COVID-19 research

Gene: MPO

Comment on list classification: Based on an external review detailing a number of publications where MPO is reviewed because of its association in the regulation of (neutrophil extracellular traps) NET formation upgrading from Amber to Green

Should also be noted that elevated levels of inflammatory mediators (including IL-6, IL-8, and MPO) in the airway of chronic/extended or recurrent RSV infection are associated with faster lung function decline in COPD patients. PMID: 32227102

Created: 22 Apr 2020, 4:25 p.m. | Last Modified: 22 Apr 2020, 4:33 p.m.

Panel Version: 0.135

Green List (high evidence)

Neutrophil extracellular traps(NETs) are produced by neutrophils to fight infection and secreted in the lung and blood. However many studies suggest that increased NET production may play a role in destruction of lung tissue and increased inflammatory response. This has been demonstrated directly by 2 studies and indirectly by the last 3 studies which study the effect of drugs (antioxidants) which work by decreasing MPO activity among other inflammatory molecules. I would highly suggest inclusion in the panel due to the MPO effect on lung tissues and the possibility that it might be the cause of ARDS in COVID-19 patients.


Neutrophil Extracellular Traps in Pulmonary Diseases: Too Much of a Good Thing?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983612/
PMID: 27574522
The detrimental effect of excessive NET release is particularly important to lung diseases, because NETs(Neutrophil extra cellular trap) can expand more easily in the pulmonary alveoli, causing lung injury. Moreover, NETs and its associated molecules are able to directly induce epithelial and endothelial cell death. In this regard, massive NET formation has been reported in several pulmonary diseases, including asthma, chronic obstructive pulmonary disease, cystic fibrosis, respiratory syncytial virus bronchiolitis, influenza, bacterial pneumonia, and tuberculosis, among others.

The characteristic feature of acute lung inflammation following influenza virus infection is the excessive infiltration of neutrophils in the lungs (142, 143)
Neutrophils have been demonstrated to play both protective and detrimental roles during influenza virus infection (143, 145, 146). Among the harmful roles played by neutrophils is the excessive production of NETs in the lungs of animals infected with influenza A H1N1 virus. NETs expressing histones and MMP-9 were found entangled with alveoli, causing increased alveolar capillary damage and obstruction of the small airways, thus confirming the link of these DNA lattices with lung damage (146). Paradoxically, the antimicrobial protein expressed on NETs, α-defensin-1, is able to directly inhibit influenza replication through the inhibition of protein kinase C (PKC) in infected cells (150); however the expression of α-defensins on NETs induced by this virus has yet to be demonstrated.



Excessive Neutrophils and Neutrophil Extracellular Traps Contribute to Acute Lung Injury of Influenza Pneumonitis
PMID: 21703402
We examined pathological manifestations in models of macrophage- or neutrophil-depleted mice challenged with sublethal doses of influenza A virus H1N1 strain PR8. Infected mice depleted of macrophages displayed excessive neutrophilic infiltration, alveolar damage, and increased viral load, later progressing into ARDS-like pathological signs with diffuse alveolar damage, pulmonary edema, hemorrhage, and hypoxemia. In contrast, neutrophil-depleted animals showed mild pathology in lungs. The brochoalveolar lavage fluid of infected macrophage-depleted mice exhibited elevated protein content, T1-α, thrombomodulin, matrix metalloproteinase-9, and myeloperoxidase activities indicating augmented alveolar-capillary damage, compared to neutrophil-depleted animals. We provide evidence for the formation of neutrophil extracellular traps (NETs), entangled with alveoli in areas of tissue injury, suggesting their potential link with lung damage. When co-incubated with infected alveolar epithelial cells in vitro, neutrophils from infected lungs strongly induced NETs generation, and augmented endothelial damage. NETs induction was abrogated by anti-myeloperoxidase antibody and an inhibitor of superoxide dismutase, thus implying that NETs generation is induced by redox enzymes in influenza pneumonia. These findings support the pathogenic effects of excessive neutrophils in acute lung injury of influenza pneumonia by instigating alveolar-capillary damage.



High Level of Neutrophil Extracellular Traps Correlates With Poor Prognosis of Severe Influenza A Infection
PMID: 29325098

Results: We found that patients with severe influenza showed elevated plasma NET level on the day of admission. Neutrophils from these patients showed higher capacity to release MPO-DNA complex in response to interleukin-8 or lipopolysaccharide stimulation. We also found that NETs from H7N9 and H1N1 patients increased the permeability of alveolar epithelial cells, and, consequently, NET production was positively correlated with acute physiology and chronic health evaluation (APACHE) II score and MODS.
Conclusions: These data indicate that high level of NETs contributes to lung injury and is correlated with severity of disease. Thus, NETs might be a key factor to predict the poor prognosis in IAV patients.

Dauricine Combined With Clindamycin Inhibits Severe Pneumonia Co-Infected by Influenza Virus H5N1 and Streptococcus Pneumoniae in Vitro and in Vivo Through NF-κB Signaling Pathway
PMID:29769163

N-acetyl-l-cystine (NAC) protects against H9N2 swine influenza virus-induced acute lung injury 24968347
Attenuation of Influenza-Like Symptomatology and Improvement of Cell-Mediated Immunity With Long-Term N-acetylcysteine Treatment 9230243
Clinical Trial

Created: 10 Apr 2020, 8:53 a.m. | Last Modified: 10 Apr 2020, 8:53 a.m.

Panel Version: 0.81

Publications

• PMID: 27574522,21703402,29325098,29769163,24968347

Red List (low evidence)

deficiency of MPO is usually asymptomatic, and not classified as an immunodeficiency by the IUIS

Created: 29 Jun 2018, 2:40 p.m.

I don't know

Comment on list classification: PMID 3208230 outlines the role of neutrophil extracellular traps (NETs) in the control of some pathogens including viruses, by virus capture and neutralization. In vivo treatment of the mice with DNase resulted in the enhanced susceptibility of IFNAR-/- mice to the CHIKV virus. Furthermore, the levels of MPO-DNA complex in acutely CHIKV-infected patients, were correlated with the levels of NETs and the viral load in the blood, suggesting that NETs are also released in natural human infection cases. Therefore, variants that result in myeloperoxidase deficiency, may well contribute to an increased susceptiblity to viral infection.
At least 9 variants have been reported in Myeloperoxidase deficiency 254600 and these could well be contributing to increased viral susceptibily.

Created: 7 Apr 2020, 2:03 p.m. | Last Modified: 7 Apr 2020, 2:03 p.m.

Panel Version: 0.60

Associated with phenotype in OMIM and not in Gen2Phen. At least 9 variants identified. Although the phenotype may not be directly relevant for this panel, patients may be recruited under this heading with recurrent fungal infections (Helen Britain).

Created: 8 May 2018, 10:38 a.m.

I don't know

Comment on list classification: Changed from Amber to Red based on external clinical expert review and review of the literature. Deficiency of MPO is notes as asymptomatic, and not classified as an immunodeficiency by the IUIS, but it is noted on the ESID classification list. Request evidences /immunological association of this gene from GRID

Created: 4 Jul 2018, 1:07 p.m.

This gene was absent from the original PanelApp PID panel dataset (review April 2018). However it was listed in external expert immunodeficiency diagnostic gene list(s) GOSH or GRID. In this combined PID panel, this gene has been rated as AMBER and needs further curational review to assess pertinence prior to v1.

Created: 20 Apr 2018, 12:25 p.m.

Original metadata downloaded from ESID Registry. ESID_Gene_original: MPO, PanelApp HGNC gene symbol check: MPO, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Phagocytic disorders / Myeloperoxidase deficiency (MPO) / Myeloperoxidase deficiency (MPO)

Created: 17 Apr 2018, 12:29 p.m.

Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: MPO, GRID_Gene_Symbol: MPO, GRID_Transcript_ENS_Community submitted: ENST00000225275, GRID_Transcript_RefSeq: NM_000250.1, GRID_Transcript_ENS_used_on_Production: ENST00000225275

Created: 17 Apr 2018, 12:12 p.m.