Lethal Influenza Infection Research Articles

Derivatives of usnic acid inhibit broad range of influenza viruses and protect mice from lethal influenza infection.

Influenza is a disease of significant morbidity and mortality, the number of anti-influenza drugs is small; many of them stimulate the appearance of resistant strains. In this work, we demonstrate activity of some usnic acid (UA) derivatives against influenza virus invitro and invivo. Organic synthesis was used to prepare compounds. Antiviral activity of the compounds invitro was evaluated by their ability to decrease the virus titer on Madin-Darby Canine Kidney cells. Invivo activity was evaluated by decrease of mortality and index of protection. Compounds were tested against a broad spectrum of influenza virus strains and showed activity against all used strains. One compound, [5] (valine enamine of UA), also significantly reduced lethality of infected animals and does not give rise to the appearance of resistant strains. Additional studies showed that hepatotoxicity of compound [5] is reduced comparatively to UA. Our results suggest that valine enamine of UA could be a potential candidate for the development of a new anti-influenza therapy.

Advax delta inulin adjuvant overcomes immune immaturity in neonatal mice thereby allowing single–dose influenza vaccine protection

Neonates are at high risk for influenza morbidity and mortality due to immune immaturity and lack of priming by prior influenza virus exposure. Inactivated influenza vaccines are ineffective in infants under six months and to provide protection in older children generally require two doses given a month apart. This leaves few options for rapid protection of infants, e.g. during an influenza pandemic. We investigated whether Advax™, a novel polysaccharide adjuvant based on delta inulin microparticles could help overcome neonatal immune hypo-responsiveness. We first tested whether it was possible to use Advax to obtain single-dose vaccine protection of neonatal pups against lethal influenza infection. Inactivated influenza A/H1N1 vaccine (iH1N1) combined with Advax™ adjuvant administered as a single subcutaneous immunization to 7-day-old mouse pups significantly enhanced serum influenza-specific IgM, IgG1, IgG2a and IgG2b levels and was associated with a 3–4 fold increase in the frequency of splenic influenza-specific IgM and IgG antibody secreting cells. Pups immunized with Advax had significantly higher splenocyte influenza-stimulated IFN-γ, IL-2, IL-4, and IL-10 production by CBA and a 3–10 fold higher frequency of IFN-γ, IL-2, IL-4 or IL-17 secreting T cells by ELISPOT. Immunization with iH1N1+Advax induced robust protection of pups against virus challenge 3 weeks later, whereas pups immunized with iH1N1 antigen alone had no protection. Protection by Advax-adjuvanted iH1N1 was dependent on memory B cells rather than memory T cells, with no protection in neonatal μMT mice that are B-cell deficient. Hence, Advax adjuvant overcame neonatal immune hypo-responsiveness and enabled single-dose protection of pups against otherwise lethal influenza infection, thereby supporting ongoing development of Advax™ as a neonatal vaccine adjuvant.

The Tie2‐agonist Vasculotide Rescues Mice From Lethal Influenza Infection Even With Delayed Administration

Severe influenza infections are characterized by the acute respiratory distress syndrome, a disorder of lung microvascular leak that manifests as pulmonary edema and severe hypoxemic respiratory failure. We reasoned that buttressing the lung endothelium with Vasculotide (VT), a Tie2-agonist tetrameric peptide, might improve survival in a murine model of severe influenza. Male C57BL6J mice were infected intranasally with a lethal dose of human influenza (X31;H3N2 subtype) and monitored for survival. Mice received daily intraperitoneal injections of VT starting at 0, 1, 2, or 3 days after infection. Infection of mice with human influenza resulted in 100% lethality by day 8. In contrast, treatment with VT alone dramatically improved survival, even if started up to 3 days after infection [83% survival, p<0.01]. Increased survival in VT-treated mice was associated with reduced lung edema and significantly improved oxygenation. We established that VT displays no intrinsic antiviral activity both in vitro and using lung homogenates of infected mice. We found that VT treatment improved endothelial barrier strength and prevented endothelial apoptosis in vitro and in vivo. To prove that the mechanism of benefit from VT requires Tie2, we repeated the infection in Tie2+/- mice. In contrast to wild-type mice, VT did not significantly improve survival from influenza in Tie2+/- animals. These results demonstrate that enhancing endothelial barrier integrity by targeting Tie2 is a novel strategy for the management of severe influenza.

A viable recombinant rhabdovirus lacking its glycoprotein gene and expressing influenza virus hemagglutinin and neuraminidase is a potent influenza vaccine.

The emergence of novel influenza viruses that cause devastating human disease is an ongoing threat and serves as an impetus for the continued development of novel approaches to influenza vaccines. Influenza vaccine development has traditionally focused on producing humoral and/or cell-mediated immunity, often against the viral surface glycoproteins hemagglutinin (HA) and neuraminidase (NA). Here, we describe a new vaccine candidate that utilizes a replication-defective vesicular stomatitis virus (VSV) vector backbone that lacks the native G surface glycoprotein gene (VSVΔG). The expression of the H5 HA of an H5N1 highly pathogenic avian influenza virus (HPAIV), A/Vietnam/1203/04 (VN1203), and the NA of the mouse-adapted H1N1 influenza virus A/Puerto Rico/8/34 (PR8) in the VSVΔG vector restored the ability of the recombinant virus to replicate in cell culture, without the requirement for the addition of trypsin. We show here that this recombinant virus vaccine candidate was nonpathogenic in mice when given by either the intramuscular or intranasal route of immunization and that the in vivo replication of VSVΔG-H5N1 is profoundly attenuated. This recombinant virus also provided protection against lethal H5N1 infection after a single dose. This novel approach to vaccination against HPAIVs may be widely applicable to other emerging strains of influenza virus. Preparation for a potentially catastrophic influenza pandemic requires novel influenza vaccines that are safe, can be produced and administered quickly, and are effective, both soon after administration and for a long duration. We have created a new influenza vaccine that utilizes an attenuated vesicular stomatitis virus (VSV) vector, to deliver and express influenza virus proteins against which vaccinated animals develop potent antibody responses. The influenza virus hemagglutinin and neuraminidase proteins, expressed on the surface of VSV particles, allowed this vaccine to grow in cell culture and induced a potent antibody response in mice that was effective against infection with a lethal influenza virus. The mice showed no adverse reactions to the vaccine, and they were protected against an otherwise lethal influenza infection after only 14 days postvaccination and after as many as 140 days postvaccination. The ability to rapidly produce this safe and effective vaccine in cell culture is additionally advantageous.

CD40 ligand preferentially modulates immune response and enhances protection against influenza virus.

CD40L, a key regulator of the immune system, was studied as both a targeting ligand and a molecular adjuvant in nucleoprotein (NP)-based host defense against influenza in mouse models with different genetic backgrounds. Adenoviral vectors secreting NP-CD40L fusion protein (denoted as rAd-SNP40L) afforded full protection of immunocompetent and immunocompromised mice (CD40L(-/-) and CD4(-/-)) against lethal influenza infection. Mechanistically, rAd-SNP40L preferentially induced early and persistent B cell germinal center formation, and accelerated Ig isotype-switching and Th1-skewed, NP-specific Ab response. Moreover, it drastically augmented primary and memory NP-specific CTL activity and polyfunctional CD8(+) T cells. The markedly enhanced nonneutralizing Abs and CTLs significantly reduced viral burdens in the lungs of mice upon lethal virus challenge. Data generated from CD40L(-/-) and CD4(-/-) mice revealed that the protection was indeed CD40L mediated but CD4(+) T cell independent, demonstrating the viability of the fusion Ags in protecting immunodeficient hosts. Notably, a single dose of rAd-SNP40L completely protected mice from lethal viral challenge 4 mo after immunization, representing the first report, to our knowledge, on NP in conjunction with a molecular adjuvant inducing a robust and long-lasting memory immune response against influenza. This platform is characterized by an increased in vivo load of CD40-targeted Ag upon the secretion of the fusion protein from adenovirus-infected cells and may represent a promising strategy to enhance the breadth, durability, and potency of Ag-specific immune responses.

Early cytokine dysregulation and viral replication are associated with mortality during lethal influenza infection.

Infection with influenza A virus (IAV) leads to acute lung injury and possibly fatal complications, especially in immunocompromised, elderly, or chronically infected individuals. Therefore, it is important to study the factors that lead to pathology and mortality in infected hosts. In this report, we analyze immune responses to infection at a sublethal (0.1 LD(50)) and lethal (1 LD(50)) dose of the highly pathogenic IAV A/Puerto Rico/8/34 (PR8). Our experiments revealed that infection with a 1 LD(50) dose induced peak viral titers at day 2 compared to day 4 in the 0.1 LD(50) dose. Moreover, early cytokine dysregulation was observed in the lethal dose with significantly elevated levels of IFN-α, TNF-α, CXCL9, IL-6, and MCP-1 produced at day 2. Early inflammatory responses following infection with 1 LD(50) correlated with a greater influx of neutrophils into the lung. However, depletion of neutrophils enhanced morbidity following IAV infection. Though no differences in CD8+ cell function were observed, CD4+ effector responses were impaired in the lungs 8 days after infection with 1 LD(50). Histological analysis revealed significant pathology in lethally infected mice at day 2 and day 6 postinfection, when viral titers remained high. Treating lethally infected mice with oseltamivir inhibited viral titers to sublethal levels, and abrogated the pathology associated with the lethal dose. Together, these results suggest that early cytokine dysregulation and viral replication play a role in pulmonary damage and high mortality in lethally infected mice.

MTOR regulates protection against lethal H5N1 influenza infection by modulating the antibody response (VAC2P.926)

Abstract Highly pathogenic H5N1 avian influenza viruses pose a continuing global threat. Current vaccines will not protect against novel pandemic viruses. Creating “universal” vaccines has been unsuccessful because the immunological mechanisms promoting heterosubtypic immunity are incompletely defined. We show that rapamycin, an immunosuppressive drug that inhibits mTOR, promotes cross-strain protection against a lethal H5N1 infection when administered during H3N2 virus immunization. Rapamycin reduced germinal center formation and inhibited B cell class-switching, yielding a unique repertoire of antibodies that mediated heterosubtypic protection. Our data establish a requirement for mTORC1 in B cell class-switching and demonstrate that rapamycin skews the antibody response away from high affinity variant epitopes, targeting more conserved elements of hemagglutinin. Our current data indicate that a primary intranasal infection with FluMist enhances heterosubtypic immunity even more, which can be further enhanced with rapamycin. In this model the CD8 T cells contribute to enhanced protection providing us a model to study the synergy between cross-reactive antibodies and CD8 T cells. These findings have intriguing implications for influenza vaccine design.

Lactobacillus fermentum CJL-112 protects mice against influenza virus infection by activating T-helper 1 and eliciting a protective immune response

We have previously reported that nasally administered Lactobacillus fermentum CJL-112 (CJL-112) efficiently improves resistance against lethal influenza infection in both mice and chicken. The aim of the present study was to understand the underlying mechanisms of the significant anti-influenza activity of this lactobacilli strain. In vitro, co-culturing of the chicken macrophage cell line HD-11 with CJL-112 significantly increased nitric oxide (NO) production. In vivo, CJL-112 was nasally administered to BALB/c mice for 21 days prior to influenza A/NWS/33 (H1N1) virus (IFV) infection. Significant up-regulation of T-helper 1 (Th1) cytokines (IL-2, IFN-γ) was observed, while the levels of T-helper 2 (Th2) cytokines (IL-4, IL-5, IL-10) was either reduced or unchanged than that in control mice were. Furthermore, IgA and specific anti-influenza IgA levels increased significantly in the treated mice than those in untreated mice. Therefore, CJL-112 likely protects the mice against lethal IFV infection via stimulation of macrophages, activation of Th1 and augmentation of IgA production, when directly delivered into the respiratory tract.

A Systems Analysis Identifies a Feedforward Inflammatory Circuit Leading to Lethal Influenza Infection

For acutely lethal influenza infections, the relative pathogenic contributions of direct viral damage to lung epithelium versus dysregulated immunity remain unresolved. Here, we take a top-down systems approach to this question. Multigene transcriptional signatures from infected lungs suggested that elevated activation of inflammatory signaling networks distinguished lethal from sublethal infections. Flow cytometry and gene expression analysis involving isolated cell subpopulations from infected lungs showed that neutrophil influx largely accounted for the predictive transcriptional signature. Automated imaging analysis, together with these gene expression and flow data, identified a chemokine-driven feedforward circuit involving proinflammatory neutrophils potently driven by poorly contained lethal viruses. Consistent with these data, attenuation, but not ablation, of the neutrophil-driven response increased survival without changing viral spread. These findings establish the primacy of damaging innate inflammation in at least some forms of influenza-induced lethality and provide a roadmap for the systematic dissection of infection-associated pathology.

MTOR regulates protection against a lethal H5N1 influenza infection by modulating the antibody response (P6184)

Abstract Highly pathogenic H5N1 avian influenza A viruses pose a serious threat for global catastrophe. Due to frequent mutations in the influenza genome, current vaccination protocols promote only strain-specific responses, and therefore fail to provide protection against novel pandemic strains. Antibodies that protect against multiple subtypes of influenza have been identified, however, these antibodies are extremely rare, and the immunological mechanisms that lead to their development are not clear. We show here that rapamycin, an immunosuppressive drug that inhibits mTOR, promoted cross-strain protection against lethal H5N1 infection when administered during H3N2 vaccination. Surprisingly, this protection did not require memory CD8 T cells, but rather required CD4 T cells and B cells, suggesting the protection was antibody-mediated. In support of this, serum from rapamycin-treated mice immunized with a H3N2 strain protected naïve mice from a lethal H5N1 infection. Our data further reveal that rapamycin reduced germinal center formation and B cell class-switching, yielding a unique repertoire of antibodies that was more protective against a lethal, heterosubtypic influenza infection. These data not only reveal a requirement for mTOR in B cell class-switching, but also indicate that a broader antibody repertoire, which provides better protection against multiple strains of influenza, can be achieved by reducing germinal center formation during the primary infection.

Fat chance for influenza

The lipid mediator PD1 protects against lethal influenza infection by inhibiting viral replication.

Early Regulation of Viral Infection Reduces Inflammation and Rescues Mx-Positive Mice from Lethal Avian Influenza Infection

Differing sensitivity of influenza A viruses to antiviral effects of the Myxovirus resistance (Mx) protein implies varying global gene expression profiles in the host. The role of Mx protein during lethal avian influenza (AI) virus infection was examined using Mx1-deficient C57BL/6 (B6-Mx1(-/-)) and congenic Mx1-expressing (B6-Mx1(+/+)) mice infected with a virulent, mouse-adapted avian H5N2 Ab/Korea/ma81/07 (Av/ma81) virus. After infection, B6-Mx1(+/+) mice were completely protected from lethal AI-induced mortality, and exhibited attenuated clinical disease and reduced viral titers and pathology in the lungs, compared with B6-Mx1(-/-) mice. Transcriptional profiling of lung tissues revealed that most of the genes up-regulated after infection are involved in activation of the immune response and host defense. Notably, more abundant and sustained expression of cytokine/chemokine genes was observed up to 3 dpi in B6-Mx1(-/-) mice, and this was associated with excessive induction of cytokines and chemokines. Consequently, massive infiltration of macrophages/monocytes and granulocytes into lung resulted in severe viral pneumonia and potentially contributed to decreased survival of B6-Mx1(-/-) mice. Taken together, our data show that dysregulated gene transcriptional activity corresponded to persistent induction of cytokine/chemokines and recruitment of cytokine-producing cells that promote inflammation in B6-Mx1(-/-) mouse lungs. Thus, we provide additional evidence of the interplay of genetic, molecular, and cellular correlates governed by the Mx1 protein that critically determine disease outcome during lethal AI virus infection.

Compromised respiratory function in lethal influenza infection is characterized by the depletion of type I alveolar epithelial cells beyond threshold levels

During influenza virus infection, it is unclear how much alveolar cell loss can be tolerated before the host succumbs to the disease. We sought to define relevant correlates of disease severity in the mouse influenza model, hypothesizing that a susceptibility threshold exists for alveolar epithelial cell loss. We compared lung pathology, virus spread, alveolar epithelial cell depletion, arterial blood oxygenation, physiological responses measured by unrestrained plethysmography, and oxygen consumption and carbon dioxide production by gas analysis in mice at intervals after infection with virus strains and doses that cause mild (x31) or severe (PR/8) influenza. Both mild and severe infections showed similar degrees of lung damage and virus dissemination until day 6 after inoculation but diverged in survival outcomes from day 9. Day 6 PR/8-infected mice had normal respiratory and gas exchange functions with 10% type I cell loss. However, day 10 PR/8-infected mice had 40% type I cell loss with a concomitant drastic decreases in tidal and minute volumes, Vo(2), Vco(2), and arterial blood oxygenation, compared with a maximum 3% type I cell loss for x31 on day 10 when they recovered body weight and respiratory functions. Alterations in breaths per minute, expiratory time, and metabolic rate were observed in both infections. A threshold for maintenance of proper respiratory function appears to be crossed once 10% of alveolar type I cells are lost. These data indicate that lethality in influenza virus infection is a matter of degree rather than quality.

Inhibition of the inflammatory cytokine tumor necrosis factor-alpha with etanercept provides protection against lethal H1N1 influenza infection in mice

IntroductionFactors implicated in influenza-mediated morbidity and mortality include robust cytokine production (cytokine storm), excessive inflammatory infiltrates, and virus-induced tissue destruction. Tumor necrosis factor-alpha (TNF-α) is an important pro-inflammatory cytokine present during influenza infection, but it is unclear whether direct inhibition of TNF-α can elicit protection against influenza infection.MethodsIn this study, the commercially available TNF-α inhibitor etanercept was used to inhibit TNF-α induced by lethal A/FM/1/47 (H1N1) influenza virus infection of mice. The effects of TNF-α inhibition on mouse survival, pathologic changes, immune cell infiltration, inflammatory cytokine secretion, Toll-like receptor expression, and activation of the NF-κB (nuclear factor kappa B) signaling pathway were evaluated.ResultsThe intranasal delivery of etanercept provided significant protection against mortality (30% of mice survived up to 14 days after infection) in mice treated with etanercept. In contrast, no survivors were found beyond 6 days in mice treated with saline after lethal challenge with H1N1 influenza virus. It was observed that etanercept significantly reduced inflammatory cell infiltration (for example, macrophages and neutrophils), inflammatory cytokine secretion (for example, interleukin-6, TNF-α, and interferon gamma), and expression of Toll-like receptors (TLR-3, TLR-4, and TLR-7). Etanercept also downregulated and inhibited the cascade proteins of the NF-κB signaling pathway (for example, MyD88, TRIF, NF-κB, and p65), as well as enhanced host control of virus replication.ConclusionsThese findings indicate that etanercept, by blocking TNF-α, can significantly downregulate excessive inflammatory immune responses and provide protection against lethal influenza infection, making its use a novel strategy for controlling severe influenza-induced viral pneumonia.

Passive immunization with a recombinant adenovirus expressing an HA (H5)-specific single-domain antibody protects mice from lethal influenza infection

One effective method for the prevention and treatment of influenza infection is passive immunization. In our study, we examined the feasibility of creating an antibody-based preparation with a prolonged protective effect against influenza virus. Single-domain antibodies (sdAbs) specific for influenza virus hemagglutinin were generated. Experiments in mouse models showed 100% survivability for both intranasal sdAbs administration 24h prior to influenza challenge and 24h after infection. sdAb-gene delivery by an adenoviral vector led to gene expression for up to 14days. Protection by a recombinant adenovirus containing the sdAb gene was observed in cases of administration prior to influenza infection (14d–24h). We also demonstrated that the single administration of a combined preparation containing sdAb DNA and protein expanded the protection time window from 14d prior to 48h after influenza infection. This approach and the application of a broad-spectrum sdAbs will allow the development of efficient drugs for the prevention and treatment of viral infections produced by pandemic virus variants and other infections.

Short-term supplementation with active hexose correlated compound improves the antibody response to influenza B vaccine

Administration of bioactive nutritional supplements near or at the time of immunization has been a recent approach to stimulate human immune response to vaccination. Active hexose correlated compound (AHCC), a mushroom extract, has been shown to protect mice against lethal primary influenza infection. Moreover, when AHCC was administered pre-vaccination in mice, they showed improved protection from lethal avian flu infection when compared to mice vaccinated alone. In this study, we hypothesized that AHCC will also improve the immune responses of healthy individuals to influenza vaccine. A randomized controlled study was performed with 30 healthy adults to evaluate the effects of AHCC supplementation on the immune response to the 2009-2010 seasonal influenza vaccine. Blood was drawn pre-vaccination and 3 wk post-vaccination. Immediately post-vaccination, the AHCC group began supplementation with AHCC (3 g/d). Flow cytometric analysis of lymphocyte subpopulations revealed that AHCC supplementation increased NKT cells (P < .1), and CD8 T cells (P < .05) post-vaccination compared to controls. Analysis of antibody production 3 weeks post-vaccination revealed that AHCC supplementation significantly improved protective antibody titers to influenza B, while the improvement was not significant in the control group. Overall, our study showed that AHCC supplementation improved some lymphocyte percentages and influenza B antibody titers over the control. Future studies are required to determine the kinetics of AHCC supplementation to improve the overall response to influenza vaccination.

Critical Role of Natural Killer Cells in Lung Immunopathology During Influenza Infection in Mice

Influenza viral infection results in excessive pulmonary inflammation that has been linked to the damage caused by immune responses and viral replication. The multifunctional cytokine interleukin (IL-15), influences the proliferation and maintenance of immune cells such as CD8(+) T cells and natural killer (NK) cells. Here we show that IL-15(-/-) mice are protected from lethal influenza infection. Irrespective of the mouse strains, the protection observed was linked to the lack of NK cells. Increased survival in the IL-15(-/-) or NK1.1(+) cell-depleted wild-type mice was associated with significantly lower lung lesions as well as decreased mononuclear cells and neutrophils in the airway lumen. Levels of interleukin 10 were significantly higher and levels of proinflammatory cytokines, including interleukin 6 and interleukin 12, were significantly lower in the bronchoalveolar lavage fluid from IL-15(-/-) and NK1.1(+) cell-depleted wild-type mice than in that from control mice. Our data suggest that NK cells significantly augment pulmonary inflammation, contributing to the pathogenesis of influenza infection.

Universal vaccine against influenza virus: Linking TLR signaling to anti‐viral protection

A vaccine protecting against all influenza strains is a long-sought goal, particularly for emerging pandemics. As previously shown, vaccines based on the highly conserved extracellular domain of M2 (M2e) may protect against all influenza A strains. Here, we demonstrate that M2e-specific monoclonal antibodies (mAbs) protect mice from a lethal influenza infection. To be protective, antibodies had to be able to bind to Fc receptors and fix complement. Furthermore, mAbs of IgG2c isotype were protective in mice, while antibodies of identical specificity, but of the IgG1 isotype, failed to prevent disease. These findings readily translated into vaccine design. A vaccine targeting M2 in the absence of a toll-like receptor (TLR) 7 ligand primarily induced IgG1, whilst the same vaccine linked to a TLR7 ligand yielded high levels of IgG2c antibodies. Although both vaccines protected mice from a lethal challenge, mice treated with the vaccine containing a TLR7 ligand showed significantly lower morbidity. In accordance with these findings, vaccination of TLR7(-/-) mice with a vaccine containing a TLR7 ligand did not result in protection from a lethal challenge. Hence, the innate immune system is required to direct isotype switching toward the more protective IgG2a/c antibodies.

The Prostanoid 15-Deoxy-Δ12,14-Prostaglandin-J2 Reduces Lung Inflammation and Protects Mice Against Lethal Influenza Infection

Growing evidence indicates that influenza pathogenicity relates to altered immune responses and hypercytokinemia. Therefore, dampening the excessive inflammatory response induced after infection might reduce influenza morbidity and mortality. Considering this, we investigated the effect of the anti-inflammatory molecule 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)) in a mouse model of lethal influenza infection. Administration of 15d-PGJ(2) on day 1 after infection, but not on day 0, protected 79% of mice against lethal influenza infection. In addition, this treatment considerably reduced the morbidity associated with severe influenza infection. Our results also showed that treatment with 15d-PGJ(2) decreased influenza-induced lung inflammation, as shown by the diminished gene expression of several proinflammatory cytokines and chemokines. Unexpectedly, 15d-PGJ(2) also markedly reduced the viral load in the lungs of infected mice. This could be attributed to maintained type I interferon gene expression levels after treatment. Interestingly, pretreatment of mice with a peroxisome proliferator-activated receptor gamma (PPARγ) antagonist before 15d-PGJ(2) administration completely abrogated its protective effect against influenza infection. Our results demonstrate for the first time that treatment of mice with 15d-PGJ(2) reduces influenza morbidity and mortality through activation of the PPARγ pathway. PPARγ agonists could thus represent a potential therapeutic avenue for influenza infections.

Cutting Edge: Tissue-Retentive Lung Memory CD4 T Cells Mediate Optimal Protection to Respiratory Virus Infection

We identify in this article a new class of lung tissue-resident memory CD4 T cells that exhibit tissue tropism and retention independent of Ag or inflammation. Tissue-resident memory CD4 T cells in the lung did not circulate or emigrate from the lung in parabiosis experiments, were protected from in vivo Ab labeling, and expressed elevated levels of CD69 and CD11a compared with those of circulating memory populations. Importantly, influenza-specific lung-resident memory CD4 T cells served as in situ protectors to respiratory viral challenge, mediating enhanced viral clearance and survival to lethal influenza infection. By contrast, memory CD4 T cells isolated from spleen recirculated among multiple tissues without retention and failed to mediate protection to influenza infection, despite their ability to expand and migrate to the lung. Our results reveal tissue compartmentalization as a major determining factor for immune-mediated protection in a key mucosal site, important for targeting local protective responses in vaccines and immunotherapies.