Contribution of Human Lung Parenchyma and Leukocyte Influx to Oxidative Stress and Immune System-Mediated Pathology following Nipah Virus Infection

Abstract

Nipah virus (NiV) is a zoonotic emerging paramyxovirus that can cause fatal respiratory illness or encephalitis in humans. Despite many efforts, the molecular mechanisms of NiV-induced acute lung injury (ALI) remain unclear. We previously showed that NiV replicates to high titers in human lung grafts in NOD-SCID/␥ mice, resulting in a robust inflammatory response. Interestingly, these mice can undergo human immune system reconstitution by the bone marrow, liver, and thymus (BLT) reconstitution method, in addition to lung tissue engraftment, giving altogether a realistic model to study human respiratory viral infections. Here, we characterized NiV Bangladesh strain (NiV-B) infection of human lung grafts from human immune systemreconstituted mice in order to identify the overall effect of immune cells on NiV pathogenesis of the lung. We show that NiV-B replicated to high titers in human lung grafts and caused similar cytopathic effects irrespective of the presence of human leukocytes in mice. However, the human immune system interfered with virus spread across lung grafts, responded to infection by leukocyte migration to small airways and alveoli of the lung grafts, and accelerated oxidative stress in lung grafts. In addition, the presence of human leukocytes increased the expression of cytokines and chemokines that regulate inflammatory influx to sites of infection and tissue damage. These results advance our understanding of how the immune system limits NiV dissemination and contributes to ALI and inform efforts to identify therapeutic targets.IMPORTANCE Nipah virus (NiV) is an emerging paramyxovirus that can cause a lethal respiratory and neurological disease in humans. Only limited data are available on NiV pathogenesis in the human lung, and the relative contribution of the innate immune response and NiV to acute lung injury (ALI) is still unknown. Using human lung grafts in a human immune system-reconstituted mouse model, we showed that the NiV Bangladesh strain induced cytopathic lesions in lung grafts similar to those described in patients irrespective of the donor origin or the presence of leukocytes. However, the human immune system interfered with virus spread, responded to infection by leukocyte infiltration in the small airways and alveolar area, induced oxidative stress, and triggered the production of cytokines and chemokines that regulate inflammatory influx by leukocytes in response to infection. Understanding how leukocytes interact with NiV and cause ALI in human lung xenografts is crucial for identifying therapeutic targets.

Host gene expression profiles in ferrets infected with genetically distinct henipavirus strains

“…Henipavirus infection results in increasing expression and broadening repertoires of mediators of inflammation, including cytokines, chemokines, CAMs, and also, increased expression levels of macrophage markers (CD14, CD40, CD80, CD86, CD274 and LY96) due to the influx of these cells into the infected lung tissue ( Fig 3E ). The development of tissue damage also coincided with the onset of clinical signs ( Fig 2B–2D ), and is possibly driven by the strong activation of NF-kb mediated responses that lead to high levels of macrophage and neutrophil infiltration in the lung, a scenario that is commonly found in respiratory infections of viral origin [ 8 , 9 , 21 , 32 , 36 ]. One caveat in this study is that tissues used for host gene expression analysis were not perfused to remove blood which could potentially “contaminate” host gene expression profiles.…”

“…After performing IN inoculation, HeV and NiV infect the epithelial cells of the upper respiratory tract, the trachea, bronchi and alveoli [ 8 , 28 ]. Then, henipavirus infected epithelial cells produce type I interferon responses [ 29 ] that activate the antiviral responses, and cytokines that activate different components of the humoral and cellular innate immune responses at the tissue level [ 8 , 28 , 30 – 32 ]. As the respiratory infection progresses, the intensity of the local responses escalate beyond a biological threshold and triggers the activation of the endothelial cells, which, in turn, orchestrate and amplify the cytokine and chemokine responses leading to systemic immune activation, as shown for influenza virus [ 33 ].…”

Vitamin E Supplementation Ameliorates Newcastle Disease Virus-Induced Oxidative Stress and Alleviates Tissue Damage in the Brains of Chickens

“…Our results indicated that virulent NDV infection in chickens decreases the activities of vital enzymes, including SOD, GST, and CAT, involved in the elimination of ROS and the maintenance of redox balance. Numerous previous studies showed that other paramyxoviruses, like respiratory syncytial virus [ 6 ], Nipah virus [ 11 , 44 ], measles virus [ 10 ], and Sendai virus [ 45 ], cause oxidative stress.…”

Henipavirus infection of the central nervous system

“…Infection of SK-N-MC cell line with NiV-M was not productive, but did induce apoptosis (Chang et al 2006(Chang et al , 2007. In contrast, primary human endothelial cells and bronchial/small airway epithelial cells have been better characterized to induce IFN and inflammatory cytokine/chemokine responses (Lo et al 2010;Satterfield et al 2015;Escaffre et al 2016Escaffre et al , 2017. Interestingly, recent in vivo studies in African green monkeys found an absence of inflammation in the brain with low levels of lymphocytes (Hammoud et al 2018).…”