Antiviral Effects of Fructans

Infectious diseases of viral origin have never received so much interest globally since the emergence of the COVID-19 pandemic disease. In contrast to bacterial infections, antibiotic treatments do not have any effect on viral infections, requiring alternative solutions to reduce the impact of viral spread on animal populations. More important than curing, preventing viral replication before disease development is probably the best strategy to minimalize the negative effects of viruses on a global scale. Fructans, known to stimulate the immune system (by either interacting directly or indirectly with the immune system), may be interesting candidates as part of this broader prevention strategy. This chapter discusses the potential antiviral properties of fructans in relation to their well-described immunomodulating, antioxidant and prebiotic attributes, as well as a possible role as protein binders which may disturb the proper function of viral proteins, and thus reduce the infection ability of certain viral strains. © 2023 Elsevier Inc. All rights reserved.

The Cholesterol-Binding Sequence in Monomeric C-Reactive Protein Binds to the SARS-CoV-2 Spike Receptor-Binding Domain and Blocks Interaction With Angiotensin-Converting Enzyme 2.

The receptor-binding domain (RBD) of the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the human angiotensin-converting enzyme 2 (ACE2) receptor, which is a prerequisite for the virus to enter the cell. C-reactive protein (CRP) is an important marker of inflammation and is a putative soluble pattern recognition receptor. Clinical elevation of CRP levels in patients with COVID-19 is one of the characteristics of the disease; however, whether CRP is involved in COVID-19 pathogenesis is unknown. Here, we report that monomeric CRP (mCRP) can bind to the SARS-CoV-2 spike RBD and competitively inhibit its binding to ACE2. Furthermore, truncated mutant peptide competition assays and surface plasmon resonance binding experiments showed that the cholesterol-binding sequence (CBS, amino acids 35-47) in mCRP was critical for mediating the binding of mCRP to spike RBD. In a cell model of spike RBD and ACE2 interaction, the CBS motif effectively reduced the binding of spike RBD to ACE2 overexpressed on the cell surface. Thus, this study highlights the pattern recognition function of mCRP in innate immunity and provides a preliminary theoretical basis for the development of the CBS motif in mCRP into a functional peptide with both diagnostic significance and potential therapeutic capabilities.

Coronaviral Infection and Interferon Response: The Virus-Host Arms Race and COVID-19.

The recent pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in unprecedented morbidity and mortality worldwide. The host cells use a number of pattern recognition receptors (PRRs) for early detection of coronavirus infection, and timely interferon secretion is highly effective against SARS-CoV-2 infection. However, the virus has developed many strategies to delay interferon secretion and disarm cellular defense by intervening in interferon-associated signaling pathways on multiple levels. As a result, some COVID-19 patients suffered dramatic susceptibility to SARS-CoV-2 infection, while another part of the population showed only mild or no symptoms. One hypothesis suggests that functional differences in innate immune integrity could be the key to such variability. This review tries to decipher possible interactions between SARS-CoV-2 proteins and human antiviral interferon sensors. We found that SARS-CoV-2 actively interacts with PRR sensors and antiviral pathways by avoiding interferon suppression, which could result in severe COVID-19 pathogenesis. Finally, we summarize data on available antiviral pharmaceutical options that have shown potential to reduce COVID-19 morbidity and mortality in recent clinical trials.

An adjuvant strategy enabled by modulation of the physical properties of microbial ligands expands antigen immunogenicity.

Activation of the innate immune system via pattern recognition receptors (PRRs) is key to generate lasting adaptive immunity. PRRs detect unique chemical patterns associated with invading microorganisms, but whether and how the physical properties of PRR ligands influence the development of the immune response remains unknown. Through the study of fungal mannans, we show that the physical form of PRR ligands dictates the immune response. Soluble mannans are immunosilent in the periphery but elicit a potent pro-inflammatory response in the draining lymph node (dLN). By modulating the physical form of mannans, we developed a formulation that targets both the periphery and the dLN. When combined with viral glycoprotein antigens, this mannan formulation broadens epitope recognition, elicits potent antigen-specific neutralizing antibodies, and confers protection against viral infections of the lung. Thus, the physical properties of microbial ligands determine the outcome of the immune response and can be harnessed for vaccine development.

K63 ubiquitination in immune signaling.

Ubc13-catalyzed K63 ubiquitination is a major control point for immune signaling. Recent evidence has shown that the control of multiple immune functions, including chronic inflammation, pathogen responses, lymphocyte activation, and regulatory signaling, is altered by K63 ubiquitination. In this review, we detail the novel cellular sensors that are dependent on K63 ubiquitination for their function in the immune signaling network. Many pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can target K63 ubiquitination to inhibit pathogen immune responses; we describe novel details of the pathways involved and summarize recent clinically relevant SARS-CoV-2-specific responses. We also discuss recent evidence that regulatory T cell (Treg) versus T helper (TH) 1 and TH17 cell subset regulation might involve K63 ubiquitination. Knowledge gaps that merit future investigation and clinically relevant pathways are also addressed.

Expressing a truncated SARS-COV-2 spike protein in mouse heart induces cardiac hypertrophy

Cardiac injury is common in hospitalized and non-hospitalized COVID- 19 patients, for which systemic inflammation stress is one of the causes (Topol, 2020). Although rare, COVID-19 cases that SARS-CoV-2 infecting cardiomyocytes (CMs) have been reported. In vitro, SARS-CoV-2 infection of human induced-pluripotent-cells derived CMs triggered innate immune responses and induced apoptosis (Bojkova et al., 2020;Chen et al., 2020). Therefore, the current literature indicates that the heart is attacked by SARS-CoV-2 directly or indirectly;however, the underlying mechanism remains largely unknown. Involved in the pathogenesis of heart diseases, Toll-like receptors (TLR) are a family of pattern recognition receptors that sense the pathogenic stimuli and signal the cardiac residential cells to cope with harsh conditions (Yu and Feng, 2018). Among the best characterized TLR signaling pathways is TLR4/NF-kB axis (Lu et al., 2008), in which TLR4 convey the danger signals through its down stream kinases, such as TAK1 and TBK1, to activate NF-kB. SARS-CoV-2 Spike protein is well known for its role of mediating virus entry into host cells, but its immunogenic role has not been clearly defined. Recently, we have found that SARS-CoV-2 Spike protein directly interacts with TLR4 and activates NFkB transcriptional activity. Pharmaceutically blocking either TBK1 or TAK1 attenuates Spike protein's immunogenic activity. To pinpoint Spike protein's role in the heart, we generated an AAV to specifically express a truncated Spike protein (S1-TM) in the CMs. Our data show that expressing S1-TM in CMs induces cardiac hypertrophy and decreases heart systolic function in mice. On the molecular level, Spike protein increases RelA (p65 subunit of the NF-kB complex) and activates the expression of pro-inflammatory cytokine genes. In summary, our study suggests that Spike protein directly interacts with TLR4 to trigger innate immune signaling, and that Spike protein induced CM innate immune responses might be one of the underlying mechanisms of cardiac injury in COVID-19.

Exploration of Pattern Recognition Receptor Agonists as Candidate Adjuvants.

Adjuvants are used to maximize the potency of vaccines by enhancing immune reactions. Components of adjuvants include pathogen-associated molecular patterns (PAMPs) and damage-associate molecular patterns (DAMPs) that are agonists for innate immune receptors. Innate immune responses are usually activated when pathogen recognition receptors (PRRs) recognize PAMPs derived from invading pathogens or DAMPs released by host cells upon tissue damage. Activation of innate immunity by PRR agonists in adjuvants activates acquired immune responses, which is crucial to enhance immune reactions against the targeted pathogen. For example, agonists for Toll-like receptors have yielded promising results as adjuvants, which target PRR as adjuvant candidates. However, a comprehensive understanding of the type of immunological reaction against agonists for PRRs is essential to ensure the safety and reliability of vaccine adjuvants. This review provides an overview of the current progress in development of PRR agonists as vaccine adjuvants, the molecular mechanisms that underlie activation of immune responses, and the enhancement of vaccine efficacy by these potential adjuvant candidates.

How dendritic cells sense and respond to viral infections.

The ability of dendritic cells (DCs) to sense viral pathogens and orchestrate a proper immune response makes them one of the key players in antiviral immunity. Different DC subsets have complementing functions during viral infections, some specialize in antigen presentation and cross-presentation and others in the production of cytokines with antiviral activity, such as type I interferons. In this review, we summarize the latest updates concerning the role of DCs in viral infections, with particular focus on the complex interplay between DC subsets and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Despite being initiated by a vast array of immune receptors, DC-mediated antiviral responses often converge towards the same endpoint, that is the production of proinflammatory cytokines and the activation of an adaptive immune response. Nonetheless, the inherent migratory properties of DCs make them a double-edged sword and often viral recognition by DCs results in further viral dissemination. Here we illustrate these various aspects of the antiviral functions of DCs and also provide a brief overview of novel antiviral vaccination strategies based on DCs targeting.

Severe Acute Respiratory Syndrome Coronavirus 2: The Role of the Main Components of the Innate Immune System.

At the end of December 2019, the COVID-19 pandemic began in Wuhan of China. COVID-19 affects different people with a wide spectrum of clinical manifestations, ranging from asymptomatic with recovery without hospitalization up to a severe acute respiratory syndrome (SARS). The innate and adaptive immunity appears responsible for the defense against the virus and recovery from the disease. The innate immune system, as the first line of defense, is essential for the detection of virus and subsequent activation of acquired immunity. The innate immune response is carried out by sentinel cells such as monocytes/macrophages and dendritic cells and by receptors known as pattern recognition receptors (PRR). These receptors can recognize various components of the virus, which lead to intracellular signaling and subsequently the synthesis of various cytokines. These cytokines then recruit other immune cells, activate adaptive immune responses, and inhibit viral spreading. The most common receptors include Toll-like receptors, C-type lectin receptors, and RIG-I like receptors. This review describes the current knowledge about the interplay between innate immune responses and SARS-CoV-2 with a focus on the innate immune cells and the role of their receptors in viral RNA recognition, as well as their mechanisms for recognizing SARS-CoV-2.

Differential roles of RIG-I like receptors in SARS-CoV-2 infection.

Retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5) sense viral RNA and activate antiviral immune responses. Herein we investigate their functions in human epithelial cells, the primary and initial target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A deficiency in MDA5, RIG-I or mitochondrial antiviral signaling protein (MAVS) enhanced viral replication. The expression of the type I/III interferon (IFN) during infection was impaired in MDA5-/- and MAVS-/-, but not in RIG-I-/-, when compared to wild type (WT) cells. The mRNA level of full-length angiotensin-converting enzyme 2 (ACE2), the cellular entry receptor for SARS-CoV-2, was ~ 2.5-fold higher in RIG-I-/- than WT cells. These data demonstrate MDA5 as the predominant SARS-CoV-2 sensor, IFN-independent induction of ACE2 and anti-SARS-CoV-2 role of RIG-I in epithelial cells.

The interferon landscape along the respiratory tract impacts the severity of COVID-19.

Severe coronavirus disease 2019 (COVID-19) is characterized by overproduction of immune mediators, but the role of interferons (IFNs) of the type I (IFN-I) or type III (IFN-III) families remains debated. We scrutinized the production of IFNs along the respiratory tract of COVID-19 patients and found that high levels of IFN-III, and to a lesser extent IFN-I, characterize the upper airways of patients with high viral burden but reduced disease risk or severity. Production of specific IFN-III, but not IFN-I, members denotes patients with a mild pathology and efficiently drives the transcription of genes that protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In contrast, compared to subjects with other infectious or noninfectious lung pathologies, IFNs are overrepresented in the lower airways of patients with severe COVID-19 that exhibit gene pathways associated with increased apoptosis and decreased proliferation. Our data demonstrate a dynamic production of IFNs in SARS-CoV-2-infected patients and show IFNs play opposing roles at distinct anatomical sites.

Molecular Mechanisms of the Toll-Like Receptor, STING, MAVS, Inflammasome, and Interferon Pathways.

Pattern recognition receptors (PRRs) form the front line of defense against pathogens. Many of the molecular mechanisms that facilitate PRR signaling have been characterized in detail, which is critical for the development of accurate PRR pathway models at the molecular interaction level. These models could support the development of therapeutics for numerous diseases, including sepsis and COVID-19. This review describes the molecular mechanisms of the principal signaling interactions of the Toll-like receptor, STING, MAVS, and inflammasome pathways. A detailed molecular mechanism network is included as Data Set S1 in the supplemental material.

Lung microbiome and coronavirus disease 2019 (COVID-19): Possible link and implications.

Coronavirus disease 2019 (COVID-19) is a rapidly emerging disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease begins as an infection of lungs, which is self-limiting in the majority of infections; however, some develop severe respiratory distress and organ failures. Lung microbiome, though neglected previously have received interest recently because of its association with several respiratory diseases and immunity. Lung microbiome can modify the risk and consequences of COVID-19 disease by activating an innate and adaptive immune response. In this review, we examine the current evidence on COVID-19 disease and lung microbiome, and how lung microbiome can affect SARS-CoV-2 infection and the outcomes of this disease. To date there is no direct evidence from human or animal studies on the role of lung microbiome in modifying COVID-19 disease; however, related studies support that microbiome can play an essential role in developing immunity against viral infections. Future studies need to be undertaken to find the relationship between lung microbiome and COVID-19 disease.