Taking AIM at Influenza: The Role of the AIM2 Inflammasome.

Influenza A viruses (IAV) are dynamic and highly mutable respiratory pathogens that present persistent public health challenges. Inflammasomes, as components of the innate immune system, play a crucial role in the early detection and response to infections. They react to viral pathogens by triggering inflammation to promote immune defences and initiate repair mechanisms.

Harnessing Endogenous Peptide Compounds as Potential Therapeutics for Severe Influenza.

Background: Excessive pulmonary inflammation and damage are characteristic features of severe influenza virus infections. LAT8881 is a synthetic 16-amino acid cyclic peptide form of a naturally occurring C-terminal fragment of human growth hormone with therapeutic efficacy against influenza. Shorter linear peptides are typically easier to manufacture and formulate for delivery than larger cyclic peptides.

Aggregated Hendra virus C-protein activates the NLRP3 inflammasome to induce inflammation.

Background: Hendra virus is an emerging virus with a geographically broad host reservoir. In humans, Hendra virus causes excessive inflammatory disease of the lung and nervous system. Our current understanding as to how Hendra virus or what factors induce inflammation is limited and as such, there are currently no therapeutic options available for patients who contract Hendra virus.

Gasdermin D promotes hyperinflammation and immunopathology during severe influenza A virus infection.

Excessive inflammation and tissue damage during severe influenza A virus (IAV) infection can lead to the development of fatal pulmonary disease. Pyroptosis is a lytic and pro-inflammatory form of cell death executed by the pore-forming protein gasdermin D (GSDMD). In this study, we investigated a potential role for GSDMD in promoting the development of severe IAV disease.

Flu on the Brain: Identification of Highly Pathogenic Influenza in the Brains of Wild Carnivores in The Netherlands.

Highly pathogenic avian influenza (HPAI) viruses circulate in wild birds and can infect domestic poultry [...

Interferon-ε is a tumour suppressor and restricts ovarian cancer.

High-grade serous ovarian cancers have low survival rates because of their late presentation with extensive peritoneal metastases and frequent chemoresistance, and require new treatments guided by novel insights into pathogenesis. Here we describe the intrinsic tumour-suppressive activities of interferon-ε (IFNε). IFNε is constitutively expressed in epithelial cells of the fallopian tube, the cell of origin of high-grade serous ovarian cancers, and is then lost during development of these tumours.

A novel dual NLRP1 and NLRP3 inflammasome inhibitor for the treatment of inflammatory diseases.

Objectives: Inflammasomes induce maturation of the inflammatory cytokines IL-1β and IL-18, whose activity is associated with the pathophysiology of a wide range of infectious and inflammatory diseases. As validated therapeutic targets for the treatment of acute and chronic inflammatory diseases, there has been intense interest in developing small-molecule inhibitors to target inflammasome activity and reduce disease-associated inflammatory burden.

Methods: We examined the therapeutic potential of a novel small-molecule inhibitor, and associated derivatives, termed ADS032 to target and reduce inflammasome-mediated inflammation .

Preclinical Mouse Model of Silicosis.

Silicosis is an untreatable occupational lung disease caused by chronic inhalation of crystalline silica. Cyclical release and reuptake of silica particles by macrophages and airway epithelial cells causes repeated tissue damage, characterized by widespread inflammation and progressive diffuse fibrosis. While inhalation is the main route of entry for silica particles in humans, most preclinical studies administer silica via the intratracheal route.

Naturally derived cytokine peptides limit virus replication and severe disease during influenza A virus infection.

Objectives: Novel host-targeted therapeutics could treat severe influenza A virus (IAV) infections, with reduced risk of drug resistance. LAT8881 is a synthetic form of the naturally occurring C-terminal fragment of human growth hormone. Acting independently of the growth hormone receptor, it can reduce inflammation-induced damage and promote tissue repair in an animal model of osteoarthritis.

Constitutive expression and distinct properties of IFN-epsilon protect the female reproductive tract from Zika virus infection.

The immunological surveillance factors controlling vulnerability of the female reproductive tract (FRT) to sexually transmitted viral infections are not well understood. Interferon-epsilon (IFNɛ) is a distinct, immunoregulatory type-I IFN that is constitutively expressed by FRT epithelium and is not induced by pathogens like other antiviral IFNs α, β and λ. We show the necessity of IFNɛ for Zika Virus (ZIKV) protection by: increased susceptibility of IFNɛ-/- mice; their "rescue" by intravaginal recombinant IFNɛ treatment and blockade of protective endogenous IFNɛ by neutralising antibody.

Another One Fights the Dust: Targeting the NLRP3 Inflammasome for the Treatment of Silicosis.

Silicosis is a multifaceted lung disease, characterized by persistent inflammation and structural remodeling. Despite its poor prognosis, there are no treatments currently available for patients with silicosis. Recent preclinical findings in models of lung fibrosis have suggested a major role for the NLRP3 (nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3) inflammasome in silica-driven inflammation and fibrosis.

Too young to die? How aging affects cellular innate immune responses to influenza virus and disease severity.

Influenza is a respiratory viral infection that causes significant morbidity and mortality worldwide. The innate immune cell response elicited during influenza A virus (IAV) infection forms the critical first line of defense, which typically is impaired as we age. As such, elderly individuals more commonly succumb to influenza-associated complications, which is reflected in most aged animal models of IAV infection.

Interleukin-1β exacerbates disease and is a potential therapeutic target to reduce pulmonary inflammation during severe influenza A virus infection.

Hyperinflammatory responses including the production of NLRP3-dependent interleukin (IL)-1β is a characteristic feature of severe and fatal influenza A virus (IAV) infections. The NLRP3 inflammasome has been shown to play a temporal role during severe IAV immune responses, with early protective and later detrimental responses. However, the specific contribution of IL-1β in modulating IAV disease in vivo is currently not well defined.

Die Another Way: Interplay between Influenza A Virus, Inflammation and Cell Death.

Influenza A virus (IAV) is a major concern to human health due to the ongoing global threat of a pandemic. Inflammatory and cell death signalling pathways play important roles in host defence against IAV infection. However, severe IAV infections in humans are characterised by excessive inflammation and tissue damage, often leading to fatal disease.

RIPLET, and not TRIM25, is required for endogenous RIG-I-dependent antiviral responses.

The innate immune system is our first line of defense against viral pathogens. Host cell pattern recognition receptors sense viral components and initiate immune signaling cascades that result in the production of an array of cytokines to combat infection. Retinoic acid-inducible gene-I (RIG-I) is a pattern recognition receptor that recognizes viral RNA and, when activated, results in the production of type I and III interferons (IFNs) and the upregulation of IFN-stimulated genes.

Repurposing drugs targeting the P2X7 receptor to limit hyperinflammation and disease during influenza virus infection.

Background And Purpose: Severe influenza A virus (IAV) infections are associated with damaging hyperinflammation that can be fatal. There is an urgent need to identify new therapeutic agents to treat severe and pathogenic IAV infections. Repurposing of drugs with an existing and studied pharmacokinetic and safety profile is a highly attractive potential strategy.

SIDT1 Localizes to Endolysosomes and Mediates Double-Stranded RNA Transport into the Cytoplasm.

dsRNA is a common by-product of viral replication and acts as a potent trigger of antiviral immunity. SIDT1 and SIDT2 are closely related members of the SID-1 transmembrane family. SIDT2 functions as a dsRNA transporter and is required to traffic internalized dsRNA from endocytic compartments into the cytosol for innate immune activation, but the role of SIDT1 in dsRNA transport and in the innate immune response to viral infection is unclear.

ADAM17 selectively activates the IL-6 trans-signaling/ERK MAPK axis in KRAS-addicted lung cancer.

Oncogenic mutations are major drivers of lung adenocarcinoma (LAC), yet the direct therapeutic targeting of KRAS has been problematic. Here, we reveal an obligate requirement by oncogenic KRAS for the ADAM17 protease in LAC In genetically engineered and xenograft (human cell line and patient-derived) -driven LAC models, the specific blockade of ADAM17, including with a non-toxic prodomain inhibitor, suppressed tumor burden by reducing cellular proliferation. The pro-tumorigenic activity of ADAM17 was dependent upon its threonine phosphorylation by p38 MAPK, along with the preferential shedding of the ADAM17 substrate, IL-6R, to release soluble IL-6R that drives IL-6 trans-signaling via the ERK1/2 MAPK pathway.

The Single Nucleotide Polymorphism Mal-D96N Mice Provide New Insights into Functionality of Mal in TLR Immune Responses.

MyD88 adaptor-like (Mal) protein is the most polymorphic of the four key adaptor proteins involved in TLR signaling. TLRs play a critical role in the recognition and immune response to pathogens through activation of the prototypic inflammatory transcription factor NF-κB. The study of single nucleotide polymorphisms in TLRs, adaptors, and signaling mediators has provided key insights into the function of the corresponding genes but also into the susceptibility to infectious diseases in humans.