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

Abdul-Careem, Mohamed Faizal; Mian, M. Firoz; Yue, Geoffry; Gillgrass, Amy; Chenoweth, Meghan J.; Barra, Nicole G.; Chew, Marianne V.; Chan, Tiffany; Al-Garawi, Amal; Jordana, Manel; Ashkar, Ali A.

doi:10.1093/infdis/jis340

Cited by 113 publications

(118 citation statements)

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“…Two genes encoded IFNinducible chemokines (CXCL10, CXCL11). The IL15 gene product induces an antiviral state through the regulation of type I IFN production and natural killer cell proliferation (26,27). AIM2 encodes an IFN-inducible cytosolic double-stranded DNA sensor (28).…”

Section: Rna Processing and Viral Detectionmentioning

confidence: 99%

Differential Responses to Rhinovirus- and Influenza-associated Pulmonary Exacerbations in Patients with Cystic Fibrosis

et al. 2014

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Rationale: The mechanism by which viruses cause exacerbations of chronic airway disease and the capacity of patients with cystic fibrosis (CF) to respond to viral infection are not precisely known.Objectives: To determine the antiviral response to infection in patients with CF.Methods: Sputum was collected from patients with CF with respiratory exacerbation. Viruses were detected in multiplex polymerase chain reaction (PCR)-based assays. Gene expression of 84 antiviral response genes was measured, using a focused quantitative PCR gene array. Measurements and Main Results:We examined 36 samples from 23 patients with respiratory exacerbation. Fourteen samples tested virus-positive and 22 virus-negative. When we compared exacerbations associated with rhinovirus (RV, n = 9) and influenza (n = 5) with virus-negative specimens, we found distinct patterns of antiviral gene expression. RV was associated with greater than twofold induction of five genes, including those encoding the monocyte-attracting chemokines CXCL10, CXCL11, and CXCL9. Influenza was associated with overexpression of 20 genes, including those encoding the cytokines tumor necrosis factor and IL-12; the kinases MEK, TBK-1, and STAT-1; the apoptosis proteins caspase-8 and caspase-10; the influenza doublestranded RNA receptor RIG-I and its downstream effector MAVS; and pyrin, an IFN-stimulated protein involved in influenza resistance. Conclusions:We conclude that virus-induced exacerbations of CF are associated with immune responses tailored to specific infections. Influenza induced a more potent response consisting of inflammation, whereas RV infection had a pronounced effect on chemokine expression. As far as we are aware, this study is the first to compare specific responses to different viruses in live patients with chronic airway disease.

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Section: Rna Processing and Viral Detectionmentioning

confidence: 99%

Differential Responses to Rhinovirus- and Influenza-associated Pulmonary Exacerbations in Patients with Cystic Fibrosis

et al. 2014

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“…The protective functions of NK cells during IAV infection have been demonstrated before (21,23). However, there are also reports indicating that NK cells exacerbate morbidity and pathology during highdose IAV infection in mice (24,25). Most of these studies were performed in B6 mice, and the roles of NK cells in other inbred mouse strains during IAV infection are less studied.…”

Section: Nk Cells Protect 129 Mice Against High-dose Pr8 Infectionmentioning

confidence: 99%

“…Several studies highlight the pivotal role of NK cells in the control of IAV infection in that defects in NK cell activity or depletion of NK cells result in delayed viral clearance and increased morbidity and mortality (21)(22)(23). However, there are also examples in which NK cells exacerbate morbidity and pathology during lethal dose influenza virus infection in mice (24,25), which indicate that NK cells may play dual roles during influenza virus infection in mice, conferring beneficial or deleterious function depending on the viral dose. Furthermore, production of IL-22 by NK and NKT cells has an important role in the repair of epithelial damage caused by IAV (26,27).…”

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confidence: 99%

Swift and Strong NK Cell Responses Protect 129 Mice against High-Dose Influenza Virus Infection

Zhou

Wang

et al. 2016

The Journal of Immunology

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It is generally unclear what roles NK cells play during influenza virus infection with regard to different host genetic backgrounds. In this study, we show that in six inbred mouse strains, NK cells play an important protective role only in 129 mice during high-dose influenza A H1N1 virus infection. Swift and strong NK cell responses efficiently control early pulmonary viral replication in 129 mice, providing survival privilege. In addition, we identified that early activation of TLRs and RIG-I signaling in 129 mice resulted in quick production of type 1 IFNs and inflammatory cytokines, which are important reasons for the swift kinetics of NK cell responses post influenza virus infection. Thus, under different microenvironments, NK cells play differential roles against viral infections. The kinetics and magnitude of NK cell responses correlate with the distinct roles that NK cells play against influenza virus infections. Thus, our works further our understandings about the complex role of NK cells during influenza virus infection.

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“…NK cells may participate in defense against respiratory pathogens via various mechanisms, including direct lysis of infected cells, production of chemokines that amplify the host's inflammatory response, production of antiviral cytokines, such as IFN-␥ and tumor necrosis factor alpha (TNF), and activation of DCs that mediate T cell differentiation and trafficking to the lung (23,26). In some instances, particularly during more severe respiratory infections, NK cells can be responsible for acute lung immune injury and mortality (27)(28)(29). While these studies suggest that NK activities can lead to both beneficial and deleterious outcomes, the role of NK cells and innate IFN-␥ and their relationship in early host defense against respiratory poxvirus infection have not been directly investigated.…”

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confidence: 99%

Natural Killer Cells and Innate Interferon Gamma Participate in the Host Defense against Respiratory Vaccinia Virus Infection

Abboud

Tahiliani

Desai

et al. 2016

J Virol

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In establishing a respiratory infection, vaccinia virus (VACV) initially replicates in airway epithelial cells before spreading to secondary sites of infection, mainly the draining lymph nodes, spleen, gastrointestinal tract, and reproductive organs. We recently reported that interferon gamma (IFN-␥) produced by CD8 T cells ultimately controls this disseminated infection, but the relative contribution of IFN-␥ early in infection is unknown. Investigating the role of innate immune cells, we found that the frequency of natural killer (NK) cells in the lung increased dramatically between days 1 and 4 postinfection with VACV. Lung NK cells displayed an activated cell surface phenotype and were the primary source of IFN-␥ prior to the arrival of CD8 T cells. In the presence of an intact CD8 T cell compartment, depletion of NK cells resulted in increased lung viral load at the time of peak disease severity but had no effect on eventual viral clearance, disease symptoms, or survival. In sharp contrast, RAG ؊/؊ mice devoid of T cells failed to control VACV and succumbed to infection despite a marked increase in NK cells in the lung. Supporting an innate immune role for NK cell-derived IFN-␥, we found that NK cell-depleted or IFN-␥-depleted RAG ؊/؊ mice displayed increased lung VACV titers and dissemination to ovaries and a significantly shorter mean time to death compared to untreated NK cell-competent RAG ؊/؊ controls. Together, these findings demonstrate a role for IFN-␥ in aspects of both the innate and adaptive immune response to VACV and highlight the importance of NK cells in T cell-independent control of VACV in the respiratory tract. IMPORTANCEHerein, we provide the first systematic evaluation of natural killer (NK) cell function in the lung after infection with vaccinia virus, a member of the Poxviridae family. The respiratory tract is an important mucosal site for entry of many human pathogens, including poxviruses, but precisely how our immune system defends the lung against these invaders remains unclear. Natural killer cells are a type of cytotoxic lymphocyte and part of our innate immune system. In recent years, NK cells have received increasing levels of attention following the discovery that different tissues contain specific subsets of NK cells with distinctive phenotypes and function. They are abundant in the lung, but their role in defense against respiratory viruses is poorly understood. What this study demonstrates is that NK cells are recruited, activated, and contribute to protection of the lung during a severe respiratory infection with vaccinia virus.

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

Cited by 113 publications

References 50 publications

Differential Responses to Rhinovirus- and Influenza-associated Pulmonary Exacerbations in Patients with Cystic Fibrosis

Differential Responses to Rhinovirus- and Influenza-associated Pulmonary Exacerbations in Patients with Cystic Fibrosis

Swift and Strong NK Cell Responses Protect 129 Mice against High-Dose Influenza Virus Infection

Natural Killer Cells and Innate Interferon Gamma Participate in the Host Defense against Respiratory Vaccinia Virus Infection

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