Molecular signatures in cetacean morbillivirus and host species proteomes: Unveiling the evolutionary dynamics of an enigmatic pathogen?

Cetacean morbillivirus (CeMV) infects marine mammals often causing a fatal respiratory and neurological disease. Recently, CeMV has expanded its geographic and host species range, with cases being reported worldwide among dolphins, whales, seals, and other aquatic mammalian species, and therefore has emerged as the most threatening nonanthropogenic factor affecting marine mammal's health and conservation. Extensive research efforts have aimed to understand CeMV epidemiology and ecology, however, the molecular mechanisms underlying its transmission and pathogenesis are still poorly understood. In particular, the field suffers from a knowledge gap on the structural and functional properties of CeMV proteins and their host interactors. Nevertheless, the body of scientific literature produced in recent years has inaugurated new investigational trends, driving future directions in CeMV molecular research. In this mini-review, the most recent literature has been summarized in the context of such research trends, and categorized into four priority research topics, such as (1) the interaction between CeMV glycoprotein and its host cell receptors across several species; (2) the CeMV molecular determinants responsible for different disease phenotype; (3) the host molecular determinants responsible for differential susceptibility to CeMV infection; (4) the CeMV molecular determinants responsible for difference virulence among circulating CeMV strains. Arguably, these are the most urgent topics that need to be investigated and that most promisingly will help to shed light on the details of CeMV evolutionary dynamics in the immediate future

Molecular signatures in cetacean morbillivirus and host species proteomes: Unveiling the evolutionary dynamics of an enigmatic pathogen?

Cetacean morbillivirus (CeMV) infects marine mammals often causing a fatal respiratory and neurological disease. Recently, CeMV has expanded its geographic and host species range, with cases being reported worldwide among dolphins, whales, seals, and other aquatic mammalian species, and therefore has emerged as the most threatening nonanthropogenic factor affecting marine mammal's health and conservation. Extensive research efforts have aimed to understand CeMV epidemiology and ecology, however, the molecular mechanisms underlying its transmission and pathogenesis are still poorly understood. In particular, the field suffers from a knowledge gap on the structural and functional properties of CeMV proteins and their host interactors. Nevertheless, the body of scientific literature produced in recent years has inaugurated new investigational trends, driving future directions in CeMV molecular research. In this mini-review, the most recent literature has been summarized in the context of such research trends, and categorized into four priority research topics, such as (1) the interaction between CeMV glycoprotein and its host cell receptors across several species; (2) the CeMV molecular determinants responsible for different disease phenotype; (3) the host molecular determinants responsible for differential susceptibility to CeMV infection; (4) the CeMV molecular determinants responsible for difference virulence among circulating CeMV strains. Arguably, these are the most urgent topics that need to be investigated and that most promisingly will help to shed light on the details of CeMV evolutionary dynamics in the immediate future

Trans synaptic assemblies link synaptic vesicles and neuroreceptors

Synaptic transmission is characterized by fast, tightly coupled processes and complex signaling pathways that require a precise protein organization, such as the previously reported nanodomain colocalization of pre and postsynaptic proteins. Here, we used cryo electron tomography to visualize synaptic complexes together with their native environment comprising interacting proteins and lipids on a 2 to 4 nm scale. Using template free detection and classification, we showed that tripartite trans synaptic assemblies subcolumns link synaptic vesicles to postsynaptic receptors and established that a particular displacement between directly interacting complexes characterizes subcolumns. Furthermore, we obtained de novo average structures of ionotropic glutamate receptors in their physiological composition, embedded in plasma membrane. These data support the hypothesis that synaptic function is carried by precisely organized trans synaptic units. It provides a framework for further exploration of synaptic and other large molecular assemblies that link different cells or cellular regions and may require weak or transient interactions to exert their functio

Lost in deletion: The enigmatic ORF8 protein of SARS-CoV-2

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome contains nine open reading frames (ORFs) that encode for accessory proteins which, although dispensable for viral replication, are important for the modulation of the host infected cell metabolism and innate immunity evasion. Among those, the ORF8 gene encodes for the homonymous multifunctional, highly immunogenic, immunoglobulin-like protein that was recently found to inhibit presentation of viral antigens by class I major histocompatibility complex, suppress the type I interferon antiviral response and interact with host factors involved in pulmonary inflammation and fibrogenesis. Moreover, the ORF8 is a hypervariable gene rapidly evolving among SARS-related coronaviruses, with a tendency to recombine and undergo deletions that are deemed to facilitate the virus adaptation to the human host. Intriguingly, SARS-CoV-2 variants isolated in the beginning of the coronavirus disease 2019 (Covid-19) pandemic that were deleted of the ORF8 gene have been associated to milder symptoms and better disease outcome. This minireview summarizes the current knowledge on the SARS-CoV-2 ORF8 protein in perspective to its potential as antiviral target and with special emphasis on the biochemical, biophysical and structural aspects of its molecular biology. (c) 2020 Elsevier Inc. All rights reserved

Antiviral drug discovery: HIV-1 RNase H, the next hit target

Antiviral drugs are a class of medication used for selectively treating viral infections. In the last three decades, the antiviral drug field has greatly developed through the interaction of several disciplines such as virology, biochemistry, chemistry, structural biology, and have reached enormous achievements. Paradigms of them are the treatments for HSV and HIV-1 infections. The latter is a striking example of the development of drugs which have turned a dreadful disease into a manageable chronic infection. However, still new anti-HIV drugs are needed, particularly drugs targeted to viral functions which are not inhibited yet by the current treatments. The HIV-1 reverse transcriptase-associated ribonuclease H (RNase H) activity is an attractive non traditional target for drug development which has been, so far, little explored. The present review is focused on the approach needed to identify valid RNase H inhibitors and lists the agents which have been reported, until now, to have an impact on the HIV-1 RNase H activity. Keywords Antiviral; drug development; HIV-1; reverse transcriptase; ribonuclease H; RNase H 1. Antiviral drug development short history The birth of drug research can be set around one hundred years ago, when chemistry reached a degree of maturity that allowed it to apply its principles and methods outside itself and when pharmacology began to be recognized as a scientific discipline (1). During the 20th century, the isolation and purification of active ingredients from medicinal plants demonstrated their value for medicine. As active principles were available, the problem of providing standardized preparations of these drugs, often still impure, was addressed. On the ground of anti-infective drug discovery programs, the first screening programs were focused on the discovery of compounds with antimicrobial activities. The identification of the natural antibiotics, penicillin, from Penicillium notatum (Alexander Fleming) and cephalosporin from Cephalosporium acremoniu

Brucella ceti and Brucella pinnipedialis genome characterization unveil genetic features that highlight their zoonotic potential

The Gram-negative bacteria Brucella ceti and Brucella pinnipedialis circulate in marine environments primarily infecting marine mammals, where they cause an often-fatal disease named brucellosis. The increase of brucellosis among several species of cetaceans and pinnipeds, together with the report of sporadic human infections, raises concerns about the zoonotic potential of these pathogens on a large scale and may pose a threat to coastal communities worldwide. Therefore, the characterization of the B. ceti and B. pinnipedialis genetic features is a priority to better understand the pathological factors that may impact global health. Moreover, an in-depth functional analysis of the B. ceti and B. pinnipedialis genome in the context of virulence and pathogenesis was not undertaken so far. Within this picture, here we present the comparative whole-genome characterization of all B. ceti and B. pinnipedialis genomes available in public resources, uncovering a collection of genetic tools possessed by these aquatic bacterial species compared to their zoonotic terrestrial relatives. We show that B. ceti and B. pinnipedialis genomes display a wide host-range infection capability and a polyphyletic phylogeny within the genus, showing a genomic structure that fits the canonical definition of closeness. Functional genome annotation led to identifying genes related to several pathways involved in mechanisms of infection, others conferring pan-susceptibility to antimicrobials and a set of virulence genes that highlight the similarity of B. ceti and B. pinnipedialis genotypes to those of Brucella spp. displaying human-infecting phenotypes

Inibithion of the HIV-1 Ribonuclease H activity by alizarine derivatives.

The HIV-1 reverse transcriptase (RT) ribonuclease H (RNase H) associated activity is responsible for the hydrolysis of the RNA component of the heteroduplex RNA:DNA replication intermediate, it is essential for viral replication and it is a validated target for drug development. Nevertheless, until now only few compounds have been able to inhibit selectively the HIV-1 RNase H function. Anthraquinones are common secondary metabolites occurring in bacteria, fungi, lichens and higher plants which have been reported to have diverse biological activities. In particular, some of them have been reported to inhibit the HIV-1 RT associated polymerase activity and the integrase activity in biochemical assays. Given the structural similarities between integrase and RNase H proteins and since diketo acid derivatives that inhibit the first has been found to inhibit also the latter, we synthesized and tested a series of alizarine derivatives. Results showed that some of them were able to inhibit in biochemical assays the HIV-1 RNase H function. The most potent derivative, 1,2-O-Bis-benzoyl-9,10-anthraquinone (K49), showed an IC50 value of 10 μM. Mechanism of action studies showed that K49 does not inhibit the HIV-1 RT associated polymerase activity at 100 µM concentrations, it does not intercalate into DNA, it is not cytotoxic and, differently from the diketo acids, it does not chelate the divalent cofactor Mg2+. Kinetic studies demonstrated that K49 is a non-competitive inhibitor and that it does not bind to the classical non-nucleoside RT inhibitors (NNRTI) binding site. In fact, the Yonetani-Theorell graphical model revealed that K49 binds to a site which is not overlapping to the nevirapine binding site. Overall, these results demonstrated that anthraquinone derivatives may selectively inhibit the HIV-1 RNase H function with a mechanism of action different from the one shown by the diketo acid derivatives

Distribution, ecology, and status of the white shark, Carcharodon carcharias, in the Mediterranean Sea

The occurrence of the white shark, Carcharodon carcharias, in the Mediterranean Sea has been reported since the Middle Ages (476–1453). Several studies have documented its presence in various areas of the basin, but no comprehensive review of the distribution and status of this species is available for the area. We compiled a total of 628 white shark records from 476 to 2015. Data suggests that the white shark is more common in the western Mediterranean Sea, especially in the Adriatic Sea and in the Sicilian Channel and is more frequently observed during summer months. However, analysis using night-time satellite imagery showed the existence of an anthropogenic bias in the distribution of white sharks. All size classes have been recorded in the region. However, the highest occurrence of young of the year has been recorded in the Sicilian Channel, in the Adriatic Sea and in the Aegean Sea, in summer, suggesting these areas might serve as nursery grounds. In the Mediterranean Sea, the white shark exhibits a broad diet. The most common prey found include small cetaceans (Tursiops truncatus, Stenella coeruleoalba), tuna (Thunnus spp.), swordfish (Xiphias gladius) and loggerhead sea turtle (Caretta caretta). A total of 53 white shark records refer to interactions between sharks and humans that resulted in a detrimental impact on humans, which include 42 bites and 11 reports of the presence of human remains in the stomach of captured animals. Analysis of the temporal variation in mean total lengths of white sharks found a decreasing trend from 1913 to 2012. The decreasing length of white sharks suggests this species might be declining in the Mediterranean Sea