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Bushra Mdkhana,1 Narjes Saheb Sharif-Askari,1 Rakhee K Ramakrishnan,1 Swati Goel,1 Qutayba Hamid,1– 3 Rabih Halwani1,2 1Sharjah Institute of Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; 2Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; 3Meakins-Christie Laboratories, Research Institute of the McGill University Health Center, Montreal, Quebec, CanadaCorrespondence: Rabih HalwaniCollege of Medicine, University of Sharjah, Sharjah, United Arab EmiratesEmail rhalwani@sharjah.ac.aeAbstract: The coronavirus disease 2019 (COVID-19) pandemic has affected millions of people and crippled economies worldwide. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for this pandemic has triggered avid research on its pathobiology to better understand the pathophysiology of COVID-19. In the absence of approved antiviral therapeutic strategies or vaccine platforms capable of effectively targeting this global threat, the hunt for effective therapeutics has led to many candidates being actively evaluated for their efficacy in controlling or preventing COVID-19. In this review, we gathered current evidence on the innate nucleic acid-sensing pathways expected to be elicited by SARS-CoV-2 and the immune evasion mechanisms they have developed to promote viral replication and infection. Within the nucleic acid-sensing pathways, SARS-CoV-2 infection and evasion mechanisms trigger the activation of NOD-signaling and NLRP3 pathways leading to the production of inflammatory cytokines, IL-1β and IL-6, while muting or blocking cGAS-STING and interferon type I and III pathways, resulting in decreased production of antiviral interferons and delayed innate response. Therefore, blocking the inflammatory arm and boosting the interferon production arm of nucleic acid-sensing pathways could facilitate early control of viral replication and dissemination, prevent disease progression, and cytokine storm development. We also discuss the rationale behind therapeutic modalities targeting these sensing pathways and their implications in the treatment of COVID-19.Keywords: COVID-19, SARS-CoV-2, innate immune system, nucleic acid sensing, immune evasion, NLRP3, cGAS-STING, coronavirus

Asthma is a chronic airway disorder associated with aberrant inflammatory and remodeling responses. Angiogenesis and associated vascular remodeling are one of the pathological hallmarks of asthma. The mechanisms underlying angiogenesis in asthmatic airways and its clinical relevance represent a relatively nascent field in asthma when compared to other airway remodeling features. Matrix metalloproteinases (MMPs) are proteases that play an important role in both physiological and pathological conditions. In addition to facilitating extracellular matrix turnover, these proteolytic enzymes cleave bioactive molecules, thereby regulating cell signaling. MMPs have been implicated in the pathogenesis of asthma by interacting with both the airway inflammatory cells and the resident structural cells. MMPs also cover a broad range of angiogenic functions, from the degradation of the vascular basement membrane and extracellular matrix remodeling to the release of a variety of angiogenic mediators and growth factors. This review focuses on the contribution of MMPs and the regulatory role exerted by them in angiogenesis and vascular remodeling in asthma as well as addresses their potential as therapeutic targets in ameliorating angiogenesis in asthma.

Mahmood Yaseen Hachim,1 Noha Mousaad Elemam,1 Rakhee K Ramakrishnan,1 Ibrahim Yaseen Hachim,1 Laila Salameh,1 Bassam Mahboub,1 Saba Al Heialy,2,3 Rabih Halwani,1 Rifat Hamoudi,1 Qutayba Hamid1,2 1Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; 2Meakins-Christie Laboratories, McGill University, Montreal, QC, Canada; 3College of Medicine, Mohammed Bin Rashid University, Dubai, United Arab EmiratesCorrespondence: Rifat HamoudiCollege of Medicine, University of Sharjah, PO Box 27272, Sharjah, United Arab EmiratesEmail rhamoudi@sharjah.ac.aeIntroduction: The proper use of serum periostin (POSTN) as a biomarker for asthma is hindered by inconsistent performance in different clinical settings.Objective: To explore patient’s factors that may affect POSTN expression locally and systematically and its utility as a biomarker for asthma development.Materials and Methods: Here we used bioinformatics analysis of publicly available transcriptomics data to confirm that POSTN is an asthma specific gene involved in core signaling pathways enriched in the bronchial epithelium during asthma. We then explored a large number of datasets to identify possible confounders that may affect the POSTN gene expression and consequently, its interpretation as a reliable biomarker for asthma. Plasma and saliva levels of POSTN were determined in locally recruited asthmatic patients (mild, moderate and severe) compared to healthy controls to confirm the bioinformatics findings.Results: Our bioinformatics results confirmed that POSTN was consistently upregulated in the bronchial epithelium in asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) bronchial epithelium. In asthma, its mRNA expression was affected by gender, sample anatomical site and type, steroid therapy, and smoking. In our cohort, plasma POSTN was upregulated in severe and non-severe asthmatic patients. Saliva POSTN was significantly higher in non-severe asthmatic patients compared to healthy and severe asthmatic patients (specifically those who are not on Xolair (omalizumab)). Patients’ BMI, inhaled steroid use and Xolair treatment affected POSTN plasma levels.Conclusion: Up to our knowledge, this is the first study examining the level of POSTN in the saliva of asthmatic patients. Both plasma and saliva POSTN levels can aid in early diagnosis of asthma. Saliva POSTN level was more sensitive than plasma POSTN in differentiating between severe and non-severe asthmatics. Patients’ characteristics like BMI, the use of inhaled steroids, or Xolair treatment should be carefully reviewed before any meaningful interpretation of POSTN level in clinical practice.Keywords: periostin, biomarkers, transcriptomics

Additional file 2: Figure. S1. Analytical flowchart outlining data curation and metrics used for analysis. Figure. S2. Bacterial sequence curation and analysis. We sequenced 16Sv4 amplicons generated from DNA samples on a MiSeq. MiSeq-generated Fastq files were quality-filtered and clustered into 97% similarity operational taxonomic units (OTUs) using the mothur software package [ http://www.mothur.org ]. The per-base raw Q30 (Phred33) scores of the forward sequencing read are summarized (A). Sequencing quality for R1 and R2 was determined using FastQC 0.11.5, the per-sequence averaged raw Q30 (Phred33) scores of the forward sequencing read are summarized (B). Figure. S3. Fungal sequence curation and analysis. We sequenced ITS2 amplicons generated from DNA samples on a MiSeq. MiSeq-generated Fastq files were quality-filtered and clustered into 97% similarity operational taxonomic units (OTUs) using the mothur software package [ http://www.mothur.org ]. The per-base raw Q30 (Phred33) scores of the forward sequencing read are summarized (A). Sequencing quality for R1 and R2 was determined using FastQC 0.11.5, the per-sequence averaged raw Q30 (Phred33) scores of the forward sequencing read are summarized (B). Figure. S4. Aggregated taxonomic composition. High quality reads were classified using Greengenes v. 13_8 as the reference database for bactria and UNITE (v. 7.1) as the reference database for fungi. We aggregated OTUs into each taxonomic rank, the aggregated taxa were visualized at each taxanomic rank using taxanomic bar plots and plotted the relative abundance of the most abundant ones for bacteria (A) and Fungi (B). The unfilled portion of the bar plots represent lower-abundance taxa.