans is caused by two main subspecies, F. tularensis (type A) and Francisella holarctica (type B).² An F. tularensis live vaccine strain (LVS) has been developed from the F. tularensis B strain as an experimental vaccine, but is not licensed for use in humans.¹ F. tularensis LVS has been used as a representative attenuated model to address the immune requirements for protection against Francisella. By using this model, the importance of IL-12 in driving interferon γ (IFN-γ) and T-helper cell 1 (Th1) responses in immunity to F. tularensis LVS infection is well described.^3–5 In contrast, IL-17 is generally thought to play a role in protection against extracellular, but not intracellular, pathogens.⁶ However, we and others recently identified a protective role for IL-17 in the induction of cellular immunity to F. tularensis LVS pulmonary infection,^7–9 by driving the production of IFN-γ through IL-12 induction.⁷ IL-17 is a proinflammatory cytokine also known to induce chemokines, such as keratinocyte chemoattractant, macrophage inflammatory protein 2 (MIP-2), and granulocyte colony-stimulating factor (G-CSF), to mediate granulopoiesis, neutrophil recruitment, and inflammation.⁶ Accordingly, the absence of IL-17 during F. tularensis LVS pulmonary infection also results in decreased induction of G-CSF and MIP-2, as well as decreased accumulation of neutrophils and lung inflammation.⁷ Neutrophil depletion alone does not affect bacterial control after pulmonary infection with F. tularensis LVS,¹⁰ suggesting that the role for IL-17 in driving Th1 responses, and not neutrophil recruitment, was the primary immune mechanism mediating protection in this model.⁷ These data together suggest that both IL-17 and IFN-γ are required for generating protective immunity to pulmonary F. tularensis LVS infection.IL-10 is an anti-inflammatory cytokine best studied for its inhibitory effects on IL-12 production and down-regulation of Th1 responses.¹¹ Accordingly, IL-10–deficient mice show enhanced protection in models of intracellular bacterial infections, such as Mycobacterium tuberculosis¹² and Listeria monocytogenes.¹³ In addition, in a cutaneous model of F. tularensis LVS infection, IL-10–deficient mice exhibit increased protection, and this was reversed when IL-17 was depleted.¹⁴ In contrast to these published studies, in the current study, we report that after pulmonary infection with F. tularensis LVS, mice deficient in IL-10 (Il10^−/−) exhibit increased mortality. We clearly demonstrate that the increased mortality in the Il10^−/−-infected mice is not associated with loss of protective immunity, because bacterial burden between wild-type and Il10^−/− mice is similar, but is caused by exacerbated inflammation and increased lung pathology. We demonstrate that the exacerbated inflammation observed in Il10^−/−-infected mice is the result of unrestrained IL-17 production and IL-17–dependent recruitment of neutrophils and resulting lung pathology. These data together suggest that, although IL-17 is required for protective immunity against pulmonary infection with F. tularensis LVS,^7,9 IL-17 production is tightly regulated by anti-inflammatory cytokines, such as IL-10. Our studies highlight how inflammatory cytokines, such as IL-17, can be beneficial for host protection, but when produced unrestrained, can mediate host pathology.     

Fecal Bacteriotherapy for Clostridium difficile Infections — Its Time Has Come

Clostridium difficile treatment failures and recurrences occur at rates of 22.3% and 22.1%, respectively. For patients who have refractory/recurrent disease, there are limited treatment options. The use of a fecal suspension from a healthy donor instilled via a nasogastric tube, during colonoscopy, or by enema in a patient with recurrent or refractory C. difficile infection has shown a response rate of 75 to 100% with minimal adverse effects. There are multiple published case series that provide variations in administration procedures. The main barrier is the need for institutions and clinics to develop protocols to ensure this treatment modality is available to patients with this debilitating and potentially fatal disease.     

Relational Memory in the Early Stage of Psychosis: A 2-Year Follow-up Study

BackgroundRelational memory, the ability to bind information into complex memories, is moderately impaired in early psychosis and severely impaired in chronic schizophrenia, suggesting relational memory may worsen throughout the course of illness. MethodsWe examined relational memory in 66 early psychosis patients and 64 healthy control subjects, with 59 patients and 52 control subjects assessed longitudinally at baseline and 2-year follow-up. Relational memory was assessed with 2 complementary tasks, to test how individuals learn relationships between items (face-scene binding task) and make inferences about trained relationships (associative inference task).ResultsThe early psychosis group showed impaired relational memory in both tasks relative to the healthy control group. The ability to learn relationships between items remained impaired in early psychosis patients, while the ability to make inferences about trained relationships improved, although never reaching the level of healthy control performance. Early psychosis patients who did not progress to schizophrenia at follow-up had better relational memory than patients who did.ConclusionsRelational memory impairments, some of which improve and are less severe in patients who do not progress to schizophrenia, are a target for intervention in early psychosis.     

Ecomorphological variation in artiodactyl calcanei using 3D geometric morphometrics

Artiodactyl postcrania are commonly used as paleoecological indicators but these studies are usually limited to artiodactyls within a single family. Here, we use 3D geometric morphometrics to analyze the morphology of calcanei from five artiodactyl families (Antilocapridae, Bovidae, Cervidae, Giraffidae, and Tragulidae) and identify common ecological trends among these families using principal component analysis. Our results indicate that antilocaprid and some bovid calcanei show convergent evolution of cursorial morphology and that other bovids have independently evolved less cursorial morphology that is more similar to cervids. This study shows that parallel ecomorphological trends can be identified in multiple families of artiodactyls, as well as within artiodactyl groups. This further suggests that the calcaneus may be a good indicator of ecology and function in fossil groups that are taxonomically ambiguous or not closely related to living taxa.     

Observations on idiopathic proctitis

This paper presents the natural history of idiopathic proctitis and concludes that this disease and idiopathic procto-colitis are two manifestations of one disease differing only in the extent of the colon involved.     

Effects on the buoyant density of rabbit platelets of ADP and agents that increase the concentration of cyclic AMP

Rabbit platelets were aggregated by adenosine diphosphate (ADP), allowed to deaggregate and then separated into density subpopulations by centrifugation through discontinuous Stractan density gradients. Although ADP causes little or no release of the contents of the amine storage granules of rabbit platelets, ADP caused a decrease in platelet density as compared with control platelets subjected to the same procedures except for exposure to ADP. The density change persisted for at least four hours. The apparent size of platelets stimulated with ADP increased initially, but returned to control values during a one-hour period. A similar decrease in platelet density was observed with an albumin density gradient. Under conditions in which aggregation did not occur in response to ADP with ethylenediaminetetraacetic acid (EDTA) in the medium, little or no decrease in platelet density was observed. Agglutination with polylysine did not change platelet density. Thus, not only agents such as thrombin and plasmin that cause the release of the contents of the platelet granules decrease platelet density, but ADP also has this effect. Platelets would be exposed to all of these stimuli during thromboembolic processes, and their effect on platelets may account for the decrease in platelet density observed previously in experiments with rabbits with indwelling aortic catheters. Agents that increase the concentration of cyclic AMP (cAMP) in platelets (PGE1, adenosine, dibutyryl cAMP, forskolin, and papaverine) also decreased platelet density. This effect persisted when the platelets were washed and resuspended in fresh medium and was also demonstrable in plasma. Platelet size was gradually increased by prostaglandin E1 (PGE1) which maintains platelets in a disc shape and does not cause the release of granule contents, indicating that the decrease in platelet density caused by PGE1 may be attributable to platelet swelling.     

Autoantibodies inhibit interleukin-7-mediated proliferation and are associated with the age-dependent loss of pre-B cells in autoimmune New Zealand Black Mice

Surface IgM+B220+ B cell precursors can be categorized as either leukosialin (CD43/S7) negative (late stage pre-B cells) or positive (pro-B/early pre-B cells). In autoimmune New Zealand Black (NZB) mice, bone marrow small pre-B cells (IgM-CD43-B220+) and pro-B/early pre-B cells (IgM-CD43+B220+) declined significantly with age. In particular, subpopulations of pro-B/early pre-B cells expressing the heat stable antigen (HSA) were found in lower proportions with age. Significant decreases in interleukin-7 (IL-7) colony forming units (CFU) were also seen in NZB mice by 6 to 8 months of age and accompanied alterations in the numbers of pro-B and pre-B cells in bone marrow. Concomitant with reduced numbers of B lineage precursor cells and IL-7 CFU in vivo, NZB mice produced serum IgM antibodies that strongly inhibited IL-7 CFU responses in vitro. Two monoclonal IgM antibodies (5G9, 2F5) derived from LPS stimulated 10-month-old NZB splenocytes recognized pre-B cell surface antigens on both pre-B cell lines and on IL-7 stimulated bone marrow pro-B/pre-B cells. However, these monoclonal antibodies (MoAb) failed to significantly stain ex vivo bone marrow cells. The 5G9 and 2F5 MoAbs also partially inhibited IL-7 CFU in vitro. These results suggest that NZB bone marrow becomes increasingly deficient in B cell precursors and especially in IL-7 responsive pre-B cells with age. IgM serum antibodies and monoclonal IgM antibodies derived from older NZB mice inhibit pre-B cell growth to IL-7. The production of such autoantibodies may interfere with B cell development in aging NZB mice by preventing IL-7-mediated proliferation.