Ubiquitination in viral entry and replication: Mechanisms and implications.

The ubiquitination process is a reversible posttranslational modification involved in many essential cellular functions, such as innate immunity, cell signaling, trafficking, protein stability, and protein degradation. Viruses can use the ubiquitin system to efficiently enter host cells, replicate and evade host immunity, ultimately enhancing viral pathogenesis. Emerging evidence indicates that enveloped viruses can carry free (unanchored) ubiquitin or covalently ubiquitinated viral structural proteins that can increase the efficiency of viral entry into host cells. Furthermore, viruses continuously evolve and adapt to take advantage of the host ubiquitin machinery, highlighting its importance during virus infection. This review discusses the battle between viruses and hosts, focusing on how viruses hijack the ubiquitination process at different steps of the replication cycle, with a specific emphasis on viral entry. We discuss how ubiquitination of viral proteins may affect tropism and explore emerging therapeutics strategies targeting the ubiquitin system for antiviral drug discovery.

Immune Response to Respiratory Viral Infections.

The respiratory system is constantly exposed to viral infections that are responsible for mild to severe diseases. In this narrative review, we focalized the attention on respiratory syncytial virus (RSV), influenza virus, and severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infections, responsible for high morbidity and mortality in the last decades. We reviewed the human innate and adaptive immune responses in the airways following infection, focusing on a particular population: newborns and pregnant women. The recent Coronavirus disease-2019 (COVID-19) pandemic has highlighted how our interest in viral pathologies must not decrease. Furthermore, we must increase our knowledge of infection mechanisms to improve our future defense strategies.

Identification and Characterization of Antigen-Specific T-Cells in Viral Infections.

Identification and characterization of CD8+ T-cells is important to determine their role in protecting and clearing viral infections. Here we provide details of the peptide-MHC (pMHC) tetramers-based approach to identify antigen-specific T-cells in human and murine samples. This method provides ex vivo quantification and functional characterization of T-cells reactive to specific viral antigens derived from CMV and rotavirus in human blood and in murine intestinal lamina propria samples, respectively.

Viral strategies to antagonize the host antiviral innate immunity: an indispensable research direction for emerging virus-host interactions.

The public's health is gravely at risk due to the current global outbreak of emerging viruses, specifically SARS-CoV-2 and MPXV. Recent studies have shown that SARS-CoV-2 mutants (such as Omicron) exhibit a higher capability to antagonize the host innate immunity, increasing their human adaptability and transmissibility. Furthermore, current studies on the strategies for MPXV to antagonize the host innate immunity are still in the initial stages. These multiple threats from emerging viruses make it urgent to study emerging virus-host interactions, especially the viral antagonism of host antiviral innate immunity. Given this, we selected several representative viruses that significantly threatened human public health and interpreted the multiple strategies for these viruses to antagonize the host antiviral innate immunity, hoping to provide ideas for molecular mechanism research that emerging viruses antagonize the host antiviral innate immunity and accelerate the research progress. The IAV, SARS-CoV-2, SARS-CoV, MERS-CoV, EBOV, DENV, ZIKV, and HIV are some of the typical viruses. Studies have shown that viruses could antagonize the host antiviral innate immunity by directly or indirectly blocking antiviral innate immune signaling pathways. Proviral host factors, host restriction factors, and ncRNAs (microRNAs, lncRNAs, circRNAs, and vtRNAs) are essential in indirectly blocking antiviral innate immune signaling pathways. Furthermore, via controlling apoptosis, ER stress, stress granule formation, and metabolic pathways, viruses may antagonize it. These regulatory mechanisms include transcriptional regulation, post-translational regulation, preventing complex formation, impeding nuclear translocation, cleavage, degradation, and epigenetic regulation.

Uncloaking the viral glycocalyx: How do viruses exploit glycoimmune checkpoints?

The surfaces of cells and enveloped viruses alike are coated in carbohydrates that play multifarious roles in infection and immunity. Organisms across all kingdoms of life make use of a diverse set of monosaccharide subunits, glycosidic linkages, and branching patterns to encode information within glycans. Accordingly, sugar-patterning enzymes and glycan binding proteins play integral roles in cell and organismal biology, ranging from glycoprotein quality control within the endoplasmic reticulum to lymphocyte migration, coagulation, inflammation, and tissue homeostasis. Unsurprisingly, genes involved in generating and recognizing oligosaccharide patterns are playgrounds for evolutionary conflicts that abound in cross-species interactions, exemplified by the myriad plant lectins that function as toxins. In vertebrates, glycans bearing acidic nine-carbon sugars called sialic acids are key regulators of immune responses. Various bacterial and fungal pathogens adorn their cells in sialic acids that either mimic their hosts' or are stolen from them. Yet, how viruses commandeer host sugar-patterning enzymes to thwart immune responses remains poorly studied. Here, we review examples of viruses that interact with sialic acid-binding immunoglobulin-like lectins (Siglecs), a family of immune cell receptors that regulate toll-like receptor signaling and govern glycoimmune checkpoints, while highlighting knowledge gaps that merit investigation. Efforts to illuminate how viruses leverage glycan-dependent checkpoints may translate into new clinical treatments that uncloak viral antigens and infected cell surfaces by removing or masking immunosuppressive sialoglycans, or by inhibiting viral gene products that induce their biosynthesis. Such approaches may hold the potential to unleash the immune system to clear long intractable chronic viral infections.

Computational design of novel chimeric multiepitope vaccine against bacterial and viral disease in tilapia (Oreochromis sp.).

Regarding several infectious diseases in fish, multiple vaccinations are not favorable. The chimeric multiepitope vaccine (CMEV) harboring several antigens for multi-disease prevention would enhance vaccine efficiency in terms of multiple disease prevention. Herein, the immunogens of tilapia's seven pathogens including E. tarda, F. columnare, F. noatunensis, S. iniae, S. agalactiae, A. hydrophila, and TiLV were used for CMEV design. After shuffling and annotating the B-cell epitopes, 5,040 CMEV primary protein structures were obtained. Secondary and tertiary protein structures were predicted by AlphaFold2 creating 25,200 CMEV. Proper amino acid alignment in the secondary structures was achieved by the Ramachandran plot. In silico determination of physiochemical and other properties including allergenicity, antigenicity, glycosylation, and conformational B-cell epitopes were determined. The selected CMEV (OSLM0467, OSLM2629, and OSLM4294) showed a predicted molecular weight (MW) of 70 kDa, with feasible sites of N- and O-glycosylation, and a number of potentially conformational B-cell epitope residues. Molecular docking, codon optimization, and in-silico cloning were tested to evaluate the possibility of protein expression. Those CMEVs will further elucidate in vitro and in vivo to evaluate the efficacy and specific immune response. This research will highlight the new era of vaccines designed based on in silico structural vaccine design.

Lyapunov functionals for a general time-delayed virus dynamic model with different CTL responses.

A time-delayed virus dynamic model is proposed with general monotonic incidence, different nonlinear CTL (cytotoxic T lymphocyte) responses [CTL elimination function pyg1(z) and CTL stimulation function cyg2(z)], and immune impairment. Indeed, the different CTL responses pose challenges in obtaining the dissipativeness of the model. By constructing appropriate Lyapunov functionals with some detailed analysis techniques, the global stability results of all equilibria of the model are obtained. By the way, we point out that the partial derivative fv(x,0) is increasing (but not necessarily strictly) in x>0 for the general monotonic incidence f(x,v). However, some papers defaulted that the partial derivative was strictly increasing. Our main results show that if the basic reproduction number R0≤1, the infection-free equilibrium E0 is globally asymptotically stable (GAS); if CTL stimulation function cyg2(z)=0 for z=0 and the CTL threshold parameter R1≤1

Prevalence of human respiratory pathogens and associated mucosal cytokine levels in young children and adults: a cross-sectional observational study in the Netherlands during the winter of 2012/2013.

Respiratory pathogens can cause severe disease and even death, especially in the very young and very old. Studies investigating their prevalence often focus on individuals presenting to healthcare providers with symptoms. However, the design of prevention strategies, e.g. which target groups to vaccinate, will benefit from knowledge on the prevalence of, risk factors for and host response to these pathogens in the general population. In this study, upper respiratory samples (n = 1311) were collected cross-sectionally during winter from 11- and 24-month old children, their parents, and adults ≥60 years of age that were recruited irrespective of seeking medical care. Almost all children, approximately two-thirds of parents and a quarter of older adults tested positive for at least one pathogen, often in the absence of symptoms. Viral interference was evident for the combination of rhinovirus and respiratory syncytial virus. Attending childcare facilities and having siblings associated with increased pathogen counts in children. On average, children showed increased levels of mucosal cytokines compared to parents and especially proinflammatory molecules associated with the presence of symptoms. These findings may guide further research into transmission patterns of respiratory pathogens and assist in determining the most appropriate strategies for the prediction and prevention of disease.

T Cell Surveillance during Cutaneous Viral Infections.

The skin is a complex tissue that provides a strong physical barrier against invading pathogens. Despite this, many viruses can access the skin and successfully replicate in either the epidermal keratinocytes or dermal immune cells. In this review, we provide an overview of the antiviral T cell biology responding to cutaneous viral infections and how these responses differ depending on the cellular targets of infection. Much of our mechanistic understanding of T cell surveillance of cutaneous infection has been gained from murine models of poxvirus and herpesvirus infection. However, we also discuss other viral infections, including flaviviruses and papillomaviruses, in which the cutaneous T cell response has been less extensively studied. In addition to the mechanisms of successful T cell control of cutaneous viral infection, we highlight knowledge gaps and future directions with possible impact on human health.

Pediatric Respiratory Viral Infection.

Reflecting on this Special Issue dedicated to pediatric respiratory viruses, it is evident that the shadow cast by the global SARS-CoV-2 pandemic has profoundly impacted individuals of all ages and backgrounds, neonates and school-aged children being vulnerable cohorts resulting from the evolving immunological profiles and limited exposures to immunity-building experienced during this unprecedented era [...].

The Antiviral Activity of Interferon-Induced Transmembrane Proteins and Virus Evasion Strategies.

Interferons (IFNs) are antiviral cytokines that defend against viral infections by inducing the expression of interferon-stimulated genes (ISGs). Interferon-inducible transmembrane proteins (IFITMs) 1, 2, and 3 are crucial ISG products and members of the CD225 protein family. Compelling evidence shows that IFITMs restrict the infection of many unrelated viruses by inhibiting the virus-cell membrane fusion at the virus entry step via the modulation of lipid composition and membrane properties. Meanwhile, viruses can evade IFITMs' restrictions by either directly interacting with IFITMs via viral glycoproteins or by altering the native entry pathway. At the same time, cumulative evidence suggests context-dependent and multifaceted roles of IFITMs in modulating virus infections and cell signaling. Here, we review the diverse antiviral mechanisms of IFITMs, the viral antagonizing strategies, and the regulation of IFITM activity in host cells. The mechanisms behind the antiviral activity of IFITMs could aid the development of broad-spectrum antivirals and enhance preparedness for future pandemics.

New technologies in therapeutic antibody development: The next frontier for treating infectious diseases.

Adaptive immunity to viral infections requires time to neutralize and clear viruses to resolve infection. Fast growing and pathogenic viruses are quickly established, are highly transmissible and cause significant disease burden making it difficult to mount effective responses, thereby prolonging infection. Antibody-based passive immunotherapies can provide initial protection during acute infection, assist in mounting an adaptive immune response, or provide protection for those who are immune suppressed or immune deficient. Historically, plasma-derived antibodies have demonstrated some success in treating diseases caused by viral pathogens; nonetheless, limitations in access to product and antibody titer reduce success of this treatment modality. Monoclonal antibodies (mAbs) have proven an effective alternative, as it is possible to manufacture highly potent and specific mAbs against viral targets on an industrial scale. As a result, innovative technologies to discover, engineer and manufacture specific and potent antibodies have become an essential part of the first line of treatment in pathogenic viral infections. However, a mAb targeting a specific epitope will allow escape variants to outgrow, causing new variant strains to become dominant and resistant to treatment with that mAb. Methods to mitigate escape have included combining mAbs into cocktails, creating bi-specific or antibody drug conjugates but these strategies have also been challenged by the potential development of escape mutations. New technologies in developing antibodies made as recombinant polyclonal drugs can integrate the strength of poly-specific antibody responses to prevent mutational escape, while also incorporating antibody engineering to prevent antibody dependent enhancement and direct adaptive immune responses.

Everlasting first impressions in B cells.

Initial imprinting by type 1 interferons shapes memory B cell generation in chronic viral infection.

Chronic and Latent Viral Infections and Leukocyte Telomere Length across the Lifespan of Female and Male Individuals Living with or without HIV.

BACKGROUND: Chronic/latent viral infections may accelerate immunological aging, particularly among people living with HIV (PLWH). We characterized chronic/latent virus infections across their lifespan and investigated their associations with leukocyte telomere length (LTL). METHODS: Participants enrolled in the CARMA cohort study were randomly selected to include n = 15 for each decade of age between 0 and >60 y, for each sex, and each HIV status. Cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 8 (HHV-8), herpes simplex virus 1 (HSV-1), and HSV-2 infection were determined serologically; HIV, hepatitis C (HCV), and hepatitis B (HBV) were self-reported. LTLs were measured using monochrome multiplex qPCR. Associations between the number of viruses, LTL, and sociodemographic factors were assessed using ordinal logistic and linear regression modeling. RESULTS: The study included 187 PLWH (105 female/82 male) and 190 HIV-negative participants (105 female/84 male), ranging in age from 0.7 to 76.1 years. Living with HIV, being older, and being female were associated with harbouring a greater number of chronic/latent non-HIV viruses. Having more infections was in turn bivariately associated with a shorter LTL. In multivariable analyses, older age, living with HIV, and the female sex remained independently associated with having more infections, while having 3-4 viruses (vs. 0-2) was associated with a shorter LTL. CONCLUSIONS: Our results suggest that persistent viral infections are more prevalent in PLWH and females, and that these may contribute to immunological aging. Whether this is associated with comorbidities later in life remains an important question.

Decoding macrophage immunometabolism in human viral infection.

Immune-metabolic interactions play a pivotal role in both host defense and susceptibility to various diseases. Immunometabolism, an interdisciplinary field, seeks to elucidate how metabolic processes impact the immune system. In the context of viral infections, macrophages are often exploited by viruses for their replication and propagation. These infections trigger significant metabolic reprogramming within macrophages and polarization of distinct M1 and M2 phenotypes. This metabolic reprogramming involves alterations in standard- pathways such as the Krebs cycle, glycolysis, lipid metabolism, the pentose phosphate pathway, and amino acid metabolism. Disruptions in the balance of key intermediates like spermidine, itaconate, and citrate within these pathways contribute to the severity of viral diseases. In this chapter, we describe the manipulation of metabolic pathways by viruses and how they crosstalk between signaling pathways to evade the immune system. This intricate interplay often involves the upregulation or downregulation of specific metabolites, making these molecules potential biomarkers for diseases like HIV, HCV, and SARS-CoV. Techniques such as Nuclear Magnetic Resonance (NMR) and Mass Spectrometry, are the evaluative ways to analyze these metabolites. Considering the importance of macrophages in the inflammatory response, addressing their metabolome holds great promise for the creating future therapeutic targets aimed at combating a wide spectrum of viral infections.

Inclusion body myositis, viral infections, and TDP-43: a narrative review.

The ubiquitous RNA-processing molecule TDP-43 is involved in neuromuscular diseases such as inclusion body myositis, a late-onset acquired inflammatory myopathy. TDP-43 solubility and function are disrupted in certain viral infections. Certain viruses, high viremia, co-infections, reactivation of latent viruses, and post-acute expansion of cytotoxic T cells may all contribute to inclusion body myositis, mainly in an age-shaped immune landscape. The virally induced senescent, interferon gamma-producing cytotoxic CD8+ T cells with increased inflammatory, and cytotoxic features are involved in the occurrence of inclusion body myositis in most such cases, in a genetically predisposed host. We discuss the putative mechanisms linking inclusion body myositis, TDP-43, and viral infections untangling the links between viruses, interferon, and neuromuscular degeneration could shed a light on the pathogenesis of the inclusion body myositis and other TDP-43-related neuromuscular diseases, with possible therapeutic implications.

S100A9: The Unusual Suspect Connecting Viral Infection and Inflammation.

The study of S100A9 in viral infections has seen increased interest since the COVID-19 pandemic. S100A8/A9 levels were found to be correlated with the severity of COVID-19 disease, cytokine storm, and changes in myeloid cell subsets. These data led to the hypothesis that S100A8/A9 proteins might play an active role in COVID-19 pathogenesis. This review explores the structures and functions of S100A8/9 and the current knowledge on the involvement of S100A8/A9 and its constituents in viral infections. The potential roles of S100A9 in SARS-CoV-2 infections are also discussed.

The role of dendritic cells in respiratory viral infection.

Respiratory viral infections represent one of the major causes of death worldwide. The recent coronavirus disease 2019 pandemic alone claimed the lives of over 6 million people around the globe. It is therefore crucial to understand how the immune system responds to these threats and how respiratory infection can be controlled and constrained. Dendritic cells (DCs) are one of the key players in antiviral immunity because of their ability to detect pathogens. They can orchestrate an immune response that will, in most cases, lead to viral clearance. Different subsets of DCs are present in the lung and each subset can contribute to antiviral responses through various mechanisms. In this review, we discuss the role of the different lung DC subsets in response to common respiratory viruses, with a focus on respiratory syncytial virus, influenza A virus and severe acute respiratory syndrome coronavirus 2. We also review how lung DC-mediated responses to respiratory viruses can lead to the worsening of an existing chronic pulmonary disease such as asthma. Throughout the review, we discuss results obtained from animal studies as well as results generated from infected patients.

Role of the intestinal microbiota in host defense against respiratory viral infections.

Viral infections, including those affecting the respiratory tract, can alter the composition of the intestinal microbiota, which, in turn, can significantly influence both innate and adaptive immune responses, resulting in either enhanced pathogen clearance or exacerbation of the infection, possibly leading to inflammatory complications. A deeper understanding of the interplay between the intestinal microbiota and host immune responses in the context of respiratory viral infections (i.e. the gut-lung axis) is necessary to develop new treatments. This review highlights key mechanisms by which the intestinal microbiota, including its metabolites, can act locally or at distant organs to combat respiratory viruses. Therapeutics aimed at harnessing the microbiota to prevent and/or help treat respiratory viral infections represent a promising avenue for future investigation.