ABSTRACT
Given the actual risk of poliomyelitis outbreaks in the region due to poliovirus derived from the Sabin vaccine or the importation of wild poliovirus, the Latin American Society of Pediatric Infectious Diseases commissioned an ad hoc group of experts from the institution's Vaccines and Biologicals Committee, to draft an official position paper on the urgent need to increase immunization levels against the disease in the region and incorporate inactivated polio vaccine exclusive schedules in all national immunization programs. This publication discusses the main conclusions and recommendations generated as a result of such activity.Copyright © 2022, Sociedad Chilena de Infectologia. All rights reserved.
ABSTRACT
RNA viruses are the major class of human pathogens responsible for many global health crises, including the COVID-19 pandemic. However, the current repertoire of U.S. Food and Drug Administration (FDA)-approved antivirals is limited to only nine out of the known 214 human-infecting RNAviruses, and almost all these antivirals target viral proteins. Traditional antiviral development generally proceeds in a virus-centric fashion, and successful therapies tend to be only marginally effective as monotherapies, due to dose-limiting toxicity and the rapid emergence of drug resistance. Host-based antivirals have potential to alleviate these shortcomings, but do not typically discriminate between infected and uninfected cells, thus eliciting unintended effects. In infected cells where host proteins are repurposed by a virus, normal host protein functions are compromised;a situation analogous to a loss-of-function mutation, and cells harboring the hypomorph have unique vulnerabilities. As well-established in model systems and in cancer therapeutics, these uniquely vulnerable cells can be selectively killed by a drug that inhibits a functionally redundant protein. This is the foundation of synthetic lethality (SL). To test if viral induced vulnerabilities can be exploited for viral therapeutics, we selectively targeted synthetic lethal partners of GBF1, a Golgi membrane protein and a critical host factor for many RNA viruses including poliovirus, Coxsackievirus, Dengue, Hepatitis C and E virus, and Ebola virus. GBF1 becomes a hypomorph upon interaction with the poliovirus protein 3A. A genome-wide chemogenomic CRISPR screen identified synthetic lethal partners of GBF1 and revealed ARF1 as the top hit. Disruption of ARF1, selectively killed cells that synthesize poliovirus 3A alone or in the context of a poliovirus replicon. Combining 3A expression with sub-lethal amounts of GCA - a specific inhibitor of GBF1 further exacerbated the GBF1-ARF1 SL effect. Together our data demonstrate proof of concept for host-based SL targeting of viral infection. We are currently testing all druggable synthetic lethal partners of GBF1 from our chemogenomic CRISPR-screen, in the context of dengue virus infection for their abilities to selectively kill infected cells and inhibit viral replication and infection. Importantly, these SL gene partners of viral-induced hypomorphs only become essential in infected cells and in principle, targeting them will have minimal effects on uninfected cells. Our strategy to target SL interactions of the viral-induced hypomorph has the potential to change the current paradigm for host-based therapeutics that can lead to broad-spectrum antivirals and can be applied to other intracellular pathogens. This work is supported by National Institutes of Health grants R01 GM112108 and P41 GM109824, R21 AI151344 and foundation grant FDN-167277 from the Canadian Institutes of Health Research.Copyright © 2023 The American Society for Biochemistry and Molecular Biology, Inc.
ABSTRACT
Fruit, vegetables, and green tea contain quercetin (a flavonoid). Some of the diet's most signifi-cant sources of quercetin are apples, onions, tomatoes, broccoli, and green tea. Antioxidant, anticancer, anti-inflammatory, antimicrobial, antibacterial, and anti-viral effects have been studied of quercetin. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus, ribonucleic acid (RNA) polymer-ase, and other essential viral life-cycle enzymes are all prevented from entering the body by quercetin. Despite extensive in vitro and in vivo investigations on the immune-modulating effects of quercetin and vitamin C treatment. 3-methyl-quercetin has been shown to bind to essential proteins necessary to convert minus-strand RNA into positive-strand RNAs, preventing the replication of viral RNA in the cytoplasm. Quercetin has been identified as a potential SARS-CoV-2 3C-like protease (3CLpro) suppressor in recent molecular docking studies and in silico assessment of herbal medicines. It has been demonstrated that quercetin increases the expression of heme oxygenase-1 through the nuclear factor erythroid-related factor 2 (Nrf2) signal network. Inhibition of heme oxygenase-1 may increase bilirubin synthesis, an endoge-nous antioxidant that defends cells. When human gingival fibroblast (HGF) cells were exposed to lipo-polysaccharide (LPS), inflammatory cytokine production was inhibited. The magnesium (Mg+2) cation complexation improves quercetin free radical scavenging capacity, preventing oxidant loss and cell death. The main objective of this paper is to provide an overview of the pharmacological effects of quercetin, its protective role against SARS-CoV-2 infection, and any potential molecular processes.Copyright © 2022 Bentham Science Publishers.
ABSTRACT
Traditionally, infectious diseases are monitored based on patient data. This is an expensive approach and might not detect the beginning of epidemics. Infectious agents are released into waste water via feces, urine and saliva. Measuring the signal in waste water can give an estimate of the epidemiological situation in the population. The approach has been used for poliovirus, SARS-CoV2, antibiotic-resistant bacteria, etc. The Estonian experience will be reviewed.
ABSTRACT
Background: Infections occur with up to twofold increased risk in patients with monoclonal gammopathy of undetermined significance (MGUS) and tenfold increased risk in multiple myeloma (MM). To reduce risk, revaccination following autologous hematopoietic cell transplantation (AHCT) is recommended to restore humoral immunity. We have previously shown that vaccine titers after AHCT have prognostic significance. In the COVID era, reliable clinical data about antibody titers is relevant yet scarce. We investigated the significance of different vaccine titers in newly diagnosed patients in different stages of the disease. Methods: The study population comprised of 77 patients with MGUS, smoldering multiple myeloma (SMM) and MM who were seen at a tertiary cancer center from 2018- 2022. All patients had antibody titers (B. pertussis, Diptheria, H. Influenzae B, Hepatitis, Influenza, Meningitis, Mumps, Rubeola, Rubella, Poliovirus, S. pneumoniae, Varicella Zoster and Tetanus) tested at the time of diagnosis, prior to start of treatment if indicated. Titers were interpreted in accordance with the manufacturers' recommendations. Patient characteristics were compared using the Kruskal- Wallis and Fisher's exact tests. Associations with % titer positivity were evaluated using the Kruskal- Wallis test. Results: There was significant difference in antibody titer positivity between the different patient groups (51.4% in MGUS, 40.5% in SMM and 34.2% in MM) (p < 0.001). There was no difference in antibody titer positivity depending on age, sex or race. Among individual pathogens, there was a significant difference between the three groups in regards to titers for Diphtheria, Mumps, Poliovirus 3, Strep pneumoniae 19, Strep pneumoniae 56 and Varicella Zoster. Conclusions: Antibody titers for vaccine preventable diseases are significantly different between patients with MGUS, SMM and MM at the time of diagnosis, with MGUS having the highest and MM having the lowest positivity. Patient related factors such as age, sex or race were not associated with antibody titer positivity. Current guidelines for revaccination are not extended to patients with MGUS and SMM and can be considered in prospective trials.