Memory CD8+ T Cells Are Sufficient To Alleviate Impaired Host Resistance to Influenza A Virus Infection Caused by Neonatal Oxygen Supplementation

Supplemental oxygen administered to preterm infants is an important clinical intervention, but it is associated with life-long changes in lung development and increased sensitivity to respiratory viral infections. The precise immunological changes caused by neonatal oxygen treatment remain poorly understood. We previously reported that adult mice exposed to supplemental oxygen as neonates display persistent pulmonary inflammation and enhanced mortality after a sublethal influenza A virus infection. These changes suggest that neonatal hyperoxia impairs the cytotoxic CD8(+) T cell response required to clear the virus. In this study, we show that although host resistance to several different strains of influenza A virus is reduced by neonatal hyperoxia, this treatment does not impair viral clearance, nor does it alter the magnitude of the virus-specific CD8(+) T cell response to primary infection. Moreover, memory T cells are sufficient to ameliorate the increased morbidity and mortality and alleviate the excessive lung damage observed in mice exposed to high oxygen levels as neonates, and we attribute this sufficiency principally to virus-specific memory CD8(+) T cells. Thus, we show that neonatal hyperoxia reduces host resistance to influenza virus infection without diminishing the function of cytotoxic T lymphocytes or the generation of virus-specific memory T cells and that CD8(+) memory T cells are sufficient to provide protection from negative consequences of this important life-saving intervention. Our findings suggest that vaccines that generate robust T cell memory may be efficacious at reducing the increased sensitivity to respiratory viral infections in people born prematurely.     

IL-36 receptor deletion attenuates lung injury and decreases mortality in murine influenza pneumonia

Influenza virus causes a respiratory disease in humans that can progress to lung injury with fatal outcome. The interleukin (IL)-36 cytokines are newly described IL-1 family cytokines that promote inflammatory responses via binding to the IL-36 receptor (IL-36R). The mechanism of expression and the role of IL-36 cytokines are poorly understood. Here, we investigated the role of IL-36 cytokines in modulating the innate inflammatory response during influenza virus-induced pneumonia in mice. The intranasal administration of influenza virus upregulated IL-36α mRNA and protein production in the lungs. In vitro, influenza virus-mediated IL-36α but not IL-36γ is induced and secreted from alveolar epithelial cells (AECs) through both a caspase-1 and caspase-3/7 dependent pathway. IL-36α was detected in microparticles shed from AECs and promoted the production of pro-inflammatory cytokines and chemokines in respiratory cells. IL-36R-deficient mice were protected from influenza virus-induced lung injury and mortality. Decreased mortality was associated with significantly reduced early accumulation of neutrophils and monocytes/macrophages, activation of lymphocytes, production of pro-inflammatory cytokines and chemokines, and permeability of the alveolar–epithelial barrier in despite impaired viral clearance. Taken together, these data indicate that IL-36 ligands exacerbate lung injury during influenza virus infection.     

Pharmacologic activation of the innate immune system to prevent respiratory viral infections

Drugs that can rapidly inhibit respiratory infection from influenza or other respiratory pathogens are needed. One approach is to engage primary innate immune defenses against viral infection, such as activating the IFN pathway. In this study, we report that a small, cell-permeable compound called 5,6-di-methylxanthenone-4-acetic acid (DMXAA) can induce protection against vesicular stomatitis virus in vitro and H1N1 influenza A virus in vitro and in vivo through innate immune activation. Using the mouse C10 bronchial epithelial cell line and primary cultures of nasal epithelial cells, we demonstrate DMXAA activates the IFN regulatory factor-3 pathway leading to production of IFN-β and subsequent high-level induction of IFN-β-dependent proteins, such as myxovirus resistance 1 (Mx1) and 2',5'-oligoadenylate synthetase 1 (OAS1). Mice treated with DMXAA intranasally elevate mRNA/protein expression of Mx1 and OAS1 in the nasal mucosa, trachea, and lung. When challenged intranasally with a lethal dose of H1N1 influenza A virus, DMXAA reduced viral titers in the lungs and protected 80% of mice from death, even when given at 24 hours before infection. These data show that agents, like DMXAA, that can directly activate innate immune pathways, such as the IFN regulatory factor-3/IFN-β system, in respiratory epithelial cells can be used to protect from influenza pneumonia and potentially in other respiratory viral infections. Development of this approach in humans could be valuable for protecting health care professionals and "first responders" in the early stages of viral pandemics or bioterror attacks.     

Replication of parainfluenza (Sendai) virus in isolated rat pulmonary type II alveolar epithelial cells.

The major objectives of this study were to determine whether alveolar type II epithelial cells isolated from rat lung and maintained in tissue culture would support productive replication of parainfluenza type 1 (Sendai) virus and to determine whether isolated type II cells from neonatal (5-day-old) rats that are more susceptible to viral-induced alveolar dysplasia supported viral replication to a greater extent than those from weanling (25-day-old) rats. Isolated and cultured type II cells from neonatal and weanling rats that were inoculated with Sendai virus supported productive replication as indicated by ultrastructural identification of budding virions and viral nucleocapsids in type II cells and by demonstration of rising titers of infectious virus from inoculated type II cell cultures. Alveolar macrophages from neonatal and weanling rats also supported viral replication, although infectious viral titers in macrophage cultures were lower than those from type II cell cultures. Only minor differences were detected between viral titers from neonatal and weanling type II epithelial cell cultures. Higher densities of viral nucleocapsids were observed in neonatal type II cells than in those from weanling rats. The results indicate that isolated type II alveolar epithelial cells support productive replication of parainfluenza virus and that type II cells are probably more efficient in supporting productive viral replication than are alveolar macrophages.     

Influenza A virus abrogates IFN-gamma response in respiratory epithelial cells by disruption of the Jak/Stat pathway

The innate immunity to viral infections induces a potent antiviral response mediated by interferons (IFN). Although IFN-gamma is detected during the acute stages of illness in the upper respiratory tract secretions and in the serum of influenza A virus-infected individuals, control of influenza A virus is not dependent upon IFN-gamma as evidenced by studies using anti-IFN-gamma Ab and IFN-gamma(-/-) mice. Thus, we hypothesized that IFN-gamma is not critical in host survival because influenza A virus has mechanisms to evade the antiviral activity of IFN-gamma. To test this, A549 cells, an epithelial cell line derived from lung adenocarcinoma, were infected with influenza virus strain A/Aichi/2/68 (H3N2) (Aichi) and/or stimulated with IFN-gamma to detect IFN-gamma-stimulated MHC class II expression. Influenza A virus infection inhibited IFN-gamma-induced up-regulation of HLA-DRalpha mRNA and the IFN-gamma induction of class II transactivator (CIITA), an obligate mediator of MHC class II expression. Nuclear translocation of Stat1alpha upon IFN-gamma stimulation was significantly inhibited in influenza A virus-infected cells and this was associated with a decrease in Tyr701 and Ser727 phosphorylation of Stat1alpha. Thus, influenza A virus subverts antiviral host defense mediated by IFN-gamma through effects on the intracellular signaling pathways.     

Cigarette smoking and innate immune responses to influenza infection

Cigarette smoking(CS) suppresses the immune system, and smoking is a well-known major risk factor for respiratory tract infections, including influenza infection. Both smoking cigarettes and passive smoking alter a wide range of immunological functions, including innate and adaptive immune responses. Past reviews on CS and innate immunity have been focused on the effects of CS on structural changes of the lung, as well as the effects on the function of alveolar macrophages, leukocytes, natural killer cells and dendritic cells. The study of innate immunity has developed rapidly in the last decade with the discovery of new receptors for virus recognition and interferon responses. This review aims to give a brief summary of recent findings on the suppressive effects of CS on the innate response to influenza virus, especially as it pertains to suppression of the function of pattern recognition receptors for influ-enza virus.     

Innate immunity to influenza virus: implications for future therapy

Innate immunity is critical in the early containment of influenza virus infection. The innate response is surprisingly complex. A variety of soluble innate inhibitors in respiratory secretions provide an initial barrier to infection. Dendritic cells, phagocytes and natural killer cells mediate viral clearance and promote further innate and adaptive responses. Toll-like receptors 3 and 7 and cytoplasmic RNA sensors are critical for activating these responses. In general, the innate response restricts viral replication without injuring the lung; however, the 1918 pandemic and H5N1 strains cause more profound, possibly harmful, innate responses. In this review, we discuss the implications of burgeoning knowledge of innate immunity for therapy of influenza.     

Excessive neutrophil levels in the lung underlie the age-associated increase in influenza mortality

Neutrophils clear viruses, but excessive neutrophil responses induce tissue injury and worsen disease. Aging increases mortality to influenza infection; however, whether this is due to impaired viral clearance or a pathological host immune response is unknown. Here we show that aged mice have higher levels of lung neutrophils than younger mice after influenza viral infection. Depleting neutrophils after, but not before, infection substantially improves the survival of aged mice without altering viral clearance. Aged alveolar epithelial cells (AECs) have a higher frequency of senescence and secrete higher levels of the neutrophil-attracting chemokines CXCL1 and CXCL2 during influenza infection. These chemokines are required for age-enhanced neutrophil chemotaxis in vitro. Our work suggests that aging increases mortality from influenza in part because senescent AECs secrete more chemokines, leading to excessive neutrophil recruitment. Therapies that mitigate this pathological immune response in the elderly might improve outcomes of influenza and other respiratory infections.     

Critical Roles of Inflammation and Apoptosis in Improved Survival in a Model of Hyperoxia-Induced Acute Lung Injury in Pneumocystis murina-Infected Mice

Pneumocystis infections increase host susceptibility to additional insults that would be tolerated in the absence of infection, such as hyperoxia. In an in vivo model using CD4-depleted mice, we previously demonstrated that Pneumocystis murina pneumonia causes significant mortality following an otherwise nonlethal hyperoxic insult. Infected mice demonstrated increased pulmonary inflammation and alveolar epithelial cell apoptosis compared to controls. To test the mechanisms underlying these observations, we examined expression of components of the Fas-Fas ligand pathway in P. murina-infected mice exposed to hyperoxia. Hyperoxia alone increased expression of Fas on the surface of type II alveolar epithelial cells; conversely, infection with P. murina led to increased lung expression of Fas ligand. We hypothesized that inhibition of inflammatory responses or direct inhibition of alveolar epithelial cell apoptosis would improve survival in P. murina-infected mice exposed to hyperoxia. Mice were depleted of CD4⁺ T cells and infected with P. murina and then were exposed to >95% oxygen for 4 days, followed by return to normoxia. Experimental groups received vehicle, dexamethasone, or granulocyte-macrophage colony-stimulating factor (GM-CSF). Compared with the vehicle-treated group, treatment with dexamethasone reduced Fas ligand expression and significantly improved survival. Similarly, treatment with GM-CSF, an agent we have shown protects alveolar epithelial cells against apoptosis, decreased Fas ligand expression and also improved survival. Our results suggest that the dual stresses of P. murina infection and hyperoxia induce lung injury via activation of the Fas-Fas ligand pathway and that corticosteroids and GM-CSF reduce mortality in P. murina-infected mice exposed to hyperoxic stress by inhibition of inflammation and apoptosis.Pneumocystis jirovecii infections remain a significant cause of morbidity and mortality in immunosuppressed individuals, including individuals with human immunodeficiency virus (HIV) infection and those receiving immunosuppressive therapy (27). Despite prompt institution of appropriate antibiotic therapy, a significant number of patients experience clinical deterioration and respiratory failure after hospital admission. The pathophysiologic mechanisms leading to deterioration in some patients have not been defined. Treatment with corticosteroids has become the standard of care for moderate to severe P. jirovecii pneumonia in patients with AIDS and has been found to decrease the rate of posthospitalization progression to respiratory failure (2, 7, 13, 22). Presumably, the beneficial effects of corticosteroids are mediated by blunting of the patients'' pulmonary inflammatory responses, but the mechanisms by which this improvement occurs are not understood.In previous work, we hypothesized that a secondary stress triggers respiratory failure in patients with P. jirovecii pneumonia (5). This secondary insult likely triggers an inflammatory response that results in detrimental effects to the host. Among potential triggers (acting alone or in combination) are drug effects, coincident bacterial infections, and supplemental oxygen therapy. We reasoned that oxidant stress might be a common mechanism precipitating progression to respiratory failure. To date, prospective or retrospective analysis of oxygen therapy as an independent predictor or respiratory failure has not been possible in patients with P. jirovecii pneumonia, with or without corticosteroid therapy. Therefore, we have used an animal model to test this concept. We previously developed a model in which mice were depleted of CD4⁺ T cells, infected with P. murina, and then exposed to a limited period of hyperoxia (5). This period of hyperoxia, by itself, caused minimal lung injury and no lethality. However, we found that P. murina-infected mice exposed to hyperoxia succumbed to this dual stress, whereas either individual insult alone did not result in death. We demonstrated that mice exposed to sublethal hyperoxia did not have an increased burden of organisms compared to mice maintained in normoxia. However, the dual stress of hyperoxia and P. murina infection resulted in significantly increased apoptosis of lung cells and in exuberant inflammatory responses. Histologically, we have identified increased apoptosis in alveolar macrophages and alveolar epithelial cells, but we have not examined the cells ex vivo or investigated the specific mechanisms by which this combined stress leads to alveolar epithelial cell apoptosis.Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a product of normal alveolar epithelial cells that has important effects on pulmonary innate immunity and surfactant homeostasis. We previously demonstrated that GM-CSF is critical for host defense against P. murina (25). GM-CSF is also an antiapoptotic factor for alveolar epithelial cells (24). In mice exposed to sustained hyperoxia, overexpression of GM-CSF conferred significant protection from alveolar epithelial cell injury and mortality (24). These effects were associated with reduced alveolar epithelial cell apoptosis, an effect that was reproduced with pharmacologic treatment with recombinant murine GM-CSF.In the present experiments, we hypothesized that the combination of inflammation due to P. murina infection and hyperoxic stress results in increased vulnerability of alveolar epithelial cells to Fas-mediated apoptosis, leading to lung injury and death. We determined that the dual insults of P. murina infection and hyperoxic stress induce components of the Fas-Fas ligand apoptotic pathway and found that treatment with GM-CSF improves survival in this immunologically relevant model of Pneumocystis pneumonia. Furthermore, treatment with corticosteroids improves survival in this model, recapitulating the benefit of treatment in human disease and providing a possible explanation for the benefits humans derive from treatment with an anti-inflammatory medication in the setting of acute infection.     

Respective roles of TLR, RIG-I and NLRP3 in influenza virus infection and immunity: impact on vaccine design

Influenza A virus is the etiological agent of a highly contagious acute respiratory disease that causes epidemics and considerable mortality annually. It has become increasingly evident that influenza viral infection is recognized by at least three classes of pattern-recognition receptors, including TLR-7, the retinoic acid inducible gene-I and nucleotide-binding domain and leucine-rich-repeat-containing protein 3, a member of the Nod-like receptor family. This article highlights the roles of different types of innate immune receptors in influenza virus immunity versus immunopathology.     

Severity of neonatal influenza infection is driven by type I interferon and oxidative stress

Neonates exhibit increased susceptibility to respiratory viral infections, attributed to inflammation at the developing pulmonary air-blood interface. IFN I are antiviral cytokines critical to control viral replication, but also promote inflammation. Previously, we established a neonatal murine influenza virus (IV) model, which demonstrates increased mortality. Here, we sought to determine the role of IFN I in this increased mortality. We found that three-day-old IFNAR-deficient mice are highly protected from IV-induced mortality. In addition, exposure to IFNβ 24 h post IV infection accelerated death in WT neonatal animals but did not impact adult mortality. In contrast, IFN IIIs are protective to neonatal mice. IFNβ induced an oxidative stress imbalance specifically in primary neonatal IV-infected pulmonary type II epithelial cells (TIIEC), not in adult TIIECs. Moreover, neonates did not have an infection-induced increase in antioxidants, including a key antioxidant, superoxide dismutase 3, as compared to adults. Importantly, antioxidant treatment rescued IV-infected neonatal mice, but had no impact on adult morbidity. We propose that IFN I exacerbate an oxidative stress imbalance in the neonate because of IFN I-induced pulmonary TIIEC ROS production coupled with developmentally regulated, defective antioxidant production in response to IV infection. This age-specific imbalance contributes to mortality after respiratory infections in this vulnerable population.     

Activation of invariant NKT cells enhances the innate immune response and improves the disease course in influenza A virus infection

Invariant NKT (iNKT) cells have an indubitable role in antiviral immunity, although the mechanisms by which these cells exert their functions are not fully elucidated. With the emerging importance of high-pathogenicity influenza A virus infections in humans, we questioned whether iNKT cells contribute to immune defence against influenza A virus and whether activation of these cells influences outcome. We show that activation of iNKT cells with alpha-galactosylceramide (alpha-GC) during influenza virus infection transiently enhanced early innate immune response without affecting T cell immunity, and reduced early viral titres in lungs of C57BL/6 mice. This is accompanied by a better disease course with improved weight loss profile. Temporal changes in iNKT cells in the liver, blood and lungs suggest activation and migration of iNKT cells from the liver to the lungs in mice that were administered alpha-GC. Improvement in viral titres appears dependent on activation of iNKT cells via the intraperitoneal route since intranasal administration of alpha-GC did not have the same effect. We conclude that activation of iNKT cells enhances early innate immune response in the lungs and contribute to antiviral immunity and improved disease course in influenza A virus infection.     

Histopathological Evaluation of the Diversity of Cells Susceptible to H5N1 Virulent Avian Influenza Virus

Patients infected with highly pathogenic avian influenza A H5N1 viruses (H5N1 HPAIV) show diffuse alveolar damage. However, the temporal progression of tissue damage and repair after viral infection remains poorly defined. Therefore, we assessed the sequential histopathological characteristics of mouse lung after intranasal infection with H5N1 HPAIV or H1N1 2009 pandemic influenza virus (H1N1 pdm). We determined the amount and localization of virus in the lung through IHC staining and in situ hybridization. IHC used antibodies raised against the virus protein and antibodies specific for macrophages, type II pneumocytes, or proliferating cell nuclear antigen. In situ hybridization used RNA probes against both viral RNA and mRNA encoding the nucleoprotein and the hemagglutinin protein. H5N1 HPAIV infection and replication were observed in multiple lung cell types and might result in rapid progression of lung injury. Both type II pneumocytes and macrophages proliferated after H5N1 HPAIV infection. However, the abundant macrophages failed to block the viral attack, and proliferation of type II pneumocytes failed to restore the damaged alveoli. In contrast, mice infected with H1N1 pdm exhibited modest proliferation of type II pneumocytes and macrophages and slight alveolar damage. These results suggest that the virulence of H5N1 HPAIV results from the wide range of cell tropism of the virus, excessive virus replication, and rapid development of diffuse alveolar damage.Seasonal, pandemic, and zoonotic influenza A virus infections show substantial morbidity and mortality in humans. Seasonal influenza A virus infections in humans are usually mild and cause pneumonia only in a few infected individuals. Pandemic influenza virus infections vary in their disease outcome. Zoonotic influenza virus infections in humans vary from self-limiting conjunctivitis to severe, often fatal, pneumonia. Highly pathogenic avian influenza H5N1 virus (H5N1 HPAIV), implicated in poultry outbreaks,^1,2 can be transmitted zoonotically to humans, as has been observed in areas of Asia and Africa.^3–5 Fatal outcomes have been reported at approximately 60% in the sporadic transmission of this avian influenza H5N1 virus to humans.^5–7 There is no evidence that the avian influenza virus has become efficiently transmissible among humans, a change that could result in a new pandemic.⁸The outcome after infection with influenza virus can range from slight to severe illness, depending on the kinds of cells that are affected during lung tissue infection.^9–11 Events occurring early in infection determine the extent of damage, which can range from bronchitis to pneumonia. In the most severe cases, diffuse alveolar damage (DAD) may be induced during the early stages, and healing and/or scarring may ensue, depending on the persistence of disease. Occasionally, bacterial infection also may occur, with associated effects expressed mainly in the later stages of the disease. Pathological damage caused by influenza viruses in humans and in animal models depends on the virulence of the infective agent and on the host response. All influenza viruses infect the respiratory tract epithelium from the nasal passages to the bronchioles; however, highly virulent viruses (eg, H1N1 1918 and H5N1 HPAIV) tend to infect pneumocytes and resident macrophages in the alveoli. In susceptible individuals, inflammation of the alveolar walls results in DAD. In contrast, low-virulence viruses (seasonal H1N1) primarily cause inflammation, congestion, and epithelial necrosis of the trachea, bronchi, and bronchioles. Tissue tropism is an important factor, and depends largely on the ability of the virus to attach to the host cell.^12–14 We investigated virus replication and histopathological progression of lung tissue in mice infected with H5N1 HPAIV, particularly focusing on the lower respiratory tract and alveoli, with direct comparison to the histopathological characteristics of mice infected with H1N1 pandemic (pdm) influenza virus 2009 virus.     

No association between mannose-binding lectin deficiency and H1N1 2009 infection observed during the first season of this novel pandemic influenza virus

Genetic variations in host immunity may influence susceptibility to novel infections like the recently emergent pandemic influenza virus. Prior studies demonstrated that mannose-binding lectin (MBL) inactivates influenza. Furthermore, MBL deficiency is common and appears to predispose to respiratory virus infections. Therefore, we studied whether MBL deficiency played a role in infection with the novel H1N1 2009 influenza strain in exposed health care workers. In a nested case-control study, we observed no association between phenotypic MBL deficiency, variously defined, and predisposition to H1N1 2009 influenza in 63 pairs of seropositive and seronegative participants. MBL appears to currently have little impact on innate immune responses to H1N1 2009 influenza.     

Innate immune response to influenza A virus in differentiated human alveolar type II cells

Alveolar Type II (ATII) cells are important targets for seasonal and pandemic influenza. To investigate the influenza-induced innate immune response in those cells, we measured the global gene expression profile of highly differentiated ATII cells infected with the influenza A virus at a multiplicity of infection of 0.5 at 4 hours and 24 hours after inoculation. Infection with influenza stimulated a significant increase in the mRNA concentrations of many host defense-related genes, including pattern/pathogen recognition receptors, IFN, and IFN-induced genes, chemokines, and suppressors of cytokine signaling. We verified these changes by quantitative real-time RT-PCR. At the protein level, we detected a robust virus-induced secretion of the three glutamic acid-leucine-arginine (ELR)-negative chemokines CXCL9, CXCL10, and CXCL11, according to ELISA. The ultraviolet inactivation of virus abolished the chemokine and cytokine response. Viral infection did not appear to alter the differentiation of ATII cells, as measured by cellular mRNA and concentrations of surfactant proteins. However, viral infection significantly reduced the secretion of surfactant protein (SP)-A and SP-D. In addition, influenza A virus triggered a time-dependent activation of phosphatidylinositol 3-kinase signaling in ATII cells. The inhibition of this pathway significantly decreased the release of infectious virus and the chemokine response, but did not alter virus-induced cell death. This study provides insights into influenza-induced innate immunity in differentiated human ATII cells, and demonstrates that the alveolar epithelium is a critical part of the initial innate immune response to influenza.     

Pneumocystis pneumonia increases the susceptibility of mice to sublethal hyperoxia

Patients with Pneumocystis pneumonia often develop respiratory failure after entry into medical care, and one mechanism for this deterioration may be increased alveolar epithelial cell injury. In vitro, we previously demonstrated that Pneumocystis is not cytotoxic for alveolar epithelial cells. In vivo, however, infection with Pneumocystis could increase susceptibility to injury by stressors that, alone, would be sublethal. We examined transient exposure to hyperoxia as a prototypical stress that does cause mortality in normal mice. Mice were depleted of CD4+ T cells and inoculated intratracheally with Pneumocystis. Control mice were depleted of CD4+ T cells but did not receive Pneumocystis. After 4 weeks, mice were maintained in normoxia, were exposed to hyperoxia for 4 days, or were exposed to hyperoxia for 4 days followed by return to normoxia. CD4-depleted mice with Pneumocystis pneumonia demonstrated significant mortality after transient exposure to hyperoxia, while all uninfected control mice survived this stress. We determined that organism burdens were not different. However, infected mice exposed to hyperoxia and then returned to normoxia demonstrated significant increases in inflammatory cell accumulation and lung cell apoptosis. We conclude that Pneumocystis pneumonia leads to increased mortality following a normally sublethal hyperoxic insult, accompanied by alveolar epithelial cell injury and increased pulmonary inflammation.     

Mathematical modeling of interaction between innate and adaptive immune responses in COVID-19 and implications for viral pathogenesis

We have applied mathematical modeling to investigate the infections of the ongoing coronavirus disease-2019 (COVID-19) pandemic caused by SARS-CoV-2 virus. We first validated our model using the well-studied influenza viruses and then compared the pathogenesis processes between the two viruses. The interaction between host innate and adaptive immune responses was found to be a potential cause for the higher severity and mortality in COVID-19 patients. Specifically, the timing mismatch between the two immune responses has a major impact on disease progression. The adaptive immune response of the COVID-19 patients is more likely to come before the peak of viral load, while the opposite is true for influenza patients. This difference in timing causes delayed depletion of vulnerable epithelial cells in the lungs in COVID-19 patients while enhancing viral clearance in influenza patients. Stronger adaptive immunity in COVID-19 patients can potentially lead to longer recovery time and more severe secondary complications. Based on our analysis, delaying the onset of adaptive immune responses during the early phase of infections may be a potential treatment option for high-risk COVID-19 patients. Suppressing the adaptive immune response temporarily and avoiding its interference with the innate immune response may allow the innate immunity to more efficiently clear the virus.     

The Role of Type I IFNs in Influenza: Antiviral Superheroes or Immunopathogenic Villains?

The important role of interferons (IFNs) in antiviral innate immune defense is well established. Although recombinant IFN-α was approved for cancer and chronic viral infection treatment by regulatory agencies in many countries starting in 1986, no IFNs are approved for treatment of influenza A virus (IAV) infection. This is partially due to the complex effects of IFNs in acute influenza infection. IAV attacks the human respiratory system and causes significant morbidity and mortality globally. During influenza infection, depending on the strain of IAV and the individual host, type I IFNs can have protective antiviral effects or can contribute to immunopathology. In the context of virus infection, the immune system has complicated mechanisms regulating the expression and effects of type I IFN to maximize the antiviral response by both activating and enhancing beneficial innate cell function, while limiting immunopathological responses that lead to exaggerated tissue damage. In this review, we summarize the complicated, but important, role of type I IFNs in influenza infections. This includes both protective and harmful effects of these important cytokines during infection.