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Immunity to the severe diarrheal disease cholera is largely mediated by lipopolysaccharide (LPS)-specific antibodies. However, the properties and protective mechanism of functionally relevant antibodies have not been well defined., Vibrio cholerae causes the severe diarrheal disease cholera. Clinical disease and current oral cholera vaccines generate antibody responses associated with protection. Immunity is thought to be largely mediated by lipopolysaccharide (LPS)-specific antibodies, primarily targeting the O-antigen. However, the properties and protective mechanism of functionally relevant antibodies have not been well defined. We previously reported on the early B cell response to cholera in a cohort of Bangladeshi patients, from which we characterized a panel of human monoclonal antibodies (MAbs) isolated from acutely induced plasmablasts. All antibodies in that previous study were expressed in an IgG1 backbone irrespective of their original isotype. To clearly determine the impact of affinity, immunoglobulin isotype and subclass on the functional properties of these MAbs, we re-engineered a subset of low- and high-affinity antibodies in different isotype and subclass immunoglobulin backbones and characterized the impact of these changes on binding, vibriocidal, agglutination, and motility inhibition activity. While the high-affinity antibodies bound similarly to O-antigen, irrespective of isotype, the low-affinity antibodies displayed significant avidity differences. Interestingly, despite exhibiting lower binding properties, variants derived from the low-affinity MAbs had comparable agglutination and motility inhibition properties to the potently binding antibodies, suggesting that how the MAb binds to the O-antigen may be critical to function. In addition, not only pentameric IgM and dimeric IgA, but also monomeric IgA, was remarkably more potent than their IgG counterparts at inhibiting motility. Finally, analyzing highly purified F(ab) versions of these antibodies, we show that LPS cross-linking is essential for motility inhibition.

Summary SARS-CoV-2, the virus responsible for COVID-19, is causing a devastating global pandemic and there is a pressing need to understand the development, specificity, and neutralizing potency of humoral immune responses during acute infection. We report a cross-sectional study of antibody responses to the receptor-binding domain (RBD) of the spike protein and virus neutralization activity in a cohort of 44 hospitalized COVID-19 patients. RBD-specific IgG responses are detectable in all patients 6 days after PCR confirmation. Isotype switching to IgG occurs rapidly, primarily to IgG1 and IgG3. Using a clinical SARS-CoV-2 isolate, neutralizing antibody titers are detectable in all patients by 6 days after PCR confirmation and correlate with RBD-specific binding IgG titers. The RBD-specific binding data were further validated in a clinical setting with 231 PCR-confirmed COVID-19 patient samples. These findings have implications for understanding protective immunity against SARS-CoV-2, therapeutic use of immune plasma, and development of much-needed vaccines., Graphical Abstract, Highlights • Cross-sectional study of 44 hospitalized COVID-19 patients. • RBD-specific IgG responses detectable in all patients 6 days after PCR confirmation. • Neutralizing titers are detectable in all patients 6 days after PCR confirmation. • RBD-specific IgG titers correlate with the neutralizing potency., Suthar et al. report on a cross-sectional study of hospitalized COVID-19 patients suggesting a correlation between the SARS-CoV-2 receptor-binding-domain-specific IgG responses and virus neutralizing antibody responses. These findings have implications for understanding protective immunity against SARS-CoV-2, therapeutic use of immune plasma, and development of vaccines.

Vibrio cholerae is a bacterial pathogen which causes the severe acute diarrheal disease cholera. Given that a symptomatic incident of cholera can lead to long term protection, a thorough understanding of the immune response to this pathogen is needed to identify parameters critical to the generation and durability of immunity. To approach this, we utilized a live attenuated cholera vaccine to model the response to V. cholerae infection in 12 naïve subjects. We found that this live attenuated vaccine induced durable vibriocidal antibody titers that were maintained at least one year after vaccination. Similar to what we previously reported in infected patients from Bangladesh, we found that vaccination induced plasmablast responses were primarily specific to the two immunodominant antigens lipopolysaccharide (LPS) and cholera toxin (CT). Interestingly, the magnitude of the early plasmablast response at day 7 predicted the serological outcome of vaccination at day 30. However, this correlation was no longer present at later timepoints. The acute responses displayed preferential immunoglobulin isotype usage, with LPS specific cells being largely IgM or IgA producing, while cholera toxin responses were predominantly IgG. Finally, CCR9 was highly expressed on vaccine induced plasmablasts, especially on IgM and IgA producing cells, suggesting a role in migration to the gastrointestinal tract. Collectively, these findings demonstrate that the use of a live attenuated cholera vaccine is an effective tool to examine the primary and long-term immune response following V. cholerae exposure. Additionally, it provides insight into the phenotype and specificity of the cells which likely return to and mediate immunity at the intestinal mucosa. A thorough understanding of these properties both in peripheral blood and in the intestinal mucosae will inform future vaccine development against both cholera and other mucosal pathogens. Trial Registration:NCT03251495., Author summary Cholera is a severe diarrheal illness which affects millions of people annually. Those most affected reside in developing countries where outbreaks can cause a devastating healthcare crisis. Despite this, much is still unknown regarding the longevity of protective immune responses or how they are generated and maintained. This includes aspects of the mucosal response where immunity is induced, as well as features of the early immune response that could predict long-term immunity. To address these issues, we examined primary humoral immune responses following administration of a live attenuated cholera vaccine to 12 human participants. This study provides insight into the development of humoral immunity and information that may prove valuable for improving cholerae vaccines and treatments.

Zika virus (ZIKV), which emerged in regions endemic to dengue virus (DENV), is vertically transmitted and results in adverse pregnancy outcomes. Antibodies to DENV can cross-react with ZIKV, but whether these antibodies influence ZIKV vertical transmission remains unclear. Here, we find that DENV antibodies increase ZIKV infection of placental macrophages (Hofbauer cells [HCs]) from 10% to over 80% and enhance infection of human placental explants. ZIKV-anti-DENV antibody complexes increase viral binding and entry into HCs but also result in blunted type I interferon, pro-inflammatory cytokine, and antiviral responses. Additionally, ZIKV infection of HCs and human placental explants is enhanced in an immunoglobulin G subclass-dependent manner, and targeting FcRn reduces ZIKV replication in human placental explants. Collectively, these findings support a role for pre-existing DENV antibodies in enhancement of ZIKV infection of select placental cell types and indicate that pre-existing immunity to DENV should be considered when addressing ZIKV vertical transmission.

Hypothesis Our objective was to evaluate whether the use of midline venous catheters in place of central line venous catheters, when appropriate, decreased the overall incidence of central line–associated bacteremia in a ventilator unit. Methods The time interval between February 2012 and February 2013 was divided into 2 periods. Group A was the first half of the year, before the introduction of midline catheters, and group B was the second half of the year, 6 months after their introduction. Central line–associated bloodstream infection (CLABSI) was calculated using the equation: (total number of CLABSI/total number of catheter days) × 1000. The Z test was used for proportions between independent groups to compare the significance in the difference in CLABSI between groups A and B. Results There was a significant decrease in the total number of catheter days on the ventilator unit in group A from 2408 catheter days in 1 year (August 1, 2011, to July 31, 2012) before the introduction of midline catheters to 1521 catheter days in group B in the following year (November 1, 2012, to October 31, 2013; P < 0.05 for both groups). Conclusions Midline catheters in place of central lines decrease the rate of CLABSI in a ventilator unit. In addition, no bloodstream infections were associated with midline catheters.

ObjectiveClostridium difficile is a toxin-producing bacterium and a leading cause of antibiotic-associated disease. The ability of C. difficile to form spores and infect antibiotic-treated persons at low multiplicity of infection (MOI) underlies its large disease burden. However, C. difficile-induced disease might also result from long-harboured C. difficile that blooms in individuals administered antibiotics.DesignMice purchased from multiple vendors and repeatedly testing negative for this pathogen by quantitative PCR bloomed C. difficile following antibiotic treatment. This endogenous C. difficile strain, herein termed LEM1, which formed spores and produced toxin, was compared with highly pathogenic C. difficile strain VPI10463.ResultsWhole-genome sequencing revealed that LEM1 and VPI10463 shared 95% of their genes, including all known virulence genes. In contrast to VPI10463, LEM1 did not induce overt disease when administered to antibiotic-treated or germ-free mice, even at high doses. Rather, blooms of LEM1 correlated with survival following VPI10463 inoculation, and exogenous administration of LEM1 before or shortly following VPI10463 inoculation prevented C. difficile-induced death. Accordingly, despite similar growth properties in vitro, LEM1 strongly outcompeted VPI10463 in mice even at 100-fold lower inocula.ConclusionsThese results highlight the difficulty of determining whether individual cases of C. difficile infection resulted from a bloom of endogenous C. difficile or a new exposure to this pathogen. In addition to impacting the design of studies using mouse models of C. difficile-induced disease, this study identified, isolated and characterised an endogenous murine spore-forming C. difficile strain able to decrease colonisation, associated disease and death induced by a pathogenic C. difficile strain.

Herein, we report the genome sequence of a Clostridium difficile strain isolated from the feces of antibiotic-treated C57BL/6 mice. We have named this strain, which differs considerably from those of the previously sequenced C. difficile strains, LEM1.

Most patients with indolent B-cell lymphomas fail to achieve complete remission with current treatment approaches and invariably relapse. During the past decade, innovative immunochemotherapy strategies have substantially improved disease control rates but not survival, thus providing the rationale for development of novel agents targeting dysregulated pathways that are operable in these hematological malignancies. Ibrutinib, a novel first-in-human Bruton's tyrosine kinase (BTK) inhibitor, has progressed into phase III trials after early-phase clinical studies demonstrated effective target inhibition, increased tumor response rates, and significant improvement in survival, particularly in patients with indolent B-cell lymphomas. Recently, the compound was designated a "breakthrough therapy" by the United States Food and Drug Administration for the treatment of patients with relapsed or refractory mantle cell lymphoma and Waldenström macroglobulinemia. This review summarizes recent achievements of ibrutinib, with a focus on its emerging role in the treatment of patients with indolent B-cell lymphoid malignancies.

A 59 years old female with a past medical history of neurofibromatosis, malignant peripheral nerve sheath tumor on chemotherapy was admitted for acute respiratory failure secondary to health care associated pneumonia. During the admission, she was suddenly found to be tachycardiac with decreased right sided breath sounds and a 3 mg/dl drop in hemoglobin. A chest x-ray showed a widened mediastinum. Computed tomography (CT) revealed right paramediastinal hematoma and a pseudo-aneurysm arising from the right internal mammary artery. She received four units of packed red blood cells. In line with her health care proxyi?½s decision, surgical intervention was withheld and she was conservatively managed for two weeks. She gradually improved, was discharged with a stable hemoglobin of 10.2 g/dl. Spontaneous hemomediastinum is an uncommon and often life threatening event. Neurofibromatosis 1 (NF1, von Recklinghauseni?½s disease) is a rare cause of effusion of blood into the mediastinum. The intercostal, subclavian and bronchial arteries are the commonest vessels involved in mediastinal hematomas. Only one case of internal mammary artery involvement has been documented so far. Here, we describe a case of spontaneous mediastinal hemorrhage as a result of pseudoaneurysmal rupture of the right internal mammary artery.

Introduction: The CDC estimates an average of around 5 central line associated blood stream infections(CLABSIs) per 1000 catheter-days in the United States. As more patients with central lines are located outside the ICU, CLABSI rates for non-ICU patients have been on the rise. There are approximate