MAVS-dependent host species range and pathogenicity of human hepatitis A virus

Although hepatotropic viruses are important causes of human disease, the intrahepatic immune response to hepatitis viruses is poorly understood due to a lack of tractable small animal models. Here we describe a murine model of hepatitis A virus (HAV) infection that recapitulates critical features of type A hepatitis in humans. We demonstrate that the capacity of HAV to evade MAVS-mediated type I interferon responses defines its host species range. HAV-induced liver injury was associated with interferon-independent intrinsic hepatocellular apoptosis and hepatic inflammation that unexpectedly results from MAVS and IRF3/7 signaling. This murine model thus reveals a previously undefined link between innate immune responses to virus infection and acute liver injury, providing a new paradigm for viral pathogenesis in the liver

A live-attenuated chlamydial vaccine protects against trachoma in nonhuman primates

In cynomolgus macaques, ocular infection with a live trachoma strain lacking the conserved 7.5-kb plasmid induced no ocular pathology but facilitated solid or partial protection from subsequent infection with a virulent strain of trachoma

Luminescent Tris(8-hydroxyquinolates) of Bismuth(III)

Luminescent homoleptic bismuth(III) complexes have been synthesized by adding several functionalized 8-hydroxyquinolate ligands to bismuth(III) chloride in a 3:1 mole ratio in either ethanol or tetrahydrofuran (THF) solvent. These complexes have been characterized by single-crystal X-ray diffraction (XRD) analysis, UV-vis spectroscopy, fluorescence spectroscopy, and density functional theory (DFT) calculations to determine their structures and photophysical properties. Reversible dimerization of the mononuclear tris(hydroxyquinolate) complexes was observed in solution and quantified using UV-vis spectroscopy. The fluorescence spectra show a blue shift for the monomer compared with homoleptic aluminum(III) hydroxyquinolate compounds. Four dimeric compounds and one monomeric isomer were characterized structurally. The bismuth(III) centers in the dimers are bridged by two oxygen atoms from the substituted hydroxyquinolate ligands. The more sterically hindered quinolate complex, tris(2-(diethoxymethyl)-8-quinolinato)bismuth, crystallizes as a monomer. The complexes all exhibit low-lying absorption and emission spectral features attributable to transitions between the HOMO (π orbital localized on the quinolate phenoxide ring) and LUMO (π* orbital localized on the quinolate pyridyl ring). Excitation and emission spectra show a concentration dependence in solution that suggests that a monomer-dimer equilibrium occurs. Electronic structure DFT calculations support trends seen in the experimental results with a HOMO-LUMO gap of 2.156 eV calculated for the monomer that is significantly larger than those for the dimers (1.772 and 1.915 eV). The close face to face approach of two quinolate rings in the dimer destabilizes the uppermost occupied quinolate π orbitals, which reduces the HOMO-LUMO gap and results in longer wavelength absorption and emission spectral features than in the monomer form

Chlamydial Infection Induces Pathobiotype-Specific Protein Tyrosine Phosphorylation in Epithelial Cells

Members of the genus Chlamydia are strict obligate intracellular pathogens that exhibit marked differences in host range and tissue tropism despite sharing a remarkable level of genomic synteny. These pathobiotype differences among chlamydiae are also mirrored in their early interactions with cultured mammalian host cells. Chlamydial attachment and entry is known to trigger protein tyrosine phosphorylation. In this study, we examined the kinetics and pattern of protein tyrosine phosphorylation induced by infection with a comprehensive collection of chlamydial strains exhibiting diversity in host, tissue, and disease tropisms. We report new findings showing that protein tyrosine phosphorylation patterns induced by infection directly correlate with the pathobiotype of the infecting organism. Patterns of protein tyrosine phosphorylation were induced following early infection that unambiguously categorized chlamydial pathobiotypes into four distinct groups: (i) Chlamydia trachomatis trachoma biovars (serovars A to H), (ii) C. trachomatis lymphogranuloma venereum biovars (serovars L1 to L3), (iii) C. muridarum, and (iv) C. pneumoniae and C. caviae. Notably, chlamydia-infected murine and human epithelial cells exhibited the same protein tyrosine phosphorylation patterns; this is indirect evidence suggesting that the phosphorylated protein(s) is of chlamydial origin. If our hypothesis is correct, these heretofore-uncharacterized proteins may represent a novel class of bacterial molecules that influence pathogen-host range or tissue tropism

Biological Characterization of Chlamydia trachomatis Plasticity Zone MACPF Domain Family Protein CT153▿ †

Chlamydia trachomatis strains are obligate intracellular human pathogens that share near genomic synteny but have distinct infection and disease organotropisms. The genetic basis for differences in the pathogen-host relationship among chlamydial strains is linked to a variable region of chlamydial genomes, termed the plasticity zone (PZ). Two groups of PZ-encoded proteins, the membrane attack complex/perforin (MACPF) domain protein (CT153) and members of the phospholipase D-like (PLD) family, are related to proteins that modify membranes and lipids, but the functions of CT153 and the PZ PLDs (pzPLDs) are unknown. Here, we show that full-length CT153 (p91) was present in the elementary bodies (EBs) of 15 C. trachomatis reference strains. CT153 underwent a rapid infection-dependent proteolytic cleavage into polypeptides of 57 and 41 kDa that was independent of de novo chlamydial protein synthesis. Following productive infection, p91 was expressed during the mid-developmental cycle and was similarly processed into p57 and p41 fragments. Infected-cell fractionation studies showed that insoluble fractions contained p91, p57, and p41, whereas only p91 was found in the soluble fraction, indicating that unprocessed CT153 may be secreted. Finally, CT153 localized to a distinct population of reticulate bodies, some of which were in contact with the inclusion membrane