Contribution of innate immune cells to pathogenesis of severe influenza virus infection

Influenza A viruses (IAVs) cause respiratory illness of varying severity based on the virus strains, host predisposition and pre-existing immunity. Ultimately, outcome and recovery from infection rely on an effective immune response comprising both innate and adaptive components. The innate immune response provides the first line of defence and is crucial to the outcome of infection. Airway epithelial cells are the first cell type to encounter the virus in the lungs, providing antiviral and chemotactic molecules that shape the ensuing immune response by rapidly recruiting innate effector cells such as NK cells, monocytes and neutrophils. Each cell type has unique mechanisms to combat virus-infected cells and limit viral replication, however their actions may also lead to pathology. This review focuses how innate cells contribute to protection and pathology, and provides evidence for their involvement in immune pathology in IAV infections.

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Avian Influenza A Virus Infects Swine Airway Epithelial Cells without Prior Adaptation

Viruses ◽

10.3390/v12060589 ◽

2020 ◽

Vol 12 (6) ◽

pp. 589 ◽

Cited By ~ 2

Author(s):

Dai-Lun Shin ◽

Wei Yang ◽

Ju-Yi Peng ◽

Bevan Sawatsky ◽

Veronika von Messling ◽

...

Keyword(s):

Immune Response ◽

Sialic Acid ◽

Epithelial Cells ◽

Influenza A ◽

Airway Epithelial Cells ◽

Sialic Acids ◽

Innate Immune ◽

Interspecies Transmission ◽

Airway Epithelial ◽

Well Differentiated

Pigs play an important role in the interspecies transmission of influenza A viruses (IAV). The porcine airway epithelium contains binding sites for both swine/human IAV (α2,6-linked sialic acids) and avian IAV (α2,3-linked sialic acids) and therefore is suited for adaptation of viruses from other species as suggested by the “mixing vessel theory”. Here, we applied well-differentiated swine airway epithelial cells to find out whether efficient infection by avian IAV requires prior adaption. Furthermore, we analyzed the influence of the sialic acid-binding activity and the virus-induced detrimental effects. Surprisingly, an avian IAV H1N1 strain circulating in European poultry and waterfowl shows increased and prolonged viral replication without inducing a strong innate immune response. This virus could infect the lower respiratory tract in our precision cut-lung slice model. Pretreating the cells with poly (I:C) and/or JAK/STAT pathway inhibitors revealed that the interferon-stimulated innate immune response influences the replication of avian IAV in swine airway epitheliums but not that of swine IAV. Further studies indicated that in the infection by IAVs, the binding affinity of sialic acid is not the sole factor affecting the virus infectivity for swine or human airway epithelial cells, whereas it may be crucial in well-differentiated ferret tracheal epithelial cells. Taken together, our results suggest that the role of pigs being the vessel of interspecies transmission should be reconsidered, and the potential of avian H1N1 viruses to infect mammals needs to be characterized in more detail.

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Innate immune response in CF airway epithelia: hyperinflammatory?

AJP Cell Physiology ◽

10.1152/ajpcell.00605.2005 ◽

2006 ◽

Vol 291 (2) ◽

pp. C218-C230 ◽

Cited By ~ 123

Author(s):

Terry E. Machen

Keyword(s):

Immune Response ◽

Epithelial Cells ◽

Innate Immune Response ◽

Cellular Signaling ◽

Basolateral Membrane ◽

Airway Epithelial Cells ◽

Innate Immune ◽

Airway Epithelial ◽

Airway Epithelia ◽

Intracellular Ca

The lack of functional cystic fibrosis (CF) transmembrane conductance regulator (CFTR) in the apical membranes of CF airway epithelial cells abolishes cAMP-stimulated anion transport, and bacteria, eventually including Pseudomonas aeruginosa, bind to and accumulate in the mucus. Flagellin released from P. aeruginosa triggers airway epithelial Toll-like receptor 5 and subsequent NF-κB signaling and production and release of proinflammatory cytokines that recruit neutrophils to the infected region. This response has been termed hyperinflammatory because so many neutrophils accumulate; a response that damages CF lung tissue. We first review the contradictory data both for and against the idea that epithelial cells exhibit larger-than-normal proinflammatory signaling in CF compared with non-CF cells and then review proposals that might explain how reduced CFTR function could activate such proinflammatory signaling. It is concluded that apparent exaggerated innate immune response of CF airway epithelial cells may have resulted not from direct effects of CFTR on cellular signaling or inflammatory mediator production but from indirect effects resulting from the absence of CFTRs apical membrane channel function. Thus, loss of Cl−, HCO3−, and glutathione secretion may lead to reduced volume and increased acidification and oxidation of the airway surface liquid. These changes concentrate proinflammatory mediators, reduce mucociliary clearance of bacteria and subsequently activate cellular signaling. Loss of apical CFTR will also hyperpolarize basolateral membrane potentials, potentially leading to increases in cytosolic [Ca2+], intracellular Ca2+, and NF-κB signaling. This hyperinflammatory effect of CF on intracellular Ca2+and NF-κB signaling would be most prominently expressed during exposure to both P. aeruginosa and also endocrine, paracrine, or nervous agonists that activate Ca2+signaling in the airway epithelia.

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Differential Induction of Type I and Type III Interferons by Swine and Human Origin H1N1 Influenza A Viruses in Porcine Airway Epithelial Cells

PLoS ONE ◽

10.1371/journal.pone.0138704 ◽

2015 ◽

Vol 10 (9) ◽

pp. e0138704 ◽

Cited By ~ 5

Author(s):

Venkatramana D. Krishna ◽

Erin Roach ◽

Nathan A. Zaidman ◽

Angela Panoskaltsis-Mortari ◽

Jessica H. Rotschafer ◽

...

Keyword(s):

Epithelial Cells ◽

Influenza A ◽

H1n1 Influenza ◽

Airway Epithelial Cells ◽

Type I ◽

Airway Epithelial ◽

Human Origin ◽

Influenza A Viruses ◽

Type Iii ◽

Differential Induction

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CF Monocyte Derived Macrophages Have an Attenuated Response to Extracellular Vesicles Secreted by Airway Epithelial Cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00621.2020 ◽

2021 ◽

Author(s):

Katja Koeppen ◽

Amanda B Nymon ◽

Roxanna Barnaby ◽

Zhongyou Li ◽

Thomas H Hampton ◽

...

Keyword(s):

Immune Response ◽

Epithelial Cells ◽

Bacterial Infection ◽

Extracellular Vesicles ◽

Cell Types ◽

Airway Epithelial Cells ◽

Innate Immune ◽

Airway Epithelial ◽

Immune Genes ◽

Innate Immune Genes

Mutations in CFTR alter macrophage responses, for example, by reducing their ability to phagocytose and kill bacteria. Altered macrophage responses may facilitate bacterial infection and inflammation in the lungs, contributing to morbidity and mortality in cystic fibrosis (CF). Extracellular vesicles (EVs) are secreted by multiple cell types in the lungs and participate in the host immune response to bacterial infection, but the effect of EVs secreted by CF airway epithelial cells (AEC) on CF macrophages is unknown. This report examines the effect of EVs secreted by primary AEC on monocyte derived macrophages (MDM) and contrasts responses of CF and WT MDM. We found that EVs generally increase pro-inflammatory cytokine secretion and expression of innate immune genes in MDM, especially when EVs are derived from AEC exposed to Pseudomonas aeruginosa, and that this effect is attenuated in CF MDM. Specifically, EVs secreted by P. aeruginosa exposed AEC induced immune response genes and increased secretion of pro-inflammatory cytokines, chemoattractants and chemokines involved in tissue repair by WT MDM, but these effects were less robust in CF MDM. We attribute attenuated responses by CF MDM to differences between CF and WT macrophages because EVs secreted by CF AEC or WT AEC elicited similar responses in CF MDM. Our findings demonstrate the importance of AEC EVs in macrophage responses and show that the Phe508del mutation in CFTR attenuates the innate immune response of MDM to EVs.

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Bromodomain Containing Protein 4 (BRD4) Regulates Expression of its Interacting Coactivators in the Innate Response to Respiratory Syncytial Virus

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.728661 ◽

2021 ◽

Vol 8 ◽

Author(s):

Xiaofang Xu ◽

Morgan Mann ◽

Dianhua Qiao ◽

Yi Li ◽

Jia Zhou ◽

...

Keyword(s):

Immune Response ◽

Extracellular Matrix ◽

Transcription Factors ◽

Respiratory Syncytial Virus ◽

Innate Immune Response ◽

Airway Epithelial Cells ◽

Innate Immune ◽

Airway Epithelial ◽

Gene Regulatory ◽

Syncytial Virus

Bromodomain-containing protein 4 plays a central role in coordinating the complex epigenetic component of the innate immune response. Previous studies implicated BRD4 as a component of a chromatin-modifying complex that is dynamically recruited to a network of protective cytokines by binding activated transcription factors, polymerases, and histones to trigger their rapid expression via transcriptional elongation. Our previous study extended our understanding of the airway epithelial BRD4 interactome by identifying over 100 functionally important coactivators and transcription factors, whose association is induced by respiratory syncytial virus (RSV) infection. RSV is an etiological agent of recurrent respiratory tract infections associated with exacerbations of chronic obstructive pulmonary disease. Using a highly selective small-molecule BRD4 inhibitor (ZL0454) developed by us, we extend these findings to identify the gene regulatory network dependent on BRD4 bromodomain (BD) interactions. Human small airway epithelial cells were infected in the absence or presence of ZL0454, and gene expression profiling was performed. A highly reproducible dataset was obtained which indicated that BRD4 mediates both activation and repression of RSV-inducible gene regulatory networks controlling cytokine expression, interferon (IFN) production, and extracellular matrix remodeling. Index genes of functionally significant clusters were validated independently. We discover that BRD4 regulates the expression of its own gene during the innate immune response. Interestingly, BRD4 activates the expression of NFκB/RelA, a coactivator that binds to BRD4 in a BD-dependent manner. We extend this finding to show that BRD4 also regulates other components of its functional interactome, including the Mediator (Med) coactivator complex and the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin (SMARC) subunits. To provide further insight into mechanisms for BRD4 in RSV expression, we mapped 7,845 RSV-inducible Tn5 transposase peaks onto the BRD4-dependent gene bodies. These were located in promoters and introns of cytostructural and extracellular matrix (ECM) formation genes. These data indicate that BRD4 mediates the dynamic response of airway epithelial cells to RNA infection by modulating the expression of its coactivators, controlling the expression of host defense mechanisms and remodeling genes through changes in promoter accessibility.

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Krüppel-Like Factor 5 regulates wound repair and the innate immune response in human airway epithelial cells.

Journal of Biological Chemistry ◽

10.1016/j.jbc.2021.100932 ◽

2021 ◽

pp. 100932

Author(s):

Alekh Paranjapye ◽

Monali NandyMazumdar ◽

James A. Browne ◽

Shih-Hsing Leir ◽

Ann Harris

Keyword(s):

Immune Response ◽

Epithelial Cells ◽

Innate Immune Response ◽

Wound Repair ◽

Airway Epithelial Cells ◽

Innate Immune ◽

Airway Epithelial ◽

Human Airway ◽

Human Airway Epithelial Cells

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Influenza virus infection increases ACE2 expression and shedding in human small airway epithelial cells

European Respiratory Journal ◽

10.1183/13993003.03988-2020 ◽

2021 ◽

pp. 2003988

Author(s):

Kelly S. Schweitzer ◽

Taylor Crue ◽

Jordan M. Nall ◽

Daniel Foster ◽

Satria Sajuthi ◽

...

Keyword(s):

Epithelial Cells ◽

Lung Injury ◽

Influenza A ◽

Viral Infections ◽

Influenza Virus Infection ◽

Airway Epithelial Cells ◽

Small Airway ◽

Small Airways ◽

Airway Epithelial ◽

Small Airway Epithelial Cells

Patients with COVID-19 caused by severe acute respiratory syndrome coronavirus (SARS-Co-V)-2 demonstrate high rates of co-infection with respiratory viruses, including influenza A (IAV), suggesting pathogenic interactions. We investigated how IAV may increase the risk for COVID-19 lung disease, focusing on the receptor Angiotensin Convertase Enzyme 2 (ACE2) and the protease TMPRSS2, which cooperate to uptake SARS-CoV-2 intracellular. We found, using single cell RNA sequencing of distal human non-diseased lung homogenates, that at baseline, ACE2 is minimally expressed in basal, goblet, ciliated, and secretory epithelial cells populating small airways. We focused on human small airway epithelial cells (SAEC), central to the pathogenesis of lung injury following viral infections. Primary SAEC from non-diseased donor lungs apically infected (at air-liquid interface) with IAV (up to 3×105 pfu; ∼1 MOI) markedly (8-fold) boosted the expression of ACE2, paralleling that of STAT1, a transcription factor activated by viruses. IAV increased the apparent electrophoretic mobility of intrac¬ellular ACE2 and generated an ACE2 fragment (90 kDa) in apical secretions, suggesting cleavage of this receptor. IAV also increased the expression of two proteases known to cleave ACE2, sheddase ADAM17 (TACE) and TMPRSS2 and increased the TMPRSS2 zymogen and its mature fragments, implicating proteolytic autoactivation. These results indicate that IAV amplifies the expression of molecules necessary for SARS-CoV-2 infection of the distal lung. Further, posttranslational changes in ACE2 by IAV may increase the vulnerability to lung injury such as ARDS during viral co-infections. These findings support prevention and treatment efforts of influenza infections during the COVID-19 pandemic.

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