The role, relevance and management of immune exhaustion in bovine infectious diseases.

Immune exhaustion is a state of immune cell dysfunction that occurs most commonly following chronic exposure to an antigen which persists after the immune response fails to remove it. Exhaustion has been studied most thoroughly with several cancers, but has also been observed in several chronic infectious diseases. The topic has mainly been studied with CD8+ T cells, but it can also occur with CD4+ T cells and other immune cell types too. Exhaustion is characterized by a hierarchical loss of effector cell functions, up-regulation of immuno-inhibitory receptors, disruption of metabolic activities, and altered chromatin landscapes. Exhaustion has received minimal attention so far in diseases of veterinary significance and this review's purpose is to describe examples where immune exhaustion is occurring in several bovine disease situations. We also describe methodology to evaluate immune exhaustion as well as the prospects of controlling exhaustion and achieving a more suitable outcome of therapy in some chronic disease scenarios.

Meeting the Challenge of Controlling Viral Immunopathology.

The mission of this review is to identify immune-damaging participants involved in antiviral immunoinflammatory lesions. We argue these could be targeted and their activity changed selectively by maneuvers that, at the same time, may not diminish the impact of components that help resolve lesions. Ideally, we need to identify therapeutic approaches that can reverse ongoing lesions that lack unwanted side effects and are affordable to use. By understanding the delicate balance between immune responses that cause tissue damage and those that aid in resolution, novel strategies can be developed to target detrimental immune components while preserving the beneficial ones. Some strategies involve rebalancing the participation of immune components using various approaches, such as removing or blocking proinflammatory T cell products, expanding regulatory cells, restoring lost protective cell function, using monoclonal antibodies (moAb) to counteract inhibitory molecules, and exploiting metabolic differences between inflammatory and immuno-protective responses. These strategies can help reverse ongoing viral infections. We explain various approaches, from model studies and some clinical evidence, that achieve innate and adaptive immune rebalancing, offering insights into potential applications for controlling chronic viral-induced lesions.

Adverse effect of VEGFR-2 (rs1870377) polymorphism on the clinical course of COVID-19 in females and males in an age-dependent manner.

The COVID-19 pandemic has affected people worldwide with varying clinical presentations ranging from mild to severe or fatal, and studies have found that age, gender, and some comorbidities can influence the severity of the disease. It would be valuable to have genetic markers that might help predict the likely outcome of infection. For this objective, genes encoding VEGFR-2 (rs1870377), CCR5Δ32 (rs333), and TLR3 (rs5743313) were analyzed for polymorphisms in the peripheral blood of 160 COVID-19 patients before COVID-19 vaccine was available in Türkiye. We observed that possession of the VEGFR-2 rs1870377 mutant allele increased the risk of severe/moderate disease in females and subjects ≥65 years of age, but was protective in males <65 years of age. Other significant results were that the CCR5Δ32 allele was protective against severe disease in subjects ≥65 years of age, while TLR3 rs5743313 polymorphism was found to be protective against severe/moderate illness in males <65 years of age. The VEGFR-2 rs1870377 mutant allele was a risk factor for severe/moderate disease, particularly in females over the age of 65. These findings suggest that genetic polymorphisms have an age- and sex-dependent influence on the severity of COVID-19, and the VEGFR-2 rs1870377 mutant allele could be a potential predictor of disease severity.

Controlling viral inflammatory lesions by inhibiting fatty acid metabolism.

Herpes simplex virus infection is a major cause of vision loss in humans. Eye damaging consequences are often driven by inflammatory cells as a result of an immune response to the virus. In the present report, we have compared the effect of inhibiting energy metabolism with etomoxir (Etox), which acts on the fatty acid oxidation pathway and 2-Deoxy-d-glucose (2DG), which acts on glycolysis for their inhibitory effects on herpetic ocular lesions. Both drugs showed similar protective effects when therapy was started on the day of infection, but some 2DG recipients succumbed to encephalitis. In contrast, all Etox recipients remained healthy. Both drugs were compared for effects on inflammatory reactions in the trigeminal ganglion (TG), where virus replicates and then establishes latency. Results indicate that 2DG significantly reduced CD8 and CD4 Th1 T cells in the TG, whereas Etox had minimal or no effect on such cells, perhaps explaining why encephalitis occurred only in 2DG recipients. Unlike treatment with 2DG, Etox therapy was largely ineffective when started at the time of lesion expression. Reasons for the differential effects were discussed as was the relevance of combining metabolic reprogramming approaches to combat viral inflammatory lesions.

Role of Innate Interferon Responses at the Ocular Surface in Herpes Simplex Virus-1-Induced Herpetic Stromal Keratitis.

Herpes simplex virus type 1 (HSV-1) is a highly successful pathogen that primarily infects epithelial cells of the orofacial mucosa. After initial lytic replication, HSV-1 enters sensory neurons and undergoes lifelong latency in the trigeminal ganglion (TG). Reactivation from latency occurs throughout the host's life and is more common in people with a compromised immune system. HSV-1 causes various diseases depending on the site of lytic HSV-1 replication. These include herpes labialis, herpetic stromal keratitis (HSK), meningitis, and herpes simplex encephalitis (HSE). HSK is an immunopathological condition and is usually the consequence of HSV-1 reactivation, anterograde transport to the corneal surface, lytic replication in the epithelial cells, and activation of the host's innate and adaptive immune responses in the cornea. HSV-1 is recognized by cell surface, endosomal, and cytoplasmic pattern recognition receptors (PRRs) and activates innate immune responses that include interferons (IFNs), chemokine and cytokine production, as well as the recruitment of inflammatory cells to the site of replication. In the cornea, HSV-1 replication promotes type I (IFN-α/ß) and type III (IFN-λ) IFN production. This review summarizes our current understanding of HSV-1 recognition by PRRs and innate IFN-mediated antiviral immunity during HSV-1 infection of the cornea. We also discuss the immunopathogenesis of HSK, current HSK therapeutics and challenges, proposed experimental approaches, and benefits of promoting local IFN-λ responses.

Can the triumph of mRNA vaccines against COVID-19 be extended to other viral infections of humans and domesticated animals?

The unprecedented success of mRNA vaccines in managing the COVID-19 pandemic raises the prospect of applying the mRNA platform to other viral diseases of humans and domesticated animals, which may lead to more efficacious vaccines for some agents. We briefly discuss reasons why mRNA vaccines achieved such success against COVID-19 and indicate what other virus infections and disease conditions might also be ripe for control using mRNA vaccines. We also evaluate situations where mRNA could prove valuable to rebalance the status of immune responsiveness and achieve success as a therapeutic vaccine approach against infections that induce immunoinflammatory lesions.

Controlling Herpes Simplex Virus-Induced Immunoinflammatory Lesions Using Metabolic Therapy: a Comparison of 2-Deoxy-d-Glucose with Metformin.

Herpes simplex virus (HSV) infection of the eye can result in a blinding immunoinflammatory lesion in the cornea called herpetic stromal keratitis (HSK). This lesion is orchestrated by T cells and can be reduced in magnitude by anti-inflammatory drugs and procedures that change the balance of cellular participants in lesions. This report evaluates the effect of drugs that cause metabolic reprogramming on lesion expression using two drugs that affect glucose metabolism: 2-deoxy-d-glucose (2DG) and metformin. Both drugs could limit HSK severity, but 2DG therapy could result in herpes encephalitis if used when replicating virus was still present. The reason metformin was a safer therapy was its lack of marked inhibitory effects on inflammatory cells particularly interferon-γ (IFN-γ)-producing Th1 and CD8 T cells in the trigeminal ganglion (TG), in which HSV latency is established and sustained. Additionally, whereas 2DG in TG cultures with established latency accelerated the termination of latency, this did not occur in the presence of metformin, likely because the inflammatory cells remained functional. Our results support the value of metabolic reprogramming to control viral immunoinflammatory lesions, but the approach used should be chosen with caution. IMPORTANCE Herpes simplex virus (HSV) infection of the eye is an example where damaging lesions are in part the consequence of a host response to the infection. Moreover, it was shown that changing the representation of cellular participants in the inflammatory reaction can minimize lesion severity. This report explores the value of metabolic reprogramming using two drugs that affect glucose metabolism to achieve cellular rebalancing. It showed that two drugs, 2-deoxy-d-glucose (2DG) and metformin, effectively diminished ocular lesion expression, but only metformin avoided the complication of HSV spreading to the central nervous system (CNS) and causing herpetic encephalitis. The report provides some mechanistic explanations for the findings.

Fraternal Twins: The Enigmatic Role of the Immune System in Alphaherpesvirus Pathogenesis and Latency and Its Impacts on Vaccine Efficacy.

Although the establishment, maintenance and reactivation from alphaherpesvirus latency is far from fully understood, some things are now manifestly clear: Alphaherpesvirus latency occurs in neurons of the peripheral nervous system and control of the process is multifactorial and complex. This includes components of the immune system, contributions from non-neuronal cells surrounding neurons in ganglia, specialized nucleic acids and modifications to the viral DNA to name some of the most important. Efficacious vaccines have been developed to control both acute varicella and zoster, the outcome of reactivation, but despite considerable effort vaccines for acute herpes simplex virus (HSV) infection or reactivated lesions have thus far failed to materialize despite considerable effort. Given the relevance of the immune system to establish and maintain HSV latency, a vaccine designed to tailor the HSV response to maximize the activity of components most critical for controlling reactivated infection might limit the severity of recurrences and hence reduce viral transmission. In this review, we discuss the current understanding of immunological factors that contribute to HSV and VZV latency, identify differences between varicella-zoster virus (VZV) and HSV that could explain why vaccines have been valuable at controlling VZV disease but not HSV, and finish by outlining possible strategies for developing effective HSV vaccines.

Controlling the Burden of COVID-19 by Manipulating Host Metabolism.

The coronavirus disease 2019 (COVID-19) pandemic caused by the coronavirus-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to cause global health problems, but its impact would be minimized if the many effective vaccines that have been developed were available and in widespread use by all societies. This ideal situation is not occurring so other means of controlling COVID-19 are needed. In this short review, we make the case that manipulating host metabolic pathways could be a therapeutic approach worth exploring. The rationale for such an approach comes from the fact that viruses cause metabolic changes in cells they infect, effective host defense mechanisms against viruses requires the activity of one or more metabolic pathways, and that hosts with metabolic defects such as diabetes are more susceptible to severe consequences after COVID-19. We describe the types of approaches that could be used to redirect various aspects of host metabolism and the success that some of these maneuvers have had at controlling other virus infections. Manipulating metabolic activities to control the outcome of COVID-19 has to date received minimal attention. Manipulating host metabolism will never replace vaccines to control COVID-19 but could be used as an adjunct therapy to the extent of ongoing infection.

Did Climate Change Influence the Emergence, Transmission, and Expression of the COVID-19 Pandemic?

The human race has survived many epidemics and pandemics that have emerged and reemerged throughout history. The novel coronavirus Severe Acute Respiratory Syndrome SARS-CoV-2/COVID-19 is the latest pandemic and this has caused major health and socioeconomic problems in almost all communities of the world. The origin of the virus is still in dispute but most likely, the virus emerged from the bats and also may involve an intermediate host before affecting humans. Several other factors also may have affected the emergence and outcome of the infection but in this review, we make a case for a possible role of climate change. The rise in industrialization-related human activities has created a marked imbalance in the homeostasis of environmental factors such as temperature and other weather and these might even have imposed conditions for the emergence of future coronavirus cycles. An attempt is made in this review to explore the effect of ongoing climate changes and discuss if these changes had a role in facilitating the emergence, transmission, and even the expression of the COVID-19 pandemic. We surmise that pandemics will be more frequent in the future and more severely impactful unless climate changes are mitigated.

Modulating glutamine metabolism to control viral immuno-inflammatory lesions.

Infection of the cornea with HSV results in an immune-inflammatory reaction orchestrated by proinflammatory T cells that is a major cause of human vision impairment. The severity of lesions can be reduced if the representation of inflammatory T cells is changed to increase the presence of T cells with regulatory function. This report shows that inhibiting glutamine metabolism using 6-Diazo-5-oxo-l-norleucine (DON) administered via intraperitoneal (IP) starting 6 days after ocular infection and continued until day 15 significantly reduced the severity of herpetic stromal keratitis lesions. The therapy resulted in reduced neutrophils, macrophages as well proinflammatory CD4 Th1 and Th17 T cells in the cornea, but had no effect on levels of regulatory T cells. A similar change in the representation of inflammatory and regulatory T cells occurred in the trigeminal ganglion (TG) the site where HSV infection establishes latency. Glutamine metabolism was shown to be required for the in-vitro optimal induction of both Th1 and Th17 T cells but not for the induction of Treg that were increased when glutamine metabolism was inhibited. Inhibiting glutamine metabolism also changed the ability of latently infected TG cells from animals previously infected with HSV to reactivate and produce infectious virus.

Inhibiting Glucose Metabolism Results in Herpes Simplex Encephalitis.

This report evaluates how HSV enters the brain to cause herpes simplex encephalitis following infection at a peripheral site. We demonstrate that encephalitis regularly occurred when BALB/c mice were infected with HSV and treated daily with 2-deoxy-d-glucose (2DG), which inhibits glucose use via the glycolysis pathway. The outcome of infection in the trigeminal ganglion (TG), the site to which the virus spreads, replicates, and establishes latency, showed marked differences in viral and cellular events between treated and untreated animals. In control-untreated mice, the replicating virus was present only during early time points, whereas in 2DG recipients, replicating virus remained for the 9-d observation period. This outcome correlated with significantly reduced numbers of innate inflammatory cells as well as T cells in 2DG-treated animals. Moreover, T cells in the TG of treated animals were less activated and contained a smaller fraction of expressed IFN-γ production compared with untreated controls. The breakdown of latency was accelerated when cultures of TG cells taken from mice with established HSV latency were cultured in the presence of 2DG. Taken together, the results of both in vivo and in vitro investigations demonstrate that the overall effects of 2DG therapy impaired the protective effects of one or more inflammatory cell types in the TG that normally function to control productive infection and prevent spread of virus to the brain.

Climate change: how it impacts the emergence, transmission, resistance and consequences of viral infections in animals and plants.

The ongoing COVID-19 pandemic has made us wonder what led to its occurrence and what can be done to avoid such events in the future. As we document, one changing circumstance that is resulting in the emergence and changing the expression of viral diseases in both plants and animals is climate change. Of note, the rapidly changing environment and weather conditions such as excessive flooding, droughts, and forest fires have raised concerns about the global ecosystem's security, sustainability, and balance. In this review, we discuss the main consequences of climate change and link these to how they impact the appearance of new viral pathogens, how they may facilitate transmission between usual and novel hosts, and how they may also affect the host's ability to manage the infection. We emphasize how changes in temperature and humidity and other events associated with climate change influence the reservoirs of viral infections, their transmission by insects and other intermediates, their survival outside the host as well the success of infection in plants and animals. We conclude that climate change has mainly detrimental consequences for the emergence, transmission, and outcome of viral infections and plead the case for halting and hopefully reversing this dangerous event.

COVID-19: disease, or no disease? - that is the question. It's the dose stupid!

The COVID-19 pandemic has raised many issues not the least of which is the reason for its high variability in consequences to the infected person. In this opinion letter, we advocate that the dose and presentation of the infecting virus is a major factor that affects whether the outcome is subclinical, tissue damaging or even lethal following infection. We briefly describe the known effects of virus dose on the course COVID-19 and discuss practical maneuvers as well as largely untested procedures that can raise the threshold dose needed to break through barriers of resistance.

Could targeting immunometabolism be a way to control the burden of COVID-19 infection?

This review portrays the metabolic consequences of Covid-19 infection at different stages of the clinical syndrome. It also describes how events can change when patients with metabolic problems are infected and the effects that diet and nutrition might play to influence the outcome of infection. We also discuss the types of maneuvers that could be used to reshape metabolic events and question if this approach could be a practical therapy used alone or in combination with other approaches to reduce the burden of Covid-19 infection.

Supplementing the Diet with Sodium Propionate Suppresses the Severity of Viral Immuno-inflammatory Lesions.

This report evaluates a dietary manipulation approach to suppress the severity of ocular infections caused by herpes simplex virus infection. The virus causes chronic damage to the cornea that results from a T-cell-orchestrated inflammatory reaction to the infection. Lesion severity can be limited if cells with regulatory activity predominate over proinflammatory T cells and nonlymphoid inflammatory cells. In this report, we show that this outcome can be achieved by including the short-chain fatty acid (SCFA) salt sodium propionate (SP) in the drinking water. Animals given the SP supplement developed significantly fewer ocular lesions than those receiving no supplement. Corneas and lymphoid organs contained fewer CD4 Th1 and Th17 T cells, neutrophils, and macrophages than those of controls, but a higher frequency of regulatory T cells (Treg) was present. The inclusion of SP in cultures to induce CD4 T cell subsets in vitro reduced the magnitude of Th1 and Th17 responses but expanded Treg induction. Dietary manipulation was an effective approach to limit the severity of viral immuno-inflammatory lesions and may be worth exploring as a means to reduce the impact of herpetic lesions in humans.IMPORTANCE Herpetic lesions are a significant problem, and they are difficult to control with therapeutics. Our studies show that the severity of herpetic lesions in a mouse model can be diminished by changing the diet to include increased levels of SCFA, which act to inhibit the involvement of inflammatory T cells. We suggest that changing the diet to include higher levels of SCFA might be a useful approach to reducing the impact of recurrent herpetic lesions in humans.

Perspective: Reducing SARS-CoV2 Infectivity and Its Associated Immunopathology.

COVID-19 has become difficult to contain in our interconnected world. In this article, we discuss some approaches that could reduce the consequences of COVID-19. We elaborate upon the utility of camelid single-domain antibodies (sdAbs), also referred to as nanobodies, which are naturally poised to neutralize viruses without enhancing its infectivity. Smaller sized sdAbs can be easily selected using microbes or the subcellular organelle display methods and can neutralize SARS-CoV2 infectivity. We also discuss issues related to their production using scalable platforms. The favorable outcome of the infection is evident in patients when the inflammatory response is adequately curtailed. Therefore, we discuss approaches to mitigate hyperinflammatory reactions initiated by SARS-CoV2 but orchestrated by immune mediators.

Determinants of Tissue-Specific Metabolic Adaptation of T Cells.

Metabolic reprogramming is a hallmark of T cell activation and function. As our understanding of T cell metabolism increases, so does our appreciation of its inherent complexity. The metabolic heterogeneity of T cells that reside in different locations, such as lymphoid and non-lymphoid tissues, presents a challenge to developing therapies that exploit metabolic vulnerabilities. The roots of metabolic heterogeneity are only beginning to be understood. Here, we propose four factors that contribute to the adaptation of T cells to their dynamic tissue environment: (1) functional status of T cells, (2) local factors unique to the tissue niche, (3) type of inflammation, and (4) time spent in a specific tissue. We review emerging concepts about tissue-specific metabolic reprogramming in T cells with particular attention to explain how such metabolic properties are used as an adaptation mechanism. Adaptation of immune cells to the local microenvironment is critical for their persistence and function. Here, Varanasi et al. review the role and types of metabolic adaptation acquired by T cells in tissues and how these adaptations might differ between tissue type, disease state, and functionality of a T cell.

Does the hygiene hypothesis apply to COVID-19 susceptibility?

In this commentary we argue that the hygiene hypothesis may apply to COVID-19 susceptibility and also that residence in low hygienic conditions acts to train innate immune defenses to minimize the severity of infection. We advocate that approaches, which elevate innate immune functions, should be used to minimize the consequences of COVID-19 infection at least until effective vaccines and antiviral therapies are developed.