Type I Interferon-Mediated Regulation of Antiviral Capabilities of Neutrophils

Interferons (IFNs) are induced by viruses and are the main regulators of the host antiviral response. They balance tissue tolerance and immune resistance against viral challenges. Like all cells in the human body, neutrophils possess the receptors for IFNs and contribute to antiviral host defense. To combat viruses, neutrophils utilize various mechanisms, such as viral sensing, neutrophil extracellular trap formation, and antigen presentation. These mechanisms have also been linked to tissue damage during viral infection and inflammation. In this review, we presented evidence that a complex cross-regulatory talk between IFNs and neutrophils initiates appropriate antiviral immune responses and regulates them to minimize tissue damage. We also explored recent exciting research elucidating the interactions between IFNs, neutrophils, and severe acute respiratory syndrome-coronavirus-2, as an example of neutrophil and IFN cross-regulatory talk. Dissecting the IFN-neutrophil paradigm is needed for well-balanced antiviral therapeutics and development of novel treatments against many major epidemic or pandemic viral infections, including the ongoing pandemic of the coronavirus disease that emerged in 2019.     

Eosinophils and Bacteria,the Beginning of a Story

Eosinophils are granulocytes primarily associated with T_H2 responses to parasites or immune hyper-reactive states, such as asthma, allergies, or eosinophilic esophagitis. However, it does not make sense from an evolutionary standpoint to maintain a cell type that is only specific for parasitic infections and that otherwise is somehow harmful to the host. In recent years, there has been a shift in the perception of these cells. Eosinophils have recently been recognized as regulators of immune homeostasis and suppressors of over-reactive pro-inflammatory responses by secreting specific molecules that dampen the immune response. Their role during parasitic infections has been well investigated, and their versatility during immune responses to helminths includes antigen presentation as well as modulation of T cell responses. Although it is known that eosinophils can present antigens during viral infections, there are still many mechanistic aspects of the involvement of eosinophils during viral infections that remain to be elucidated. However, are eosinophils able to respond to bacterial infections? Recent literature indicates that Helicobacter pylori triggers T_H2 responses mediated by eosinophils; this promotes anti-inflammatory responses that might be involved in the long-term persistent infection caused by this pathogen. Apparently and on the contrary, in the respiratory tract, eosinophils promote T_H17 pro-inflammatory responses during Bordetella bronchiseptica infection, and they are, in fact, critical for early clearance of bacteria from the respiratory tract. However, eosinophils are also intertwined with microbiota, and up to now, it is not clear if microbiota regulates eosinophils or vice versa, or how this connection influences immune responses. In this review, we highlight the current knowledge of eosinophils as regulators of pro and anti-inflammatory responses in the context of both infection and naïve conditions. We propose questions and future directions that might open novel research avenues in the future.     

Interplay between Autophagy and Herpes Simplex Virus Type 1: ICP34.5, One of the Main Actors

Herpes simplex virus type 1 (HSV-1) is a neurotropic virus that occasionally may spread to the central nervous system (CNS), being the most common cause of sporadic encephalitis. One of the main neurovirulence factors of HSV-1 is the protein ICP34.5, which although it initially seems to be relevant only in neuronal infections, it can also promote viral replication in non-neuronal cells. New ICP34.5 functions have been discovered during recent years, and some of them have been questioned. This review describes the mechanisms of ICP34.5 to control cellular antiviral responses and debates its most controversial functions. One of the most discussed roles of ICP34.5 is autophagy inhibition. Although autophagy is considered a defense mechanism against viral infections, current evidence suggests that this antiviral function is only one side of the coin. Different types of autophagic pathways interact with HSV-1 impairing or enhancing the infection, and both the virus and the host cell modulate these pathways to tip the scales in its favor. In this review, we summarize the recent progress on the interplay between autophagy and HSV-1, focusing on the intricate role of ICP34.5 in the modulation of this pathway to fight the battle against cellular defenses.     

Apoptosis during ZIKA Virus Infection: Too Soon or Too Late?

Cell death by apoptosis is a major cellular response in the control of tissue homeostasis and as a defense mechanism in the case of cellular aggression such as an infection. Cell self-destruction is part of antiviral responses, aimed at limiting the spread of a virus. Although it may contribute to the deleterious effects in infectious pathology, apoptosis remains a key mechanism for viral clearance and the resolution of infection. The control mechanisms of cell death processes by viruses have been extensively studied. Apoptosis can be triggered by different viral determinants through different pathways as a result of virally induced cell stresses and innate immune responses. Zika virus (ZIKV) induces Zika disease in humans, which has caused severe neurological forms, birth defects, and microcephaly in newborns during the last epidemics. ZIKV also surprised by revealing an ability to persist in the genital tract and in semen, thus being sexually transmitted. Mechanisms of diverting antiviral responses such as the interferon response, the role of cytopathic effects and apoptosis in the etiology of the disease have been widely studied and debated. In this review, we examined the interplay between ZIKV infection of different cell types and apoptosis and how the virus deals with this cellular response. We illustrate a duality in the effects of ZIKV-controlled apoptosis, depending on whether it occurs too early or too late, respectively, in neuropathogenesis, or in long-term viral persistence. We further discuss a prospective role for apoptosis in ZIKV-related therapies, and the use of ZIKV as an oncolytic agent.     

Gal-3BP in Viral Infections: An Emerging Role in Severe Acute Respiratory Syndrome Coronavirus 2

Galectin-3 binding protein (Gal-3BP) is a multifunctional glycoprotein involved in cell–cell and cell–matrix interactions known to be upregulated in cancer and various viral infections, including HIV-1, HCV, and SARS-CoV-2, with a key role in regulating the antiviral immune response. Studies have identified a direct correlation between circulating levels of Gal-3BP and the severity of disease and/or disease progression for some viral infections, including SARS-CoV-2, suggesting a role of Gal-3BP in these processes. Due to Gal-3BP’s complex biology, the molecular mechanisms underlying its role in viral diseases have been only partially clarified. Gal-3BP induces the expression of interferons (IFNs) and proinflammatory cytokines, including interleukin-6 (IL-6), mainly interacting with galectin-3, targeting the TNF receptor-associated factors (TRAF-6 and TRAF-3) complex, thus having a putative role in the modulation of TGF-β signaling. In addition, an antiviral activity of Gal-3BP has been ascribed to a direct interaction of the protein with virus components. In this review, we explored the role of Gal-3BP in viral infections and the relationship between Gal-3BP upregulation and disease severity and progression, mainly focusing on SARS-CoV-2. Augmented knowledge of Gal-3BP’s role in virus infections can be useful to evaluate its possible use as a prognostic biomarker and as a putative target to block or attenuate severe disease.     

Correlation between Type I Interferon Associated Factors and COVID-19 Severity

Antiviral type I interferons (IFN) produced in the early phase of viral infections effectively inhibit viral replication, prevent virus-mediated tissue damages and promote innate and adaptive immune responses that are all essential to the successful elimination of viruses. As professional type I IFN producing cells, plasmacytoid dendritic cells (pDC) have the ability to rapidly produce waste amounts of type I IFNs. Therefore, their low frequency, dysfunction or decreased capacity to produce type I IFNs might increase the risk of severe viral infections. In accordance with that, declined pDC numbers and delayed or inadequate type I IFN responses could be observed in patients with severe coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as compared to individuals with mild or no symptoms. Thus, besides chronic diseases, all those conditions, which negatively affect the antiviral IFN responses lengthen the list of risk factors for severe COVID-19. In the current review, we would like to briefly discuss the role and dysregulation of pDC/type I IFN axis in COVID-19, and introduce those type I IFN-dependent factors, which account for an increased risk of COVID-19 severity and thus are responsible for the different magnitude of individual immune responses to SARS-CoV-2.     

Viral Infection and Airway Epithelial Immunity in Asthma

Viral respiratory tract infections are associated with asthma development and exacerbation in children and adults. In the course of immune responses to viruses, airway epithelial cells are the initial platform of innate immunity against viral invasion. Patients with severe asthma are more vulnerable than those with mild to moderate asthma to viral infections. Furthermore, in most cases, asthmatic patients tend to produce lower levels of antiviral cytokines than healthy subjects, such as interferons produced from immune effector cells and airway epithelial cells. The epithelial inflammasome appears to contribute to asthma exacerbation through overactivation, leading to self-damage, despite its naturally protective role against infectious pathogens. Given the mixed and complex immune responses in viral-infection-induced asthma exacerbation, this review examines the diverse roles of airway epithelial immunity and related potential therapeutic targets and discusses the mechanisms underlying the heterogeneous manifestations of asthma exacerbations.     

Role of CD4+ T Cells in the Control of Viral Infections: Recent Advances and Open Questions

CD4+ T cells orchestrate adaptive immune responses through their capacity to recruit and provide help to multiple immune effectors, in addition to exerting direct effector functions. CD4+ T cells are increasingly recognized as playing an essential role in the control of chronic viral infections. In this review, we present recent advances in understanding the nature of CD4+ T cell help provided to antiviral effectors. Drawing from our studies of natural human immunodeficiency virus (HIV) control, we then focus on the role of high-affinity T cell receptor (TCR) clonotypes in mediating antiviral CD4+ T cell responses. Last, we discuss the role of TCR affinity in determining CD4+ T cell differentiation, reviewing the at times divergent studies associating TCR signal strength to the choice of a T helper 1 (Th1) or a T follicular helper (Tfh) cell fate.     

Viral Infection Modulates Mitochondrial Function

Mitochondria are important organelles involved in metabolism and programmed cell death in eukaryotic cells. In addition, mitochondria are also closely related to the innate immunity of host cells against viruses. The abnormality of mitochondrial morphology and function might lead to a variety of diseases. A large number of studies have found that a variety of viral infections could change mitochondrial dynamics, mediate mitochondria-induced cell death, and alter the mitochondrial metabolic status and cellular innate immune response to maintain intracellular survival. Meanwhile, mitochondria can also play an antiviral role during viral infection, thereby protecting the host. Therefore, mitochondria play an important role in the interaction between the host and the virus. Herein, we summarize how viral infections affect microbial pathogenesis by altering mitochondrial morphology and function and how viruses escape the host immune response.     

Bacterial and Viral Co-Infection in the Intestine: Competition Scenario and Their Effect on Host Immunity

Bacteria and viruses are both important pathogens causing intestinal infections, and studies on their pathogenic mechanisms tend to focus on one pathogen alone. However, bacterial and viral co-infections occur frequently in clinical settings, and infection by one pathogen can affect the severity of infection by another pathogen, either directly or indirectly. The presence of synergistic or antagonistic effects of two pathogens in co-infection can affect disease progression to varying degrees. The triad of bacterial–viral–gut interactions involves multiple aspects of inflammatory and immune signaling, neuroimmunity, nutritional immunity, and the gut microbiome. In this review, we discussed the different scenarios triggered by different orders of bacterial and viral infections in the gut and summarized the possible mechanisms of synergy or antagonism involved in their co-infection. We also explored the regulatory mechanisms of bacterial–viral co-infection at the host intestinal immune interface from multiple perspectives.     

Role of Immune Cells in Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) develops almost entirely in the presence of chronic inflammation. Chronic hepatitis B virus (HBV) infection with recurrent immune-mediated liver damage ultimately leads to cirrhosis and HCC. It is widely accepted that HBV infection induces the dysfunction of the innate and adaptive immune responses that engage various immune cells. Natural killer (NK) cells are associated with early antiviral and antitumor properties. On the other hand, inflammatory cells release various cytokines and chemokines that may promote HCC tumorigenesis. Moreover, immunosuppressive cells such as regulatory T cells (Treg) and myeloid-derived suppressive cells play a critical role in hepatocarcinogenesis. HBV-specific CD8+ T cells have been identified as pivotal players in antiviral responses, whilst extremely activated CD8+ T cells induce enormous inflammatory responses, and chronic inflammation can facilitate hepatocarcinogenesis. Controlling and maintaining the balance in the immune system is an important aspect in the management of HBV-related HCC. We conducted a review of the current knowledge on the immunopathogenesis of HBV-induced inflammation and the role of such immune activation in the tumorigenesis of HCC based on the recent studies on innate and adaptive immune cell dysfunction in HBV-related HCC.     

Interleukin-21 in Viral Infections

Interleukin (IL)-21 is a cytokine that affects the differentiation and function of lymphoid and myeloid cells and regulates both innate and adaptive immune responses. In addition to regulating the immune response to tumor and viral infections, IL-21 also has a profound effect on the development of autoimmune and inflammatory diseases. IL-21 is produced mainly from CD4⁺ T cells—in particular, follicular helper T (Tfh) cells—which have a great influence on the regulation of antibody production. It is also an important cytokine for the activation of CD8⁺ T cells, and its role in recovering the function of CD8⁺ T cells exhausted by chronic microbial infections and cancer has been clarified. Thus, IL-21 plays an extremely important role in viral infections, especially chronic viral infections. In this review, I will introduce the findings to date on how IL-21 is involved in some typical viral infections and the potential of treating viral diseases with IL-21.     

Roles of Infection in Psoriasis

Psoriasis is a chronic, immune-mediated disorder with cutaneous and systemic manifestations. Genetic predisposition, environmental factors, and immune dysfunction all contribute to the pathogenesis of psoriasis with host-microbe interaction governing the progression of this disease. Emerging evidence has indicated that infection is an environmental trigger for psoriasis and plays multiple roles in its maintenance as evidenced by the frequent association between guttate psoriasis onset and acute streptococcal infection. Different infectious factors act on immune cells to produce inflammatory cytokines that can induce or aggravate psoriasis. In addition to bacterial infections, viral and fungal infections have also been shown to be strongly associated with the onset or exacerbation of psoriasis. Intervention of skin microbiota to treat psoriasis has become a hot research topic. In this review, we summarize the effects of different infectious factors (bacteria, viruses, and fungi) on psoriasis, thereby providing insights into the manipulation of pathogens to allow for the identification of improved therapeutic options for the treatment of this condition.     

Antiviral Effects of Animal Toxins: Is There a Way to Drugs?

Viruses infect all types of organisms, causing viral diseases, which are very common in humans. Since viruses use the metabolic pathways of their host cells to replicate, they are difficult to eradicate without affecting the cells. The most effective measures against viral infections are vaccinations and antiviral drugs, which selectively inhibit the viral replication cycle. Both methods have disadvantages, which requires the development of new approaches to the treatment of viral diseases. In the study of animal venoms, it was found that, in addition to toxicity, venoms exhibit other types of biological activity, including an antiviral one, the first mention of which dates back to middle of the last century, but detailed studies of their antiviral activity have been conducted over the past 15 years. The COVID-19 pandemic has reinforced these studies and several compounds with antiviral activity have been identified in venoms. Some of them are very active and can be considered as the basis for antiviral drugs. This review discusses recent antiviral studies, the found compounds with high antiviral activity, and the possible mechanisms of their action. The prospects for using the animal venom components to create antiviral drugs, and the expected problems and possible solutions are also considered.     

CD85k Contributes to Regulatory T Cell Function in Chronic Viral Infections

Regulatory T cells (Tregs) prevent excessive immune responses and limit immune pathology upon infections. To fulfill this role in different immune environments elicited by different types of pathogens, Tregs undergo functional specialization into distinct subsets. During acute type 1 immune responses, type 1 Tregs are induced and recruited to the site of ongoing Th1 responses to efficiently control Th1 responses. However, whether a similar specialization process also takes place following chronic infections is still unknown. In this study, we investigated Treg specialization in persistent viral infections using lymphocytic choriomeningitis virus (LCMV) and murine cytomegalovirus (MCMV) infection as models for chronic and latent infections, respectively. We identify CD85k as a Th1-specific co-inhibitory receptor with sustained expression in persistent viral infections and show that recombinant CD85k inhibits LCMV-specific effector T cells. Furthermore, expression of the CD85k ligand ALCAM is induced on LCMV-specific and exhausted T cells during chronic LCMV infection. Finally, we demonstrate that type 1 Tregs arising during chronic LCMV infection suppress Th1 effector cells in an ALCAM-dependent manner. These results extend the current knowledge of Treg specialization from acute to persistent viral infections and reveal an important functional role of CD85k in Treg-mediated suppression of type 1 immunity.     

Malnutrition and Dietary Habits Alter the Immune System Which May Consequently Influence SARS-CoV-2 Virulence: A Review

COVID-19, resulting from the SARS-CoV-2 virus, is a major pandemic that the world is fighting. SARS-CoV-2 primarily causes lung infection by attaching to the ACE2 receptor on the alveolar epithelial cells. However, the ACE2 receptor is also present in intestinal epithelial cells, suggesting a link between nutrition, virulence and clinical outcomes of COVID-19. Respiratory viral infections perturb the gut microbiota. The gut microbiota is shaped by our diet; therefore, a healthy gut is important for optimal metabolism, immunology and protection of the host. Malnutrition causes diverse changes in the immune system by repressing immune responses and enhancing viral vulnerability. Thus, improving gut health with a high-quality, nutrient-filled diet will improve immunity against infections and diseases. This review emphasizes the significance of dietary choices and its subsequent effects on the immune system, which may potentially impact SARS-CoV-2 vulnerability.     

Role of Selenium in Viral Infections with a Major Focus on SARS-CoV-2

Viral infections have afflicted human health and despite great advancements in scientific knowledge and technologies, continue to affect our society today. The current coronavirus (COVID-19) pandemic has put a spotlight on the need to review the evidence on the impact of nutritional strategies to maintain a healthy immune system, particularly in instances where there are limited therapeutic treatments. Selenium, an essential trace element in humans, has a long history of lowering the occurrence and severity of viral infections. Much of the benefits derived from selenium are due to its incorporation into selenocysteine, an important component of proteins known as selenoproteins. Viral infections are associated with an increase in reactive oxygen species and may result in oxidative stress. Studies suggest that selenium deficiency alters immune response and viral infection by increasing oxidative stress and the rate of mutations in the viral genome, leading to an increase in pathogenicity and damage to the host. This review examines viral infections, including the novel SARS-CoV-2, in the context of selenium, in order to inform potential nutritional strategies to maintain a healthy immune system.     

Phages and HIV-1: From Display to Interplay

The complex hide-and-seek game between HIV-1 and the host immune system has impaired the development of an efficient vaccine. In addition, the high variability of the virus impedes the long-term control of viral replication by small antiviral drugs. For more than 20 years, phage display technology has been intensively used in the field of HIV-1 to explore the epitope landscape recognized by monoclonal and polyclonal HIV-1-specific antibodies, thereby providing precious data about immunodominant and neutralizing epitopes. In parallel, biopanning experiments with various combinatorial or antibody fragment libraries were conducted on viral targets as well as host receptors to identify HIV-1 inhibitors. Besides these applications, phage display technology has been applied to characterize the enzymatic specificity of the HIV-1 protease. Phage particles also represent valuable alternative carriers displaying various HIV-1 antigens to the immune system and eliciting antiviral responses. This review presents and summarizes the different studies conducted with regard to the nature of phage libraries, target display mode and biopanning procedures.     

The Role of Chemokines in Hepatitis C Virus-Mediated Liver Disease

The hepatitis C virus (HCV) is a global health problem affecting more than 170 million people. A chronic HCV infection is associated with liver fibrosis, liver cirrhosis and hepatocellular carcinoma. To enable viral persistence, HCV has developed mechanisms to modulate both innate and adaptive immunity. The recruitment of antiviral immune cells in the liver is mainly dependent on the release of specific chemokines. Thus, the modulation of their expression could represent an efficient viral escape mechanism to hamper specific immune cell migration to the liver during the acute phase of the infection. HCV-mediated changes in hepatic immune cell chemotaxis during the chronic phase of the infection are significantly affecting antiviral immunity and tissue damage and thus influence survival of both the host and the virus. This review summarizes our current understanding of the HCV-mediated modulation of chemokine expression and of its impact on the development of liver disease. A profound knowledge of the strategies used by HCV to interfere with the host’s immune response and the pro-fibrotic and pro-carcinogenic activities of HCV is essential to be able to design effective immunotherapies against HCV and HCV-mediated liver diseases.