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The ongoing SARS‐CoV‐2 pandemic stresses the need for effective antiviral drugs that can quickly be applied in order to reduce morbidity, mortality, and ideally viral transmission. By repurposing of broadly active antiviral drugs and compounds that are known to inhibit viral replication of related viruses, several advances could be made in the development of treatment strategies against COVID‐19. The nucleoside analog remdesivir, which is known for its potent in vitro activity against Ebolavirus and other RNA viruses, was recently shown to reduce the time to recovery in patients with severe COVID‐19. It is to date the only approved antiviral for treating COVID‐19. Here, we provide a mechanism and evidence‐based comparative review of remdesivir and other repurposed drugs with proven in vitro activity against SARS‐CoV‐2. Graphical Abstract This comprehensive review discusses preclinical and clinical outcomes of remdesivir and other repurposed antiviral drugs against SARS‐CoV‐2.

Cells of the innate immune system represent the first line of defense against SARS‐CoV‐2 and play an essential role in activating adaptive immunity, which mediates long‐term protection. In addition, the same cells are key drivers of tissue damage by causing the hyperinflammatory state and cytokine storm that makes COVID‐19 a deadly disease. Thus, careful dissection of the host–pathogen interaction on a cellular level is essential to understanding SARS‐CoV‐2 pathogenesis and developing new treatment modalities against COVID‐19. In their recent work, Goffinet and colleagues (Kazmierski et al , 2022) investigate the cell‐intrinsic responses of human primary peripheral blood mononuclear cells (PBMCs) exposed to SARS coronaviruses. Graphical Abstract It remains unknown whether innate immune signaling events require infection and active production of SARS‐CoV‐2 in immune cells. Goffinet and colleagues (Kazmierski et al , 2022) address this question by studying cell‐intrinsic responses of human PBMC exposed to SARS coronaviruses.

The toll-like receptor 4 (TLR4) is a central regulator of innate immunity that primarily recognizes bacterial lipopolysaccharide cell wall constituents to trigger cytokine secretion. We identify the intramembrane protease RHBDL4 as a negative regulator of TLR4 signaling. We show that RHBDL4 triggers degradation of TLR4’s trafficking factor TMED7. This counteracts TLR4 transport to the cell surface. Notably, TLR4 activation mediates transcriptional upregulation of RHBDL4 thereby inducing a negative feedback loop to reduce TLR4 trafficking to the plasma membrane. This secretory cargo tuning mechanism prevents the over-activation of TLR4-dependent signaling in an in vitro Mycobacterium tuberculosis macrophage infection model and consequently alleviates septic shock in a mouse model. A hypomorphic RHBDL4 mutation linked to Kawasaki syndrome, an ill-defined inflammatory disorder in children, further supports the pathophysiological relevance of our findings. In this work, we identify an RHBDL4-mediated axis that acts as a rheostat to prevent over-activation of the TLR4 pathway. Toll-like receptor 4 (TLR4) is a key pattern recognition receptor that primarily responds to ligation of bacterial lipopolysaccharide. Here the authors suggest the intramembrane protease RHBDL4 as a regulator of TLR4 signaling.

Mycobacterium tuberculosis ( Mtb ) infection represents a global health problem and is characterized by formation of granuloma with a necrotic center and a systemic inflammatory response. Inflammasomes have a crucial role in the host immune response towards Mtb . These intracellular multi-protein complexes are assembled in response to pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Inflammasome platforms activate caspases, leading to the maturation of the proinflammatory cytokines interleukin (IL)-1 and 18 and the cleavage of gasdermin D (GSDMD), a pore-forming protein responsible for cytokine release and pyroptotic cell death. Recent in vitro and in vivo findings have highlighted the importance of inflammasome signaling and subsequent necrotic cell death in Mtb -infected innate immune cells. However, we are just beginning to understand how inflammasomes contribute to disease or to a protective immune response in tuberculosis (TB). A detailed molecular understanding of inflammasome-associated pathomechanisms may foster the development of novel host-directed therapeutics or vaccines with improved activity. In this mini-review, we discuss the regulatory and molecular aspects of inflammasome activation and the associated immunological consequences for Mtb pathogenesis.

Our understanding of the immune response in tuberculosis (TB) remains incomplete. This applies in particular to extrapulmonary TB (EPTB), a highly heterogeneous disease affecting up to 30% of patients in certain regions. Based on data-driven clustering of blood transcriptomes in an EPTB patient cohort, we define three highly distinct immunotypes. Combining bulk with single-cell RNA-sequencing delineates immunological trajectories characterized by dynamic IFN- and IL-1-mediated signalling in monocytes, alongside hyperactivation of T and NK cells, ultimately resulting in extensive immune dysregulation. Integrative analysis of multi-omics data provides deep insights into different layers of the anti-tuberculous immune response and the identification of immunotypes enabling stratification strategies for personalized host-directed treatments. In addition, our comprehensive approach helps to develop an accurate diagnostic gene expression signature for both EPTB and pulmonary TB highlighting the translational potential of our data. This work uses gene expression and single cell analyses to group extrapulmonary tuberculosis patients into three immune types, revealing immune pathways driving pathogenesis and markers that could improve diagnosis and guide tailored treatments.

Infections with viral pathogens are widespread and can cause a variety of different diseases. In-depth knowledge about viral triggers initiating an immune response is necessary to decipher viral pathogenesis. Inflammasomes, as part of the innate immune system, can be activated by viral pathogens. However, viral structural components responsible for inflammasome activation remain largely unknown. Here we analyzed glycoproteins derived from SARS-CoV-1/2, HCMV and HCV, required for viral entry and fusion, as potential triggers of NLRP3 inflammasome activation and pyroptosis in THP-1 macrophages. All tested glycoproteins were able to potently induce NLRP3 inflammasome activation, indicated by ASC-SPECK formation and secretion of cleaved IL-1β. Lytic cell death via gasdermin D (GSDMD), pore formation, and pyroptosis are required for IL-1β release. As a hallmark of pyroptosis, we were able to detect cleavage of GSDMD and, correspondingly, cell death in THP-1 macrophages. CRISPR-Cas9 knockout of NLRP3 and GSDMD in THP-1 macrophages confirmed and strongly support the evidence that viral glycoproteins can act as innate immunity triggers. With our study, we decipher key mechanisms of viral pathogenesis by showing that viral glycoproteins potently induce innate immune responses. These insights could be beneficial in vaccine development and provide new impulses for the investigation of vaccine-induced innate immunity.

Human cytomegalovirus (HCMV) causes serious complications to immune compromised hosts. Dendritic cells (iDCgB) expressing granulocyte-macrophage colony-stimulating factor, interferon-alpha and HCMV-gB were developed to promote de novo antiviral adaptive responses. Mice reconstituted with a human immune system (HIS) were immunized with iDCgB and challenged with HCMV, resulting into 93% protection. Immunization stimulated the expansion of functional effector memory CD8+ and CD4+ T cells recognizing gB. Machine learning analyses confirmed bone marrow T/CD4+, liver B/IgA+ and spleen B/IgG+ cells as predictive biomarkers of immunization (≈87% accuracy). CD8+ and CD4+ T cell responses against gB were validated. Splenic gB-binding IgM-/IgG+ B cells were sorted and analyzed at a single cell level. iDCgB immunizations elicited human-like IgG responses with a broad usage of various IgG heavy chain V gene segments harboring variable levels of somatic hypermutation. From this search, two gB-binding human monoclonal IgGs were generated that neutralized HCMV infection in vitro. Passive immunization with these antibodies provided proof-of-concept evidence of protection against HCMV infection. This HIS/HCMV in vivo model system supported the validation of novel active and passive immune therapies for future clinical translation.

The scaffolding protein NEDD9 coordinates signaling downstream of integrins by interacting with focal adhesion kinase (FAK) and thereby promotes cell migration. NEDD9 expression is altered in a number of clinical conditions such as cancer, but its role in innate immunity against infections remains elusive. Transcriptome analysis of Salmonella Typhimurium ( S T)-infected murine macrophages showed downregulation of NEDD9 and genes belonging to its signaling network. Bacterial infections induced host-mediated lysosomal degradation of NEDD9 in macrophages and PBMCs isolated from patients suffering from bloodstream infection. However, S T induced translocation of NEDD9 from the cytoplasm to S T-containing phagosomes and prevented their phagolysosome-mediated clearance by FAK/AKT activation, reflecting a bacterial evasion mechanism. Complete loss of NEDD9 significantly reduced bacterial burden and enhanced inflammation upon S T infection both in vitro and in vivo. Mechanistically, we show that NEDD9 activates the FAK-AKT pathway allowing phosphorylation of FAK and AKT to impair phagolysosomal-mediated clearance of bacteria. Our study has thus identified NEDD9 as a critical regulator of lysosomal function in macrophages and a potential host-directed therapeutic target to treat bacterial infections. Classification: Biological Sciences, Microbiology Macrophages downregulate NEDD9 to counteract S T mediated FAK-AKT activation . Upon infection with S T NEDD9 is translocated from the cytosol to S T-containing phagosomes. Loss of NEDD9 results in enhanced lysosomal capacities supporting bacterial clearance. Strikingly, S T recruits and activates FAK and AKT to suppress endosome-lysosome fusion, thereby bypassing lysosome-mediated pathogen clearance. Created in BioRender. Robinson, N. (2021) BioRender.com/n17r483.

Durable cell‐mediated immune responses require efficient innate immune signaling and the release of pro‐inflammatory cytokines. How precisely mRNA vaccines trigger innate immune cells for shaping antigen specific adaptive immunity remains unknown. Here, we show that SARS‐CoV‐2 mRNA vaccination primes human monocyte‐derived macrophages for activation of the NLRP3 inflammasome. Spike protein exposed macrophages undergo NLRP3‐driven pyroptotic cell death and subsequently secrete mature interleukin‐1β. These effects depend on activation of spleen tyrosine kinase (SYK) coupled to C‐type lectin receptors. Using autologous cocultures, we show that SYK and NLRP3 orchestrate macrophage‐driven activation of effector memory T cells. Furthermore, vaccination‐induced macrophage priming can be enhanced with repetitive antigen exposure providing a rationale for prime‐boost concepts to augment innate immune signaling in SARS‐CoV‐2 vaccination. Collectively, these findings identify SYK as a regulatory node capable of differentiating between primed and unprimed macrophages, which modulate spike protein‐specific T cell responses. Synopsis Innate immune signalling in monocytes following SARS‐CoV‐2 mRNA vaccination is not well understood. This study reports that macrophages isolated from vaccinated individuals participating in a longitudinal study undergo NLRP3 inflammasome activation upon re‐exposure to the SARS‐CoV‐2 spike protein (S‐protein). SARS‐CoV‐2 vaccination leads to macrophage reprogramming and phosphorylation of the spleen tyrosine kinase (SYK). Stimulation of macrophages with the S‐protein activates the NLRP3 inflammasome via SYK coupled to C‐type lectins. Macrophage SYK, NLRP3 and interleukin‐β are required for autologous T cell activation following vaccination. Booster vaccinations potently prime macrophages for Interleukin‐β secretion and pyroptosis. Graphical Abstract Innate immune signalling in monocytes following SARS‐CoV‐2 mRNA vaccination is not well understood. This study reports that macrophages isolated from vaccinated individuals participating in a longitudinal study undergo NLRP3 inflammasome activation upon re‐exposure to the SARS‐CoV‐2 spike protein (S‐protein).