Lessons Learned From Clinical Trials of Immunotherapeutics for COVID-19.

The COVID-19 pandemic caused by the SARS-CoV-2 virus was arguably one of the worst public health disasters of the last 100 years. As many infectious disease experts were focused on influenza, MERS, ZIKA, or Ebola as potential pandemic-causing agents, SARS-CoV-2 appeared to come from nowhere and spread rapidly. As with any zoonotic agent, the initial pathogen was able to transmit to a new host (humans), but it was poorly adapted to the immune environment of the new host and resulted in a maladapted immune response.

Sodium Pyruvate Nasal Spray Reduces the Severity of Nasal Inflammation and Congestion in Patients with Allergic Rhinitis.

As an anti-inflammatory and antioxidant, sodium pyruvate significantly reduces inflammatory cytokines and oxygen radicals such as interleukin (IL) IL-6, IL-8, Monocyte Chemoattractant Protein-1, and hydrogen peroxide. Thus, sodium pyruvate holds promise as a treatment for many respiratory diseases, including allergic rhinitis (AR). Novel treatments for AR are needed as current medications, including steroids, often fail to treat severe symptoms.

The effect of hypochlorous acid on the filtration performance and bacterial decontamination of N95 filtering facemask respirators.

Background: Stabilized hypochlorous acid (HOCl) is increasingly used as a hospital disinfectant and antiseptic, yet its effect on N95 filtration facemask respirators (FFR) is unknown. These FFRs could also contribute to fomite-based transmission of nosocomial infections if worn for extended use between patient rooms.

Methods: Filtration performance of N95 FFR fabric swatches was assessed after various levels of HOCl exposure.

What came first, the virus or the egg: Innate immunity during viral coinfections.

Infections with any pathogen can be severe and present with numerous complications caused by the pathogen or the host immune response to the invading microbe. However, coinfections, also called polymicrobial infections or secondary infections, can further exacerbate disease. Coinfections are more common than is often appreciated.

Pyruvate affects inflammatory responses of macrophages during influenza A virus infection.

Pyruvate is the end product of glycolysis and transported into the mitochondria for use in the tricarboxylic acid (TCA) cycle. It is also a common additive in cell culture media. We discovered that inclusion of sodium pyruvate in culture media during infection of mouse bone marrow derived macrophages with influenza A virus impaired cytokine production (IL-6, IL-1β, and TNF-α).

Antifungal Norditerpene Oidiolactones from the Fungus , a Potential Biocontrol Agent for White-Nose Syndrome in Bats.

White-nose syndrome (WNS) is a devastating disease of hibernating bats caused by the fungus . We obtained 383 fungal and bacterial isolates from the Soudan Iron Mine, an important bat hibernaculum in Minnesota, then screened this library for antifungal activity to develop biological control treatments for WNS. An extract from the fungus was subjected to bioassay-guided fractionation, which led to the isolation of 14 norditerpene and three anthraquinone metabolites.

Common Differences: The Ability of Inflammasomes to Distinguish Between Self and Pathogen Nucleic Acids During Infection.

The innate immune system detects the presence of pathogens based on detection of non-self. In other words, most pathogens possess intrinsic differences that can distinguish them from host cells. For example, bacteria and fungi have cell walls comprised of peptidoglycan and carbohydrates (like mannans), respectively.

Enhanced IL-1β production is mediated by a TLR2-MYD88-NLRP3 signaling axis during coinfection with influenza A virus and Streptococcus pneumoniae.

Viral-bacterial coinfections, such as with influenza A virus and Streptococcus pneumoniae (S.p.), are known to cause severe pneumonia.

The Inflammasome: Regulation of Nitric Oxide and Antimicrobial Host Defence.

Nitric oxide (NO) is a gaseous signalling molecule that plays diverse physiological functions including antimicrobial host defence. During microbial infection, NO is synthesized by inducible NO synthase (iNOS), which is expressed by host immune cells through the recognition of microbial pattern molecules. Therefore, sensing pathogens or their pattern molecules by pattern recognition receptors (PRRs), which are located at the cell surface, endosomal and phagosomal compartment, or in the cytosol, is key in inducing iNOS and eliciting antimicrobial host defence.

Interaction of the Human Respiratory Syncytial Virus matrix protein with cellular adaptor protein complex 3 plays a critical role in trafficking.

Human Respiratory Syncytial Virus (HRSV) is a leading cause of bronchopneumonia in infants and the elderly. To date, knowledge of viral and host protein interactions within HRSV is limited and are critical areas of research. Here, we show that HRSV Matrix (M) protein interacts with the cellular adaptor protein complex 3 specifically via its medium subunit (AP-3Mu3A).

Deficiency of the NOD-Like Receptor NLRC5 Results in Decreased CD8 T Cell Function and Impaired Viral Clearance.

Pathogen recognition receptors are vital components of the immune system. Engagement of these receptors is important not only for instigation of innate immune responses to invading pathogens but also for initiating the adaptive immune response. Members of the NOD-like receptor (NLR) family of pathogen recognition receptors have important roles in orchestrating this response.

Inflammasome activation by nucleic acids and nucleosomes in sterile inflammation… or is it sterile?

Inflammasomes are multiprotein complexes that form in the cytoplasm in response to cellular damage and cytosolic pathogen-associated molecules during infection. These complexes play important roles in initiating innate and adaptive immune responses to infectious disease. In addition, inflammasomes are now recognized as important mediators of sterile inflammation in various autoimmune and autoinflammatory diseases.

Integrating Inflammasome Signaling in Sexually Transmitted Infections.

Inflammasomes are cytosolic multiprotein platforms with pivotal roles in infectious diseases. Activation of inflammasomes results in proinflammatory cytokine signaling and pyroptosis. Sexually transmitted infections (STIs) are a major health problem worldwide, yet few studies have probed the impact of inflammasome signaling during these infections.

Cathepsin B modulates lysosomal biogenesis and host defense against Francisella novicida infection.

Lysosomal cathepsins regulate an exquisite range of biological functions, and their deregulation is associated with inflammatory, metabolic, and degenerative diseases in humans. In this study, we identified a key cell-intrinsic role for cathepsin B as a negative feedback regulator of lysosomal biogenesis and autophagy. Mice and macrophages lacking cathepsin B activity had increased resistance to the cytosolic bacterial pathogen Francisella novicida Genetic deletion or pharmacological inhibition of cathepsin B down-regulated mechanistic target of rapamycin activity and prevented cleavage of the lysosomal calcium channel TRPML1.

Inflammasome control of viral infection.

The inflammasome is a caspase-1 containing complex that activates the proinflammatory cytokines IL-1β and IL-18 and results in the proinflammatory cell death known as pyroptosis. Numerous recent publications have highlighted the importance of inflammasome activation in the control of virus infection. Inflammasome activation during viral infection is dependent on a variety of upstream receptors including the NOD-like receptor, RIG-I-like receptor and AIM2-like receptor families.

The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease.

The ketone bodies β-hydroxybutyrate (BHB) and acetoacetate (AcAc) support mammalian survival during states of energy deficit by serving as alternative sources of ATP. BHB levels are elevated by starvation, caloric restriction, high-intensity exercise, or the low-carbohydrate ketogenic diet. Prolonged fasting reduces inflammation; however, the impact that ketones and other alternative metabolic fuels produced during energy deficits have on the innate immune response is unknown.

Reactive oxygen species regulate caspase-11 expression and activation of the non-canonical NLRP3 inflammasome during enteric pathogen infection.

Enteropathogenic and enterohemorrhagic bacterial infections in humans are a severe cause of morbidity and mortality. Although NOD-like receptors (NLRs) NOD2 and NLRP3 have important roles in the generation of protective immune responses to enteric pathogens, whether there is crosstalk among NLRs to regulate immune signaling is not known. Here, we show that mice and macrophages deficient in NOD2, or the downstream adaptor RIP2, have enhanced NLRP3- and caspases-11-dependent non-canonical inflammasome activation in a mouse model of enteropathogenic Citrobacter rodentium infection.

Nucleotide oligomerization and binding domain 2-dependent dendritic cell activation is necessary for innate immunity and optimal CD8+ T Cell responses to influenza A virus infection.

Unlabelled: Nucleotide oligomerization and binding domain (NOD)-like receptors (NLRs) are important in the innate immune response to viral infection. Recent findings have implicated NLRP3, NOD2, and NLRX1 as important players in the innate antiviral response, but their roles in the generation of adaptive immunity to viruses are less clear. We demonstrate here that NOD2 is critical for both innate and adaptive immune responses necessary for controlling viral replication and survival during influenza A virus (IAV) infection.

Unsolved Mysteries in NLR Biology.

NOD-like receptors (NLRs) are a class of cytoplasmic pattern-recognition receptors. Although most NLRs play some role in immunity, their functions range from regulating antigen presentation (NLRC5, CIITA) to pathogen/damage sensing (NLRP1, NLRP3, NLRC1/2, NLRC4) to suppression or modulation of inflammation (NLRC3, NLRP6, NLRP12, NLRX1). However, NLRP2, NLRP5, and NLRP7 are also involved in non-immune pathways such as embryonic development.

The expanding role of NLRs in antiviral immunity.

Nucleotide oligomerization and binding domain (NOD)-like receptors (NLRs) are a major constituent of the cytosolic innate immune-sensing machinery and participate in a wide array of pathways including nuclear factor κB (NF-κB), mitogen-activated protein kinase (MAPK), inflammasome, and type I interferon (IFN) signaling. NLRs have known roles in autoimmune, autoinflammatory, and infectious diseases. With respect to virus infection, NLRP3 is the most extensively studied NLR, including mechanisms of activation and inhibition.

A Novel Lactococcal Vaccine Expressing a Peptide from the M2 Antigen of H5N2 Highly Pathogenic Avian Influenza A Virus Prolongs Survival of Vaccinated Chickens.

A cost-effective and efficacious influenza vaccine for use in commercial poultry farms would help protect against avian influenza outbreaks. Current influenza vaccines for poultry are expensive and subtype specific, and therefore there is an urgent need to develop a universal avian influenza vaccine. We have constructed a live bacterial vaccine against avian influenza by expressing a conserved peptide from the ectodomain of M2 antigen (M2e) on the surface of Lactococcus lactis (LL).

Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection.

NOD2 receptor and the cytosolic protein kinase RIPK2 regulate NF-κB and MAP kinase signaling during bacterial infections, but the role of this immune axis during viral infections has not been addressed. We demonstrate that Nod2(-/-) and Ripk2(-/-) mice are hypersusceptible to infection with influenza A virus. Ripk2(-/-) cells exhibited defective autophagy of mitochondria (mitophagy), leading to enhanced mitochondrial production of superoxide and accumulation of damaged mitochondria, which resulted in greater activation of the NLRP3 inflammasome and production of IL-18.

The role of inflammasome modulation in virulence.

Pathogens frequently exist in an immunological balancing act with their host. Pathogens must not only replicate within a host but also transmit effectively between hosts to perpetuate their species. On the other hand, the host seeks to maintain homeostasis by clearing pathogens.

Inflammasome-independent role of the apoptosis-associated speck-like protein containing CARD (ASC) in the adjuvant effect of MF59.

Clinical studies have indicated that subvirion inactivated vaccines against avian influenza viruses, particularly H5N1, are poorly immunogenic in humans. As a consequence, the use of adjuvants has been championed for the efficient vaccination of a naïve population against avian influenza. Aluminum salts (alum) and the oil-in-water emulsion MF59 are safe and effective adjuvants that are being used with influenza vaccines, but the mechanism underlying their stimulation of the immune system remains poorly understood.