Abstract 13747: Targeting Urokinase-Type Plasminogen Activator (uPA) and the uPA Receptor, Reduces Vascular Inflammation and Lung Hemorrhage in Systemic Lupus and SARS CoV2 Infection in Mouse Models of Respiratory Distress Syndromes

Introduction: Acute respiratory distress syndromes with vascular inflammation and alveolar hemorrhage have high mortality and limited treatment. Autoimmune disease and severe viral infection cause vascular inflammation and hemorrhage. Serine protease coagulation pathways increase inflammatory cell activation and damage. Viruses have evolved highly effective immune modulating ser ine p roteinase in hibitors, serpins . Myxomavirus Serp-1 improves survival and reduces inflammation, vasculitis and lung hemorrhage in MHV68 gamma herpes infections (P < 0.01). Serp-1 also reduces Lupus alveolar hemorrhage (DAH) and proved safe and effective in a randomized, blinded, dose escalating trial in patients with coronary stent implant. Hypothesis: We hypothesize that treatment with PEGylated Serp-1 (PEGSerp-1) will reduce hemorrhage and inflammatory vasculitis in autoimmune and infectious lung disease. Methods: Pristane induced DAH and SARS-CoV-2 virus infections were treated with PEGSerp-1 in mouse models. Results: Serp-1 and PEGSerp-1 given daily IP for 14 days significantly reduced pristane induced DAH (N = 30 C57Bl/6 mice; P < 0.05) at 14 days follow up. PEGSerp-1 also reduced lung hemorrhage given for 7days treatment (N = 6 mice; P <0.01) or when given 7 days after pristane induction of DAH (N = 6 mice; P < 0.01). Macrophage invasion (P < 0.01), Prussian blue staining for hemosiderosis, C5b-9 complex deposition and soluble uPAR (suPAR) were significantly reduced with PEGSerp-1 treatment. PEGSerp-1 given daily after SARS-CoV-2 infection (48hrs, BALB/c mice, N = 16) also significantly reduced lung inflammation; decreased F4/80+ and iNOS+ macrophage staining (P < 0.02). Virus titer was also reduced in TMPRS2+ Vero cells (10μg/mL), and in SARS infected lungs. PEG Serp-1 homes to areas of pristane lung damage, but not normal lungs, indicating targeting of protease activation. No adverse effects were detected. Conclusion: Treatment for vascular inflammation and hemorrhage in severe autoimmune and virus induced respiratory distress syndromes is very limited. Targeting thrombolytic and inflammatory serine protease uPA/ uPAR complex activation provides a new therapeutic approach to severe respiratory distress in autoimmune disease and viral infection.

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Molecular Mimicry by Herpes Simplex Virus-Type 1:Autoimmune Disease After Viral Infection

PEDIATRICS ◽

10.1542/peds.104.2.s1.403a ◽

1999 ◽

Vol 104 (2) ◽

pp. 403-403

Author(s):

J. E. Gern

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Autoimmune Disease ◽

Viral Infection ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Molecular Mimicry ◽

Simplex Virus

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Nitric oxide and interval hypoxic training in COVID-19 rehabilitation— new research direction

Fizioterapevt (Physiotherapist) ◽

10.33920/med-14-2108-04 ◽

2021 ◽

pp. 30-41

Author(s):

Tatyana Nikolaevna Tsyganova ◽

Egor Egorov ◽

Tamara Nikolaevna Voronina

Keyword(s):

Nitric Oxide ◽

Acute Respiratory Distress Syndrome ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Viral Infection ◽

Distress Syndrome ◽

The Body ◽

Lung Damage ◽

Specific Method ◽

Hypoxic Training

COVID-19, a disease caused by the novel coronavirus SARS-CoV-2, primarily affects lung tissue and disrupts gas exchange, leading to acute respiratory distress syndrome, systemic hypoxia, and lung damage. The search for methods of prevention and rehabilitation, especially after suffering from pneumonia caused by COVID-19, is on the agenda. This article discusses the possibilities of the interval hypoxic training (IHT) method for preventing infections by initiating nitric oxide production in the body. One of the main effects of IHT is the balanced stimulation of nitric oxide (NO) secretion. Over the past two decades, there has been an increasing interest in the function of nitric oxide (NO) in the human body. Nitric oxide plays a key role in maintaining normal vascular function and regulating inflammatory processes, including those leading to lung damage and the development of acute respiratory distress syndrome (ARDS). Our immune system destroys bacteria and viruses by oxidative burst, i.e. when oxygen accumulates inside the cell. This process also involves nitric oxide, a signaling molecule that has an antibacterial and antiviral effect, as well as regulates vascular tone and affects the permeability of the cell wall. Interval hypoxytherapy enhances endogenous oxidative protection and increases the amount of nitric oxide, thus allowing the body’s cells to resist infection more effectively. Mitochondrial NOS induction and mitochondrial NO synthesis increase under the action of pathogenic factors on the cell. By modulating the activity of mtNOS and the synthesis of mitochondrial NO, it is possible to increase the resistance to hypoxic effects. Interval hypo-hyperoxic training as an effective non-specific method of increasing the body’s defenses is indispensable not only in the prevention of viral infection, but also in rehabilitation after viral pneumonia, as well as as a method that reduces the severity of viral infection in the event of infection.

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Molecular Mimicry by Herpes Simplex Virus-Type 1:Autoimmune Disease After Viral Infection

PEDIATRICS ◽

10.1542/peds.104.s2.403b ◽

1999 ◽

Vol 104 (Supplement_2) ◽

pp. 403-403

Author(s):

James E. Gern

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Autoimmune Disease ◽

Viral Infection ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Molecular Mimicry ◽

Simplex Virus

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The Early Gene hhi1 Reactivates Heliothis zea Nudivirus 1 in Latently Infected Cells

Journal of Virology ◽

10.1128/jvi.01548-09 ◽

2009 ◽

Vol 84 (2) ◽

pp. 1057-1065 ◽

Cited By ~ 18

Author(s):

Yueh-Lung Wu ◽

Carol P. Wu ◽

Song-Tay Lee ◽

Han Tang ◽

Chi-Hua Chang ◽

...

Keyword(s):

Viral Infection ◽

Critical Role ◽

Heliothis Zea ◽

Virus Titer ◽

Viral Reactivation ◽

Early Gene ◽

Mechanistic Study ◽

Early Genes ◽

Latently Infected ◽

Infected Cells

ABSTRACT Heliothis zea nudivirus 1 (HzNV-1), previously known as Hz-1 virus, is an insect virus able to establish both productive and latent infections in several lepidopteran insect cells. Here, we have cloned and characterized one of the HzNV-1 early genes, hhi1, which maps to the HindIII-I fragment of the viral genome. During the productive viral infection, a 6.2-kb hhi1 transcript was detectable as early as 0.5 h postinfection (hpi). The level of transcript reached a maximum at 2 hpi and gradually decreased after 4 hpi. The transcript was not detectable during the latent phase of viral infection. Upon cycloheximide treatment, much higher levels of hhi1 transcript were detected throughout the productive viral infection cycle, suggesting that newly synthesized proteins are not needed for the expression of hhi1. Nevertheless, viral coinfection can further stimulate the expression of transfected hhi1 promoter in a plasmid. Transient hhi1 expression in latently infected cells resulted in a significant increase in virus titer and viral DNA propagation, suggesting that hhi1 plays a critical role in viral reactivation. Additional experiments showed that six early genes, which possibly function in transcription or DNA replication, were activated in the latent cells upon hhi1 transfection. Among these six genes, orf90 and orf121 expression could be induced by hhi1 alone without the need for other viral genes. Our discovery should be useful for future mechanistic study of the switches of latent/productive HzNV-1 viral infections.

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INTERLEUKIN-1 RECEPTORS IN THE BRAIN IN RELATION TO VIRAL INFECTION, STRESS AND AUTOIMMUNE DISEASE

Behavioural Pharmacology ◽

10.1097/00008877-199605001-00112 ◽

1996 ◽

Vol 7 (Supplement 1) ◽

pp. 49

Author(s):

C HEIDBREDER ◽

T S SHIPPENBERG

Keyword(s):

Autoimmune Disease ◽

Viral Infection ◽

Interleukin 1 ◽

The Brain

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Comparison of Type I Interferon Expression in Adult and Neonatal Mice during Respiratory Viral Infection

10.29007/ltkw ◽

2019 ◽

Author(s):

Zifeng Liang

Keyword(s):

Immune Response ◽

Viral Infection ◽

Mouse Models ◽

Post Infection ◽

Type I Interferon ◽

Sendai Virus ◽

Killer Cell ◽

Type I ◽

Respiratory Viral Infection ◽

Neonatal Mice

The aim of this paper is to identify the difference of type I interferon expression in 2- day neonatal and six-to-eight-weeks adult mice infected by Sendai virus (SeV), a single- stranded RNA virus of the family Paramyxoviridae. Sendai virus mimics the influence of respiratory syncytial virus (RSV) on humans, but does not infect humans. Although RSV has a fatal impact on people across age groups, little is understood about this common virus and the disparity between neonatal and adult immune response to it. It has been suggested by past findings that Type I interferon mRNA is present in higher levels in adults than in neonates, however there is a greater amount of interferon proteins in neonates rather than adults. To test the hypothesis that neonates are more capable of interferon production and preventing the translation of viral protein, I observed mouse models of respiratory viral infection and determined the expression of IFN-α1, IFN-α2, IFN-α5, IFN-α6, IFN-α7, IFN-β in archived mouse lung tissue samples harvested on different days post-infection with quantitative real time PCR. Expression of Glyceraldehyde 3-phosphate dehydrogenase(GAPDH), a housekeeping gene expressed constitutively in all mouse models, was used as a positive control of the experiment. To determine the ideal concentration of primer used in qPCR, primer reconstitution, primer optimization, and gel electrophoresis were conducted in advance. In addition, technical replicates and biological replicates were used to reduce error and confirm results in qPCR. In accordance with previous discovery, I found an upward trend in adults’ interferon expression from post-infection day 1 to day 5, and levels off in day 7. In contrast, neonatal levels were much higher on day 1 and remained high over the course of infection. This explains how type I interferon expression is altered in neonates to help them clear the virus at the same efficiency as adults without causing inflammation. Future research on immune response differences in human infection should focus on the evaluation of interferon protein amounts, as well as the analysis of activation of molecules downstream of the type I interferon receptors, such as signal transducer and activator of transcription (STAT) protein family. It is also crucial to compare immune cells like macrophages and natural killer cell activity in adult and neonatal mice during viral infection.

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