Endothelial cell tropism is a determinant of H5N1 pathogenesis in mammalian species

Tundup, Smanla; Kandasamy, Matheswaran; Perez, Jasmine T.; Mena, Ignacio; Steel, John; Nagy, Tamás; Albrecht, Randy A.; Manicassamy, Balaji

doi:10.1371/journal.ppat.1006270

Cited by 48 publications

(55 citation statements)

References 66 publications

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“…The importance of a functional endothelial barrier was demonstrated in a model of E. coli pneumonia, in which blockade of the interaction between integrin αvβ3 and its binding partner IQGAP1 at the endothelial cell-cell junction led to excesses in lung extravascular plasma and water, as well as increased lung weight within just 5 h of infection (216). It has also been shown that influenza infection can lead to vascular leak (217,218). This loss of barrier integrity stems, at least in part, from active infection of endothelial cells by influenza virus.…”

Section: Pulmonary Endothelial Cell Tolerance Mechanisms Endothelial mentioning

confidence: 99%

“…Cytokine storm following pulmonary infection is detrimental to the host, as limiting its magnitude has been shown to improve survival. For example, limiting H5N1 influenza infection in endothelial cells using microRNAs both reduced cytokine storm and improved survival (218). Similarly, treatment with an S1P1 antagonist during influenza infection reduced mortality in an endothelial cell-specific manner (226).…”

Section: Contribution Of Endothelial Cells To Cytokine Stormmentioning

confidence: 99%

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Surviving Deadly Lung Infections: Innate Host Tolerance Mechanisms in the Pulmonary System

et al. 2018

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Much research on infectious diseases focuses on clearing the pathogen through the use of antimicrobial drugs, the immune response, or a combination of both. Rapid clearance of pathogens allows for a quick return to a healthy state and increased survival. Pathogen-targeted approaches to combating infection have inherent limitations, including their pathogen-specific nature, the potential for antimicrobial resistance, and poor vaccine efficacy, among others. Another way to survive an infection is to tolerate the alterations to homeostasis that occur during a disease state through a process called host tolerance or resilience, which is independent from pathogen burden. Alterations in homeostasis during infection are numerous and include tissue damage, increased inflammation, metabolic changes, temperature changes, and changes in respiration. Given its importance and sensitivity, the lung is a good system for understanding host tolerance to infectious disease. Pneumonia is the leading cause of death for children under five worldwide. One reason for this is because when the pulmonary system is altered dramatically it greatly impacts the overall health and survival of a patient. Targeting host pathways involved in maintenance of pulmonary host tolerance during infection could provide an alternative therapeutic avenue that may be broadly applicable across a variety of pathologies. In this review, we will summarize recent findings on tolerance to host lung infection. We will focus on the involvement of innate immune responses in tolerance and how an initial viral lung infection may alter tolerance mechanisms in leukocytic, epithelial, and endothelial compartments to a subsequent bacterial infection. By understanding tolerance mechanisms in the lung we can better address treatment options for deadly pulmonary infections.

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Section: Pulmonary Endothelial Cell Tolerance Mechanisms Endothelial mentioning

confidence: 99%

Section: Contribution Of Endothelial Cells To Cytokine Stormmentioning

confidence: 99%

Surviving Deadly Lung Infections: Innate Host Tolerance Mechanisms in the Pulmonary System

et al. 2018

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“…Over the past 20 years, H5N1 viruses from infected domestic poultry have crossed the species barrier, causing severe and often fatal infections in humans with mortality rates as high as 60% (9). Many of the viral components critical for the enhanced virulence of H5N1 have been identified through the generation of recombinant and/or reassortant viruses (10) (11, 12). Prior studies have shown that the multibasic cleavage site (MBS) in the viral hemagglutinin of H5N1 facilitates higher viral replication and mediates extrapulmonary spread (13-15).…”

Section: Introductionmentioning

confidence: 99%

“…Prior studies have shown that the multibasic cleavage site (MBS) in the viral hemagglutinin of H5N1 facilitates higher viral replication and mediates extrapulmonary spread (13-15). In addition, our group has recently demonstrated that the endothelial cell tropism of H5N1 contributes to barrier disruption, microvascular leakage, and subsequent mortality (12). Moreover, polymorphisms that increase viral replication have been identified in the viral polymerase subunits of H5N1 strains (16-20).…”

Section: Introductionmentioning

confidence: 99%

Suppression of Cytotoxic T Cell Functions and Decreased Levels of Tissue Resident Memory T cell During H5N1 infection

Kandasamy

Furlong

Perez

et al. 2020

Preprint

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25Seasonal influenza virus infections cause mild illness in healthy adults, as timely viral 26 clearance is mediated by the functions of cytotoxic T cells. However, avian H5N1 influenza 27 virus infections can result in prolonged and fatal illness across all age groups, which has been 28 attributed to the overt and uncontrolled activation of host immune responses. Here we 29 investigate how excessive innate immune responses to H5N1 impair subsequent adaptive T 30 cell responses in the lungs. Using recombinant H1N1 and H5N1 strains sharing 6 internal 31 genes, we demonstrate that H5N1 (2:6) infection in mice causes higher stimulation and 32 increased migration of lung dendritic cells to the draining lymph nodes, resulting in higher 33 numbers of virus specific T cells in the lungs. Despite robust T cell responses in the lungs, 34 H5N1 (2:6) infected mice showed inefficient and delayed viral clearance as compared to H1N1 35 infected mice. In addition, we observed higher levels of inhibitory signals including increased 36 PD1 and IL-10 expression by cytotoxic T cells in H5N1 (2:6) infected mice, suggesting that 37 delayed viral clearance of H5N1 (2:6) was due to suppression of T cell functions in vivo. 38

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“…Influenza A virus infections of extrapulmonary tissues, including the heart, spleen, kidney, thymus, and brain have been reported for various mouse models of infection (Fislova et al, 2009;Kotaka et al, 1990;Tundup et al, 2017). However, relevant models in which significant cardiac pathogenesis occurs are lacking, thus hindering advancement in the study of cardiac complications of influenza virus infection.…”

Section: Introductionmentioning

confidence: 99%

IFITM3 protects the heart during influenza virus infection

Kenney

McMichael

Imas

et al. 2019

Preprint

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Influenza virus primarily targets the lungs, but dissemination and damage to heart tissue is also known to occur in severe infections. Despite this knowledge, influenza virus-induced cardiac pathogenesis and its underlying mechanisms have been difficult to study due to a lack of small animal models. In humans, polymorphisms in the gene encoding interferoninduced transmembrane protein 3 (IFITM3), an antiviral restriction factor, are associated with susceptibility to severe influenza, but whether IFITM3 deficiencies contribute to other aspects of pathogenesis, including cardiac dysfunction, is unknown. We now show that IFITM3 deficiency in a newly generated knockout (KO) mouse model exacerbates illness and mortality following influenza A virus infection. Enhanced pathogenesis correlated with increased replication of virus in the lungs, spleens, and hearts of KO mice relative to wildtype (WT) mice. IFITM3 KO mice exhibited normal cardiac function at baseline, but developed severely aberrant electrical activity upon infection, including decreased heart rate and irregular, arrhythmic RR (interbeat) intervals. In contrast, WT mice exhibited a mild decrease in heart rate without irregularity of RR intervals. Heightened cardiac virus titers and electrical dysfunction in KO animals was accompanied by increased activation of fibrotic pathways and fibrotic lesions in the heart. Our findings reveal an essential role for IFITM3 in controlling influenza virus replication and pathogenesis in heart tissue and establish IFITM3 KO mice as a powerful model to study virus-induced cardiac dysfunction.3

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Endothelial cell tropism is a determinant of H5N1 pathogenesis in mammalian species

Cited by 48 publications

References 66 publications

Surviving Deadly Lung Infections: Innate Host Tolerance Mechanisms in the Pulmonary System

Surviving Deadly Lung Infections: Innate Host Tolerance Mechanisms in the Pulmonary System

Suppression of Cytotoxic T Cell Functions and Decreased Levels of Tissue Resident Memory T cell During H5N1 infection

IFITM3 protects the heart during influenza virus infection

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