Passive administration of monoclonal antibodies to Anthrolysin O prolong survival in mice lethally infected with Bacillus anthracis

<p>Abstract</p> <p>Background</p> <p><it>Bacillus anthracis </it>has two major virulence factors: a tripartite toxin that produces lethal and edema toxins and a polyglutamic acid capsule. A recent report suggested that a toxin belonging to the cholesterol dependant cytolysin (CDC) family, anthrolysin O (ALO) was a new virulence factor for <it>B. anthracis </it>but subsequent studies have questioned its relevance in pathogenesis. In this study, we examined the immunogenicity of recombinant anthrolysin O (rALO) in mice.</p> <p>Results</p> <p>BALB/c mice immunized with rALO and boosted after two weeks, produce sera with strong Ab responses with a predominance of IgG1 and IgG2a. Five hybridomas to rALO were recovered representing the IgM, IgG1, and IgG2b isotypes. Passive administration of 3 of the five monoclonal antibodies (mAbs) to rALO prior to infection with lethal intravenous (i.v.) <it>B. anthracis </it>Sterne strain infection in mice was associated with enhanced average survival and a greater likelihood of surviving infection. A combination of two mAbs to ALO was more effective than either mAb separately. One mAb (64F8) slowed the toxicity of rALO for J774.16 macrophage-like cells.</p> <p>Conclusion</p> <p>Our results suggest that ALO contributes to the virulence of <it>B. anthracis </it>Sterne strain in this infection model and that Ab response to ALO may contribute to protection in certain circumstances.</p

The Neisseria Lipooligosaccharide-Specific Alpha-2,3-Sialyltransferase is a Surface-Exposed Outer Membrane Protein

Neisseria gonorrhoeae and Neisseria meningitidis express an similar to43-kDa alpha-2,3-sialyltransferase (Lst) that sialylates the surface lipooligosaccharide (LOS) by using exogenous (in all N. gonorrhoeae strains and some N. meningitidis serogroups) or endogenous (in other N. meningitidis serogroups) sources of 5\u27-cytidinemonophospho-N-acetylneuraminic acid (CMP-NANA). Sialylation of LOS can protect N. gonorrhoeae and N. meningitidis from complement-mediated serum killing and from phagocytic killing by neutrophils. The precise subcellular location of Lst has not been determined. We confirm and extend previous studies by demonstrating that Lst is located in the outer membrane and is surface exposed in both N. gonorrhoeae and N. meningitidis. Western immunoblot analysis of subcellular fractions of N. gonorrhoeae strain F62 and N. meningitidis strain MC58not subset of3 (an acapsulate serogroup B strain) performed with rabbit antiserum raised against recombinant Lst revealed;an similar to43-kDa protein exclusively in outer membrane preparations of both pathogens. Inner membrane, periplasmic, cytoplasmic, and culture supernatant fractions were devoid of Lst, as determined by Western blot analysis. Consistent with this finding, outer membrane fractions of N, gonorrhoeae were significantly enriched for sialyltransferase enzymatic activity. A trace of enzymatic activity was detected in inner membrane fractions, which may have represented Lst in transit to the outer membrane or may have represented inner membrane contamination of outer membrane preparations. Subcellular preparations of an isogenic lst insertion knockout mutant of N. gonorrhoeae F62 (strain ST01) expressed neither a 43-kDa immunoreactive protein nor sialyltransferase activity. Anti-Lst rabbit antiserum bound to whole cells of N. meningitidis MC58not subset of3 and wild-type N. gonorrhoeae F62 but not to the Lst mutant ST01, indicating the surface exposure of the enzyme. Although the anti-Lst antiserum avidly bound enzymatically active, recombinant Lst, it inhibited Lst (sialyltransferase) activity by only about 50% at the highest concentration of antibody, used. On the contrary, anti-Lst antiserum did not inhibit sialylation of whole N. gonorrhoeae cells in the presence of exogenous CMP-NANA, suggesting that the antibody did not bind to or could not access the enzyme active site on the surface of viable Neisseria cells. Taken together, these results indicate that Lst is an outer membrane, surface-exposed glycosyltransferase. To our knowledge, this is the first demonstration of the localization of a bacterial glycosyltransferase to the outer membrane of gram-negative bacteria

Anthrolysin O and Other Gram-positive Cytolysins Are Toll-like Receptor 4 Agonists

Exposure of bone marrow–derived macrophages (BMDMs) to low concentrations of Bacillus anthracis lethal toxin (LT), whose catalytic subunit is lethal factor (LF), results in induction of a robust apoptotic response dependent on activation of Toll-like receptor (TLR)4. A similar TLR4-dependent apoptotic response is observed when BMDMs are infected with live B. anthracis (Sterne strain). However, TLR4 is considered to be a specific signaling receptor for lipopolysaccharide (LPS), a typical product of gram-negative bacteria, whereas B. anthracis is gram-positive. To understand how B. anthracis can activate TLR4, we analyzed its culture supernatants and found them to contain a potent TLR4-stimulating activity that can also induce apoptosis in macrophages in which the antiapoptotic p38 MAP kinase (whose activation is prevented by LF) was inhibited. Purification of this activity suggested it consists of anthrolysin O (ALO), a member of the cholesterol-dependent cytolysin (CDC) family. We show that recombinant ALO can activate TLR4 in a manner independent of LPS contamination and, together with LT, can induce macrophage apoptosis. We also provide genetic evidence that ALO is required for induction of macrophage apoptosis in response to infection with live B. anthracis and that other CDC family members share the ability to activate TLR4

The Sloan Digital Sky Survey Quasar Lens Search. III. Constraints on Dark Energy from the Third Data Release Quasar Lens Catalog

We present cosmological results from the statistics of lensed quasars in the Sloan Digital Sky Survey (SDSS) Quasar Lens Search. By taking proper account of the selection function, we compute the expected number of quasars lensed by early-type galaxies and their image separation distribution assuming a flat universe, which is then compared with 7 lenses found in the SDSS Data Release 3 to derive constraints on dark energy under strictly controlled criteria. For a cosmological constant model (w=-1) we obtain \Omega_\Lambda=0.74^{+0.11}_{-0.15}(stat.)^{+0.13}_{-0.06}(syst.). Allowing w to be a free parameter we find \Omega_M=0.26^{+0.07}_{-0.06}(stat.)^{+0.03}_{-0.05}(syst.) and w=-1.1\pm0.6(stat.)^{+0.3}_{-0.5}(syst.) when combined with the constraint from the measurement of baryon acoustic oscillations in the SDSS luminous red galaxy sample. Our results are in good agreement with earlier lensing constraints obtained using radio lenses, and provide additional confirmation of the presence of dark energy consistent with a cosmological constant, derived independently of type Ia supernovae.Comment: 9 pages, 3 figures, 2 tables, accepted for publication in A

Spectra of Hydrogen-poor Superluminous Supernovae from the Palomar Transient Factory

Most Type I superluminous supernovae (SLSNe-I) reported to date have been identified by their high peak luminosities and spectra lacking obvious signs of hydrogen. We demonstrate that these events can be distinguished from normal-luminosity SNe (including Type Ic events) solely from their spectra over a wide range of light-curve phases. We use this distinction to select 19 SLSNe-I and four possible SLSNe-I from the Palomar Transient Factory archive (including seven previously published objects). We present 127 new spectra of these objects and combine these with 39 previously published spectra, and we use these to discuss the average spectral properties of SLSNe-I at different spectral phases. We find that Mn II most probably contributes to the ultraviolet spectral features after maximum light, and we give a detailed study of the O II features that often characterize the early-time optical spectra of SLSNe-I. We discuss the velocity distribution of O II, finding that for some SLSNe-I this can be confined to a narrow range compared to relatively large systematic velocity shifts. Mg II and Fe II favor higher velocities than O II and C II, and we briefly discuss how this may constrain power-source models. We tentatively group objects by how well they match either SN 2011ke or PTF12dam and discuss the possibility that physically distinct events may have been previously grouped together under the SLSN-I label

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Deep JWSTNIRCam imaging of Supernova 1987A

International audienceJWST/NIRCam obtained high angular-resolution (0.05-0.1''), deep near-infrared 1--5 micron imaging of Supernova (SN) 1987A taken 35 years after the explosion. In the NIRCam images, we identify: 1) faint H2 crescents, which are emissions located between the ejecta and the equatorial ring, 2) a bar, which is a substructure of the ejecta, and 3) the bright 3-5 micron continuum emission exterior to the equatorial ring. The emission of the remnant in the NIRCam 1-2.3 micron images is mostly due to line emission, which is mostly emitted in the ejecta and in the hot spots within the equatorial ring. In contrast, the NIRCam 3-5 micron images are dominated by continuum emission. In the ejecta, the continuum is due to dust, obscuring the centre of the ejecta. In contrast, in the ring and exterior to the ring, synchrotron emission contributes a substantial fraction to the continuum. Dust emission contributes to the continuum at outer spots and diffuse emission exterior to the ring, but little within the ring. This shows that dust cooling and destruction time scales are shorter than the synchrotron cooling time scale, and the time scale of hydrogen recombination in the ring is even longer than the synchrotron cooling time scale. With the advent of high sensitivity and high angular resolution images provided by JWST/NIRCam, our observations of SN 1987A demonstrate that NIRCam opens up a window to study particle-acceleration and shock physics in unprecedented details, probed by near-infrared synchrotron emission, building a precise picture of how a SN evolves

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

A gravitational-wave standard siren measurement of the Hubble constant

The detection of GW170817 (ref. 1) heralds the age of gravitational-wave multi-messenger astronomy, with the observations of gravitational-wave and electromagnetic emission from the same transient source. On 17 August 2017 the network of Advanced Laser Interferometer Gravitational-wave Observatory (LIGO)2 and Virgo3 detectors observed GW170817, a strong signal from the merger of a binary neutron-star system. Less than two seconds after the merger, a γ-ray burst event, GRB 170817A, was detected consistent with the LIGO–Virgo sky localization region4–6). The sky region was subsequently observed by optical astronomy facilities7, resulting in the identification of an optical transient signal within about 10 arcseconds of the galaxy NGC 4993 (refs 8–13). GW170817 can be used as a standard siren14–18, combining the distance inferred purely from the gravitational-wave signal with the recession velocity arising from the electromagnetic data to determine the Hubble constant. This quantity, representing the local expansion rate of the Universe, sets the overall scale of the Universe and is of fundamental importance to cosmology. Our measurements do not require any form of cosmic ‘distance ladder’19; the gravitational-wave analysis directly estimates the luminosity distance out to cosmological scales. Here we report H0 = kilometres per second per megaparsec, which is consistent with existing measurements20,21, while being completely independent of them