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/γ 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 system-reconstituted 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.

Download Full-text

COVID-19 treatment modalities

10.31219/osf.io/u56fc ◽

2020 ◽

Author(s):

Mohamed M. Gamaleldin ◽

SHAIMAA M. NASHAT

Keyword(s):

Clinical Trial ◽

Immune System ◽

Mortality Rate ◽

Treatment Modalities ◽

Virus Spread ◽

Human Immune System ◽

Research Article ◽

Antiviral Medication ◽

Effective Role ◽

Human Immune

COVID-19 infections virus spread worldwide and impact many countries with sever economical sequences. The effective antiviral medication or vaccination for the virus is unavailable until the present date and it takes months or years to discover the effective treatment or test the efficacy of the discovered treatment.Based on these facts, the human immune system against the virus may have an effective role to regulate the infection and reduce the mortality rate among the infected patients. This proposed research article aims to explore the available medication/ natural supplementation to boost the immunity system of the patients against COVID-19 infections and reduce the mortality rate among infected patients. Methods: a proposed clinical trial will be carried out to investigate the effect of the different treatment modalities on the human immune system against COVID-19 infection.

Download Full-text

Faculty Opinions recommendation of The genetic architecture of the human immune system: a bioresource for autoimmunity and disease pathogenesis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725390605.793505391 ◽

2015 ◽

Author(s):

Toshihiro Nakajima ◽

Satoko Aratani

Keyword(s):

Immune System ◽

Genetic Architecture ◽

Human Immune System ◽

Disease Pathogenesis ◽

System A ◽

Human Immune

Download Full-text

721 AT1412, a patient-derived CD9 antibody in preclinical development promoting tumor immune infiltration and inducing tumor rejection

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0721 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A763-A763

Author(s):

Remko Schotte ◽

Julien Villaudy ◽

Martijn Kedde ◽

Wouter Pos ◽

Daniel Go ◽

...

Keyword(s):

T Cells ◽

Immune System ◽

T Cell ◽

Tumor Cells ◽

Tumor Rejection ◽

Human Immune System ◽

Preclinical Development ◽

High Affinity ◽

Human Immune ◽

A375 Melanoma

BackgroundAdaptive immunity to cancer cells forms a crucial part of cancer immunotherapy. Recently, the importance of tumor B-cell signatures were shown to correlate with melanoma survival. We investigated whether tumor-targeting antibodies could be isolated from a patient that cured (now 13 years tumor-free) metastatic melanoma following adoptive transfer of ex vivo expanded autologous T cells.MethodsPatient‘s peripheral blood B cells were isolated and tested for the presence of tumor-reactive B cells using AIMM’s immmortalisation technology. Antibody AT1412 was identified by virtue of its differential binding to melanoma cells as compared to healthy melanocytes. AT1412 binds the tetraspanin CD9, a broadly expressed protein involved in multiple cellular activities in cancer and induces ADCC and ADCP by effector cells.ResultsSpontaneous immune rejection of tumors was observed in human immune system (HIS) mouse models implanted with CD9 genetically-disrupted A375 melanoma (A375-CD9KO) tumor cells, while A375wt cells were not cleared. Most notably, no tumor rejection of A375-CD9KO tumors was observed in NSG mice, indicating that blockade of CD9 makes tumor cells susceptible to immune rejection.CD9 has been described to regulate integrin signaling, e.g. LFA-1, VLA-4, VCAM-1 and ICAM-1. AT1412 was shown to modulate CD9 function by enhancing adhesion and transmigration of T cells to endothelial (HUVEC) cells. AT1412 was most potently enhancing transendothelial T-cell migration, in contrast to a high affinity version of AT1412 or other high affinity anti-CD9 reference antibodies (e.g. ALB6). Enhanced immune cell infiltration is also observed in immunodeficient mice harbouring a human immune system (HIS). AT1412 strongly enhanced CD8 T-cell and macrophage infiltration resulting in tumor rejection (A375 melanoma). PD-1 checkpoint blockade is further sustaining this effect. In a second melanoma model carrying a PD-1 resistant and highly aggressive tumor (SK-MEL5) AT1412 together with nivolumab was inducing full tumor rejection, while either one of the antibodies alone did not.ConclusionsThe safety of AT1412 has been assessed in preclinical development and is well tolerated up to 10 mg/kg (highest dose tested) by non human primates. AT1412 demonstrated a half-life of 8.5 days, supporting 2–3 weekly administration in humans. Besides transient thrombocytopenia no other pathological deviations were observed. No effect on coagulation parameters, bruising or bleeding were observed macro- or microscopically. The thrombocytopenia is reversible, and its recovery accelerated in those animals developing anti-drug antibodies. First in Human clinical study is planned to start early 2021.Ethics ApprovalStudy protocols were approved by the Medical Ethical Committee of the Leiden University Medical Center (Leiden, Netherlands).ConsentBlood was obtained after written informed consent by the patient.

Download Full-text

Transplacental priming of the human immune system with environmental allergens can occur early in gestation

Journal of Allergy and Clinical Immunology ◽

10.1067/mai.2000.108710 ◽

2000 ◽

Vol 106 (3) ◽

pp. 530-536 ◽

Cited By ~ 77

Author(s):

Zsolt Szépfalusi ◽

Josefa Pichler ◽

Stefan Elsässer ◽

Katalin van Duren ◽

Christof Ebner ◽

...

Keyword(s):

Immune System ◽

Human Immune System ◽

Human Immune

Download Full-text

Antimicrobial peptides: The ancient arm of the human immune system

Virulence ◽

10.4161/viru.1.5.12983 ◽

2010 ◽

Vol 1 (5) ◽

pp. 440-464 ◽

Cited By ~ 389

Author(s):

Jochen Wiesner ◽

Andreas Vilcinskas

Keyword(s):

Immune System ◽

Antimicrobial Peptides ◽

Human Immune System ◽

Human Immune

Download Full-text

On the use of multiple heterogeneous devices to speedup the execution of a computational model of the Human Immune System

Applied Mathematics and Computation ◽

10.1016/j.amc.2015.03.072 ◽

2015 ◽

Vol 267 ◽

pp. 304-313 ◽

Cited By ~ 2

Author(s):

T.M. do Nascimento ◽

J.M. de Oliveira ◽

M.P. Xavier ◽

A.B. Pigozzo ◽

R.W. dos Santos ◽

...

Keyword(s):

Immune System ◽

Computational Model ◽

Human Immune System ◽

Heterogeneous Devices ◽

Human Immune

Download Full-text

Al-Muddaththir of the Quran Linked to the Covid-19 and Spanish Flu Pandemics: Circumstantial Evidence

Journal of Quranic Sciences and Research ◽

10.30880/jqsr.2021.02.02.003 ◽

2021 ◽

Vol 02 (02) ◽

Author(s):

Baback Khodadoost ◽

Keyword(s):

Immune System ◽

Circumstantial Evidence ◽

The Moon ◽

Human Immune System ◽

Main Emphasis ◽

Spanish Flu ◽

Human Immune

Recently there have been speculations concerning a possible link between the covid-19 pandemic and al-Muddaththir, the 74th chapter of the Quran. An examination of this chapter presented in this article shows further evidences in support of these speculations. It is shown that indications of not only the current Covid-19 pandemic, but also the horrific 1918 Spanish flu can be detected in chapter 74. The main emphasis of this article will be to demonstrate the timings of the pandemic events as they appear to have been encoded in four of the chapter verses. The concept of Translational-Coding and in particular, its use in decoding one of the time-informing verses will be explained. A remarkable scheme of al-Muddaththir to announce the exact occurring years of the two major pandemics, will also be exposed. Coincidences of the Super Moon occurrences with major events of both, Covid-19 and Spanish flu pandemics, will be shown as the possible reason for “by the moon” swearing in verse 74:32. In connection with these observed coincidences, possible effect of the moon’s differential gravity on suppression of the human immune system during a Super Moon occurrence will be addressed. Some other verses in al-Muddaththir with possible relevance to the pandemic perspective of this chapter will also be discussed.

Download Full-text