Damping excessive viral-induced IFN-γ rescues the impaired anti-Aspergillus host immune response in influenza-associated pulmonary aspergillosis.

Background: Influenza-associated pulmonary aspergillosis (IAPA) is a severe fungal superinfection in critically ill influenza patients that is of incompletely understood pathogenesis. Despite the use of contemporary therapies with antifungal and antivirals, mortality rates remain unacceptably high. We aimed to unravel the IAPA immunopathogenesis as a means to develop adjunctive immunomodulatory therapies.

Exploration of isatin-based inhibitors of SARS-CoV-2 Nsp15 endoribonuclease.

The global health crisis caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) urges the development of new antiviral agents with broad coronavirus coverage. Due to its key role in viral evasion from the host innate immune response, the coronavirus Nsp15 uridine-specific endoribonuclease (EndoU) is of high interest as a drug target. Considering that the isatin scaffold is well-known for its versatile pharmacological properties, we synthesized and evaluated a series of compounds carrying an isatin core.

One-pot synthesis, characterization and antiviral properties of new benzenesulfonamide-based spirothiazolidinones.

A novel series of benzenesulfonamide substituted spirothiazolidinone derivatives (3a-j) were synthesized, characterized and evaluated for their antiviral activity. The spirocyclic compounds were prepared by the condensation of 4-(aminosulfonyl)-2-methoxybenzohydrazide, appropriate cyclic ketones and 2-mercaptopropionic acid in a one-pot reaction. The structures of the new compounds were established by IR, H NMR, C NMR (APT), and elemental analysis.

Profiling Bacteria in the Lungs of Patients with Severe Influenza Versus COVID-19 with or without Aspergillosis.

The influence of the lung bacterial microbiome, including potential pathogens, in patients with influenza-associated pulmonary aspergillosis (IAPA) or coronavirus disease (COVID-19)-associated pulmonary aspergillosis (CAPA) has yet to be explored. To explore the composition of the lung bacterial microbiome and its association with viral and fungal infection, immunity, and outcome in severe influenza versus COVID-19 with or without aspergillosis. We performed a retrospective study in mechanically ventilated patients with influenza and COVID-19 with or without invasive aspergillosis in whom BAL for bacterial culture (with or without PCR) was obtained within 2 weeks after ICU admission.

The coronavirus nsp15 endoribonuclease: A puzzling protein and pertinent antiviral drug target.

The SARS-CoV-2 pandemic has bolstered unprecedented research efforts to better understand the pathogenesis of coronavirus (CoV) infections and develop effective therapeutics. We here focus on non-structural protein nsp15, a hexameric component of the viral replication-transcription complex (RTC). Nsp15 possesses uridine-specific endoribonuclease (EndoU) activity for which some specific cleavage sites were recently identified in viral RNA.

Novel pentafluorosulfanyl-containing triclocarban analogs selectively kill Gram-positive bacteria.

Unlabelled: Novel antimicrobial agents are needed to combat antimicrobial resistance. This study tested novel pentafluorosulfanyl-containing triclocarban analogs for their potential antibacterial efficacy. Standard procedures were used to produce pentafluorosulfanyl-containing triclocarban analogs.

A Novel Heterozygous Variant in AICDA Impairs Ig Class Switching and Somatic Hypermutation in Human B Cells and is Associated with Autosomal Dominant HIGM2 Syndrome.

B cells and their secreted antibodies are fundamental for host-defense against pathogens. The generation of high-affinity class switched antibodies results from both somatic hypermutation (SHM) of the immunoglobulin (Ig) variable region genes of the B-cell receptor and class switch recombination (CSR) which alters the Ig heavy chain constant region. Both of these processes are initiated by the enzyme activation-induced cytidine deaminase (AID), encoded by AICDA.

Novel 2-indolinone derivatives as promising agents against respiratory syncytial and yellow fever viruses.

A vaccine or antiviral drug for respiratory syncytial virus (RSV) infections and a specific antiviral drug for yellow fever virus (YFV) infections has not yet been developed. In this study, 2-indolinone-based -(4-sulfamoylphenyl)hydrazinecarbothioamides were synthesized. Along with these new compounds, previously synthesized 2-indolinone-based -(3-sulfamoylphenyl)hydrazinecarbothioamides were evaluated against various DNA and RNA viruses.

Management Challenges of Extrapulmonary Nontuberculous Mycobacterial Infection: A Single-Center Case Series and Literature Review.

Extrapulmonary nontuberculous mycobacterial (NTM) disease remains largely enigmatic, yet these mycobacteria are increasingly acknowledged as important opportunistic pathogens in humans. Traditionally, NTM infections have been identified across various anatomical locations, with the respiratory system being the most affected and best understood. Historically, extrapulmonary NTM infection was predominantly associated with HIV/AIDS, with Mycobacterium avium lymphadenopathy being the most commonly reported.

Amphiphilic Sialic Acid Derivatives as Potential Dual-Specific Inhibitors of Influenza Hemagglutinin and Neuraminidase.

In the shadow of SARS-CoV-2, influenza seems to be an innocent virus, although new zoonotic influenza viruses evolved by mutations may lead to severe pandemics. According to WHO, there is an urgent need for better antiviral drugs. Blocking viral hemagglutinin with multivalent -acetylneuraminic acid derivatives is a promising approach to prevent influenza infection.

Longevity of the humoral and cellular responses after SARS-CoV-2 booster vaccinations in immunocompromised patients.

We assessed the humoral and cellular immune responses after two booster mRNA vaccine administrations [BNT162b2 (Pfizer-BioNTech vaccine)] in cohorts of immunocompromised patients (n = 199) and healthy controls (HC) (n = 54). All patients living with HIV (PLWH) and chronic kidney disease (CKD) patients and almost all (98.2%) of the primary immunodeficiency (PID) patients had measurable antibodies 3 and 6 months after administration of the third and fourth vaccine dose, comparable to the HCs.

Exploration of 1,2,3-triazolo fused triterpenoids as inhibitors of human coronavirus 229E targeting the viral nsp15 protein.

The coronavirus disease-19 (COVID-19) pandemic has raised major interest in innovative drug concepts to suppress human coronavirus (HCoV) infections. We previously reported on a class of 1,2,3-triazolo fused betulonic acid derivatives causing strong inhibition of HCoV-229E replication via the viral nsp15 protein, which is proposedly related to compound binding at an intermonomer interface in hexameric nsp15. In the present study, we further explored the structure-activity relationship (SAR), by varying the substituent at the 1,2,3-triazolo ring as well as the triterpenoid skeleton.

PRO-2000 exhibits SARS-CoV-2 antiviral activity by interfering with spike-heparin binding.

Here, we report on the anti-SARS-CoV-2 activity of PRO-2000, a sulfonated polyanionic compound. In Vero cells infected with the Wuhan, alpha, beta, delta or omicron variant, PRO-2000 displayed EC values of 1.1 μM, 2.

Novel Polymyxin-Inspired Peptidomimetics Targeting the SARS-CoV-2 Spike:hACE2 Interface.

Though the bulk of the COVID-19 pandemic is behind, the search for effective and safe anti-SARS-CoV-2 drugs continues to be relevant. A highly pursued approach for antiviral drug development involves targeting the viral spike (S) protein of SARS-CoV-2 to prevent its attachment to the cellular receptor ACE2. Here, we exploited the core structure of polymyxin B, a naturally occurring antibiotic, to design and synthesize unprecedented peptidomimetics (PMs), intended to target contemporarily two defined, non-overlapping regions of the S receptor-binding domain (RBD).

The RNA polymerase III-RIG-I axis in antiviral immunity and inflammation.

Nucleic acid sensors survey subcellular compartments for atypical or mislocalized RNA or DNA, ultimately triggering innate immune responses. Retinoic acid-inducible gene-I (RIG-I) is part of the family of cytoplasmic RNA receptors that can detect viruses. A growing literature demonstrates that mammalian RNA polymerase III (Pol III) transcribes certain viral or cellular DNA sequences into immunostimulatory RIG-I ligands, which elicits antiviral or inflammatory responses.

Loss of GM-CSF-dependent instruction of alveolar macrophages in COVID-19 provides a rationale for inhaled GM-CSF treatment.

GM-CSF promotes myelopoiesis and inflammation, and GM-CSF blockade is being evaluated as a treatment for COVID-19-associated hyperinflammation. Alveolar GM-CSF is, however, required for monocytes to differentiate into alveolar macrophages (AMs) that control alveolar homeostasis. By mapping cross-species AM development to clinical lung samples, we discovered that COVID-19 is marked by defective GM-CSF-dependent AM instruction and accumulation of pro-inflammatory macrophages.

Nucleoside analogs for management of respiratory virus infections: mechanism of action and clinical efficacy.

The COVID-19 pandemic has accelerated the development of nucleoside analogs to treat respiratory virus infections, with remdesivir being the first compound to receive worldwide authorization and three other nucleoside analogs (i.e. favipiravir, molnupiravir, and bemnifosbuvir) in the pipeline.

mutations predispose to herpes simplex encephalitis by disrupting biogenesis of the host-derived RIG-I ligand .

Herpes simplex virus 1 (HSV-1) infects several billion people worldwide and can cause life-threatening herpes simplex encephalitis (HSE) in some patients. Monogenic defects in components of the type I interferon system have been identified in patients with HSE, emphasizing the role of inborn errors of immunity underlying HSE pathogenesis. Here, we identify compound heterozygous loss-of-function mutations in the gene encoding for transcription factor IIIA (TFIIIA), a component of the RNA polymerase III complex, in a patient with common variable immunodeficiency and HSE.

Synthesis and Anticancer and Antiviral Activities of C-2'-Branched Arabinonucleosides.

d-Arabinofuranosyl-pyrimidine and -purine nucleoside analogues containing alkylthio-, acetylthio- or 1-thiosugar substituents at the C2' position were prepared from the corresponding 3',5'--silylene acetal-protected nucleoside 2'-exomethylenes by photoinitiated, radical-mediated hydrothiolation reactions. Although the stereochemical outcome of the hydrothiolation depended on the structure of both the thiol and the furanoside aglycone, in general, high d-arabino selectivity was obtained. The cytotoxic effect of the arabinonucleosides was studied on tumorous SCC (mouse squamous cell) and immortalized control HaCaT (human keratinocyte) cell lines by MTT assay.

Development and optimization of biologically contained Marburg virus for high-throughput antiviral screening.

Comparable to the related Ebola virus, Marburg virus is an emerging zoonotic pathogen that causes hemorrhagic fever with a high mortality rate. Therefore, handling of Ebola virus and Marburg virus is limited to biosafety level 4 facilities, of which only a limited number exists worldwide. However, researchers have developed several virus alternatives that are safe to handle in lower biosafety settings.

Semisynthetic teicoplanin derivatives with dual antimicrobial activity against SARS-CoV-2 and multiresistant bacteria.

Patients infected with SARS-CoV-2 risk co-infection with Gram-positive bacteria, which severely affects their prognosis. Antimicrobial drugs with dual antiviral and antibacterial activity would be very useful in this setting. Although glycopeptide antibiotics are well-known as strong antibacterial drugs, some of them are also active against RNA viruses like SARS-CoV-2.

A Versatile Class of 1,4,4-Trisubstituted Piperidines Block Coronavirus Replication In Vitro.

There is a clear need for novel antiviral concepts to control SARS-CoV-2 infection. Based on the promising anti-coronavirus activity observed for a class of 1,4,4-trisubstituted piperidines, we here conducted a detailed analysis of the structure-activity relationship of these structurally unique inhibitors. Despite the presence of five points of diversity, the synthesis of an extensive series of analogues was readily achieved by Ugi four-component reaction from commercially available reagents.

Impact of SARS-CoV-2 Spike Mutations on Its Activation by TMPRSS2 and the Alternative TMPRSS13 Protease.

The continuous emergence of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) urges better understanding of the functional motifs in the spike (S) protein and their tolerance to mutations. Here, we focused on the S2' motif, which, during virus entry, requires cleavage by a host cell protease to release the fusion peptide. Though belonging to an immunogenic region, the SARS-CoV-2 S2' motif (811-KPSKR-815) has shown hardly any variation, with its three basic (K/R) residues being >99.