Chikungunya nsP4 homology modeling reveals a common motif with Zika and Dengue RNA polymerases as a potential therapeutic target.

Among the diseases transmitted by vectors, there are those caused by viruses named arboviruses (arthropod-borne viruses). In past years, viruses transmitted by mosquitoes have been of relevance in global health, such as Chikungunya (CHIKV), Dengue (DENV), and Zika (ZIKV), which have Aedes aegypti as a common vector, thus raising the possibility of multi-infection. Previous reports have described the general structure of RNA-dependent RNA polymerases termed right-hand fold, which is conserved in positive single-stranded RNA viruses. Here, we report a comparison between sequences and the computational structure of RNA-dependent RNA polymerases from CHIKV, DENV, and ZIKV and the conserved sites to be considered for the design of an antiviral drug against the three viruses. We show that the sequential identity between consensus sequences from CHIKV and DENV is 8.1% and the similarity is 15.1%; the identity between CHIKV and ZIKV is 9.3%, and the similarity is 16.6%; and the identity between DENV and ZIKV is 68.6%, and the similarity is 79.2%. Nevertheless, the structural alignment shows that the root-mean-square deviation (RMSD) measurement value in general structure comparison between CHIKV RdRp and ZIKV RdRp was 1.248 Å, RMSD between CHIKV RdRp and DENV RdRp was 1.070 Å, and RMSD between ZIKV RdRp and DENV RdRp was 1.106 Å. Despite the low identity and similarity of CHIKV sequence with DENV and ZIKV, we show that A, B, C, and E motifs are structurally well conserved. These structural similarities offer a window into drug design against these arboviruses giving clues about critical target sites.

Utility of Proteomics in Emerging and Re-Emerging Infectious Diseases Caused by RNA Viruses.

Emerging and re-emerging infectious diseases due to RNA viruses cause major negative consequences for the quality of life, public health, and overall economic development. Most of the RNA viruses causing illnesses in humans are of zoonotic origin. Zoonotic viruses can directly be transferred from animals to humans through adaptation, followed by human-to-human transmission, such as in human immunodeficiency virus (HIV), severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and, more recently, SARS coronavirus 2 (SARS-CoV-2), or they can be transferred through insects or vectors, as in the case of Crimean-Congo hemorrhagic fever virus (CCHFV), Zika virus (ZIKV), and dengue virus (DENV). At the present, there are no vaccines or antiviral compounds against most of these viruses. Because proteins possess a vast array of functions in all known biological systems, proteomics-based strategies can provide important insights into the investigation of disease pathogenesis and the identification of promising antiviral drug targets during an epidemic or pandemic. Mass spectrometry technology has provided the capacity required for the precise identification and the sensitive and high-throughput analysis of proteins on a large scale and has contributed greatly to unravelling key protein-protein interactions, discovering signaling networks, and understanding disease mechanisms. In this Review, we present an account of quantitative proteomics and its application in some prominent recent examples of emerging and re-emerging RNA virus diseases like HIV-1, CCHFV, ZIKV, and DENV, with more detail with respect to coronaviruses (MERS-CoV and SARS-CoV) as well as the recent SARS-CoV-2 pandemic.

Atlantic salmon endothelial cells from the heart were more susceptible than fibroblasts from the bulbus arteriosus to four RNA viruses but protected from two viruses by dsRNA pretreatment.

Heart diseases caused by viruses are major causes of Atlantic salmon aquaculture loss. Two Atlantic salmon cardiovascular cell lines, an endothelial cell line (ASHe) from the heart and a fibroblast cell line (BAASf) from the bulbus arteriosus, were evaluated for their response to four fish viruses, CSV, IPNV, VHSV IVa and VHSV IVb, and the innate immune agonist, double-stranded RNA mimic poly IC. All four viruses caused cytopathic effects in ASHe and BAASf. However, ASHe was more susceptible to all four viruses than BAASf. When comparing between the viruses, ASHe cells were found to be moderately susceptible to CSV and VHSV IVb, but highly susceptible to IPNV and VHSV IVa induced cell death. All four viruses were capable of propagating in the ASHe cell line, leading to increases in virus titre over time. In BAASf, CSV and IPNV produced more than one log increase in titre from initial infection, but VHSV IVb and IVa did not. When looking at the antiviral response of both cell lines, Mx proteins were induced in ASHe and BAASf by poly IC. All four viruses induced Mx proteins in BAASf, while only CSV and VHSV IVb induced Mx proteins in ASHe. IPNV and VHSV IVa suppressed Mx proteins expression in ASHe. Pretreatment of ASHe with poly IC to allow for Mx proteins accumulation protected the culture from subsequent infections with IPNV and VHSV IVa, resulting in delayed cell death, reduced virus titres and reduced viral proteins expression. These data suggest that endothelial cells potentially can serve as points of infections for viruses in the heart and that two of the four viruses, IPNV and VHSV IVa, have mechanisms to avoid or downregulate antiviral responses in ASHe cells. Furthermore, the high susceptibility of the ASHe cell line to IPNV and VHSV IVa can make it a useful tool for studying antiviral compounds against these viruses and for general detection of fish viruses.

RNA viruses and microRNAs: challenging discoveries for the 21st century.

RNA viruses represent the predominant cause of many clinically relevant viral diseases in humans. Among several evolutionary advantages acquired by RNA viruses, the ability to usurp host cellular machinery and evade antiviral immune responses is imperative. During the past decade, RNA interference mechanisms, especially microRNA (miRNA)-mediated regulation of cellular protein expression, have revolutionized our understanding of host-viral interactions. Although it is well established that several DNA viruses express miRNAs that play crucial roles in their pathogenesis, expression of miRNAs by RNA viruses remains controversial. However, modulation of the miRNA machinery by RNA viruses may confer multiple benefits for enhanced viral replication and survival in host cells. In this review, we discuss the current literature on RNA viruses that may encode miRNAs and the varied advantages of engineering RNA viruses to express miRNAs as potential vectors for gene therapy. In addition, we review how different families of RNA viruses can alter miRNA machinery for productive replication, evasion of antiviral immune responses, and prolonged survival. We underscore the need to further explore the complex interactions of RNA viruses with host miRNAs to augment our understanding of host-virus interplay.

Biological terrorism.

A biological terrorism event could have a large impact on the general population and health care system. The impact of an infectious disaster will most likely be great to emergency departments, and the collaboration between emergency and infectious disease specialists will be critical in developing an effective response. A bioterrorism event is a disaster that requires specific preparations beyond the usual medical disaster planning. An effective response would include attention to infection control issues and plans for large-scale vaccination or antimicrobial prophylaxis. This article addresses some general issues related to preparing an effective response to a biological terrorism event. It will also review organisms and toxins that could be used in biological terrorism, including clinical features, management, diagnostic testing, and infection control.

Infections and vaccinations preceding childhood Guillain-Barré syndrome: a prospective study.

INTRODUCTION: We performed a prospective, multicentre study in children with Guillain-Barré syndrome (GBS), diagnosed according to international criteria, to investigate the frequency and aetiology of antecedent diseases. All infections and vaccinations occurring within a 6-week period prior to the onset of GBS were documented. MATERIALS AND METHODS: Stool cultures, standardised serological investigations and PCR analyses for 24 different infective agents were performed. Serological findings were regarded as significant if specific immunoglobulin (Ig)M or IgA antibodies were detected, if the IgM enzyme immunoassay or immunfluorescence assay findings were confirmed by immunoblot, if complement fixation test titres rose fourfold or if geometric titres were more than threefold higher than in uninfected control persons. Ninety-five children with GBS were included in the study over a 40-month period. Preceding events were reported in 82%. RESULTS: Microbiological studies carried out on 84 patients resulted in a probable diagnosis in 46 (55%). Coxsackieviruses (15%), Chlamydia pneumoniae (8%), cytomegalovirus (7%) and Mycoplasma pneumoniae (7%) were the most frequently involved agents. Serological evidence of a Campylobacter jejuni infection was found in six patients (7%). Eight children had been vaccinated during the 6 weeks preceding the onset of GBS; in six of these children concomitant infectious diseases were reported, and in one child the time between vaccination and GBS was extremely short. CONCLUSION: We conclude that, in contrast to adults, Campylobacter spp. does not seem to play a major role in childhood GBS in German-speaking countries. The aetiology of antecedent diseases is distributed over a wide spectrum of paediatric infectious diseases. Most of the children who had been vaccinated showed concomitant infectious diseases, thus obscuring the causative role for GBS.

Toward novel vaccines and therapies based on negative-strand RNA viruses.

The study of negative-strand RNA viruses has suggested new strategies to produce more attenuated viruses. Reverse genetics has allowed the implementation of the strategies, and new or improved monovalent vaccines are being developed. In addition, recombinant viruses expressing foreign proteins or epitopes have been produced with the aim of developing multivalent vaccines capable of stimulating humoral and cellular immune responses against more than one pathogen. Finally, recombinant viruses that selectively enter cells expressing tumor markers or the HIV envelope protein have been engineered and shown to lyse target cells. Preclinical and clinical trials of improved and multivalent vaccines and therapeutic (oncolytic) viruses are ongoing.

Vesicular stomatitis virus: an exciting new therapeutic oncolytic virus candidate for cancer or just another chapter from Field's Virology?

Selected mutant strains of vesicular stomatitis virus (VSV) are described that are unable to combat endogenous IFN-beta signaling within infected normal cells and as a result are dramatically more selective for productive growth in tumor cells having a defective antiviral response. The VSV mutants may have the potential to be used clinically as a systemic oncolytic agent for the treatment of distal and metastatic cancers.

Viral diseases of the oral mucosa.

A wide variety of both DNA and RNA viruses affect the oral cavity. When considered in conjunction with cutaneous features, careful examination of the oral mucosa and oropharynx aids the clinician in making a diagnosis. Examination of the oral cavity should be incorporated as a regular component of the dermatologic examination because diagnostic clues are readily available to assist in the evaluation of infectious processes.

Mimotopes of viral antigens and biologically important molecules as candidate vaccines and potential immunotherapeutics.

Antigen recognition by antibodies or ligand-receptor interactions involve small areas of the molecule named epitopes that are normally conformational in nature. The availability of combinatorial peptide libraries has provided a powerful tool for selecting novel sequences which mimic conformational epitopes (mimotopes) either structurally and/or immunologically. These mimotopes can be particularly useful in a number of situations, including: the development of vaccines against tumors, infectious diseases or allergic conditions; the design of molecules which can act as agonists or antagonists of various biologically-important molecules; and for the development of diagnostic assays. This article reviews the authors work on the application of combinatorial peptide libraries to identify mimotopes of protective B-cell epitopes from various pathogens, and the search for molecules able to block the biological activities of TNF-alpha, a cytokine which plays a key role in inflammation.

Viral skin infections: diagnosis and treatment considerations.

Skin lesions are prominent features of many viral diseases. In some instances, characteristic skin lesions suggest a specific viral illness, the diagnosis of which can be quickly established by appropriate procedures. In addition to clinical manifestations, laboratory methods including virus isolation are used to diagnose viral infections. In viral diseases, prophylaxis has proved more successful than the specific treatment of established infection. However, recent progress in molecular biology has facilitated the development of new vaccines and new drugs to treat viral infections.

[Quasispecies and molecular evolution of viruses]. / Cuasiespecies y evolución molecular de virus.

Ribonucleic acid (RNA) viruses evolve as complex distributions of genetically different but closely related variants termed viral quasispecies. The precise genome of a quasispecies cannot be defined, since the consensus genome is an average of many variants. The dynamics of quasispecies has considerable implications for the understanding of the adaptability and pathogenic potential of viruses, and in addition, for the design of preventive and therapeutic measures for the diseases caused by these viruses. The authors summarise current knowledge on the structure of quasispecies, and the biological implications of this structure.