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Dr. Karen Mossman
McMaster University, Canada

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0 Virology
0 Innate antiviral response
0 viral and host factors
0 Innate immunity
0 Viro-immunotherapy

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Innate antiviral response
Innate immunity
Interferon signaling
viral and host factors

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Review
Published: 13 August 2021 in Virology Journal
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The emergence of a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and more recently, the independent evolution of multiple SARS-CoV-2 variants has generated renewed interest in virus evolution and cross-species transmission. While all known human coronaviruses (HCoVs) are speculated to have originated in animals, very little is known about their evolutionary history and factors that enable some CoVs to co-exist with humans as low pathogenic and endemic infections (HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1), while others, such as SARS-CoV, MERS-CoV and SARS-CoV-2 have evolved to cause severe disease. In this review, we highlight the origins of all known HCoVs and map positively selected for mutations within HCoV proteins to discuss the evolutionary trajectory of SARS-CoV-2. Furthermore, we discuss emerging mutations within SARS-CoV-2 and variants of concern (VOC), along with highlighting the demonstrated or speculated impact of these mutations on virus transmission, pathogenicity, and neutralization by natural or vaccine-mediated immunity.

ACS Style

Jalen Singh; Pranav Pandit; Andrew G. McArthur; Arinjay Banerjee; Karen Mossman. Evolutionary trajectory of SARS-CoV-2 and emerging variants. Virology Journal 2021, 18, 1 -21.

AMA Style

Jalen Singh, Pranav Pandit, Andrew G. McArthur, Arinjay Banerjee, Karen Mossman. Evolutionary trajectory of SARS-CoV-2 and emerging variants. Virology Journal. 2021; 18 (1):1-21.

Chicago/Turabian Style

Jalen Singh; Pranav Pandit; Andrew G. McArthur; Arinjay Banerjee; Karen Mossman. 2021. "Evolutionary trajectory of SARS-CoV-2 and emerging variants." Virology Journal 18, no. 1: 1-21.

Article
Published: 12 July 2021 in Communications Biology
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Triple negative breast cancer holds a dismal clinical outcome and as such, patients routinely undergo aggressive, highly toxic treatment regimens. Clinical trials for TNBC employing immune checkpoint blockade in combination with chemotherapy show modest prognostic benefit, but the percentage of patients that respond to treatment is low, and patients often succumb to relapsed disease. Here, we show that a combination immunotherapy platform utilizing low dose chemotherapy (FEC) combined with oncolytic virotherapy (oHSV-1) increases tumor-infiltrating lymphocytes, in otherwise immune-bare tumors, allowing 60% of mice to achieve durable tumor regression when treated with immune checkpoint blockade. Whole-tumor RNA sequencing of mice treated with FEC + oHSV-1 shows an upregulation of B cell receptor signaling pathways and depletion of B cells prior to the start of treatment in mice results in complete loss of therapeutic efficacy and expansion of myeloid-derived suppressor cells. Additionally, RNA sequencing data shows that FEC + oHSV-1 suppresses genes associated with myeloid-derived suppressor cells, a key population of cells that drive immune escape and mediate therapeutic resistance. These findings highlight the importance of tumor-infiltrating B cells as drivers of antitumor immunity and their potential role in the regulation of myeloid-derived suppressor cells.

ACS Style

Alyssa Vito; Omar Salem; Nader El-Sayes; Ian P. MacFawn; Ana L. Portillo; Katy Milne; Danielle Harrington; Ali A. Ashkar; Yonghong Wan; Samuel T. Workenhe; Brad H. Nelson; Tullia C. Bruno; Karen L. Mossman. Immune checkpoint blockade in triple negative breast cancer influenced by B cells through myeloid-derived suppressor cells. Communications Biology 2021, 4, 1 -19.

AMA Style

Alyssa Vito, Omar Salem, Nader El-Sayes, Ian P. MacFawn, Ana L. Portillo, Katy Milne, Danielle Harrington, Ali A. Ashkar, Yonghong Wan, Samuel T. Workenhe, Brad H. Nelson, Tullia C. Bruno, Karen L. Mossman. Immune checkpoint blockade in triple negative breast cancer influenced by B cells through myeloid-derived suppressor cells. Communications Biology. 2021; 4 (1):1-19.

Chicago/Turabian Style

Alyssa Vito; Omar Salem; Nader El-Sayes; Ian P. MacFawn; Ana L. Portillo; Katy Milne; Danielle Harrington; Ali A. Ashkar; Yonghong Wan; Samuel T. Workenhe; Brad H. Nelson; Tullia C. Bruno; Karen L. Mossman. 2021. "Immune checkpoint blockade in triple negative breast cancer influenced by B cells through myeloid-derived suppressor cells." Communications Biology 4, no. 1: 1-19.

Preprint content
Published: 07 June 2021
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The angiotensin-converting enzyme 2 (ACE2) protein has been highly studied as a key catalytic regulator of the renin-angiotensin system (RAS), involved in fluid homeostasis and blood pressure modulation. In addition to its important physiological role as a broadly-expressed membrane-bound protein, ACE2 serves as a cell-surface receptor for some viruses - most notably, coronaviruses such as SARS-CoV and SARS-CoV-2. Differing levels of ACE2 expression may impact viral susceptibility and subsequent changes to expression may be a pathogenic mechanism of disease risk and manifestation. Therefore, an improved understanding of how ACE2 expression is regulated at the genomic and transcriptional level may help us understand not only how the effects of pre-existing conditions (e.g., chronic obstructive pulmonary disease) may manifest with increased COVID-19 incidence, but also the mechanisms that regulate ACE2 levels following viral infection. Here, we initially perform bioinformatic analyses of several datasets to generate hypotheses about ACE2 gene-regulatory mechanisms in the context of immune signaling and chronic oxidative stress. We then identify putative non-coding regulatory elements within ACE2 intronic regions as potential determinants of ACE2 expression activity. We perform functional validation of our computational predictions in vitro via targeted CRISPR-Cas9 deletions of the identified ACE2 cis -regulatory elements in the context of both immunological stimulation and oxidative stress conditions. We demonstrate that intronic ACE2 regulatory elements are responsive to both immune signaling and oxidative-stress pathways, and this contributes to our understanding of how expression of this gene may be modulated at both baseline and during immune challenge. Our work supports the further pursuit of these putative mechanisms in our understanding, prevention, and treatment of infection and disease caused by ACE2-utilizing viruses such as SARS-CoV, SARS-CoV-2, and future emerging SARS-related viruses.

ACS Style

Daniel Richard; Pushpanathan Muthuirulan; Jennifer Aguiar; Andrew Doxey; Arinjay Banerjee; Karen Mossman; Jeremy Hirota; Terence D. Capellini. Intronic regulation of SARS-CoV-2 receptor (ACE2) expression mediated by immune signaling and oxidative stress pathways. 2021, 1 .

AMA Style

Daniel Richard, Pushpanathan Muthuirulan, Jennifer Aguiar, Andrew Doxey, Arinjay Banerjee, Karen Mossman, Jeremy Hirota, Terence D. Capellini. Intronic regulation of SARS-CoV-2 receptor (ACE2) expression mediated by immune signaling and oxidative stress pathways. . 2021; ():1.

Chicago/Turabian Style

Daniel Richard; Pushpanathan Muthuirulan; Jennifer Aguiar; Andrew Doxey; Arinjay Banerjee; Karen Mossman; Jeremy Hirota; Terence D. Capellini. 2021. "Intronic regulation of SARS-CoV-2 receptor (ACE2) expression mediated by immune signaling and oxidative stress pathways." , no. : 1.

Review
Published: 05 May 2021 in International Journal of Molecular Sciences
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Programmed cell death protein 1 (PD-1), a receptor on T cells, and its ligand, PD-L1, have been a topic of much interest in cancer research. Both tumour and virus-infected cells can upregulate PD-L1 to suppress cytotoxic T-cell killing. Research on the PD-1/PD-L1 axis has led to the development of anti-PD-1/PD-L1 immune checkpoint blockades (ICBs) as promising cancer therapies. Although effective in some cancer patients, for many, this form of treatment is ineffective due to a lack of immunogenicity in the tumour microenvironment (TME). Despite the development of therapies targeting the PD-1/PD-L1 axis, the mechanisms and pathways through which these proteins are regulated are not completely understood. In this review, we discuss the latest research on molecules of inflammation and innate immunity that regulate PD-L1 expression, how its expression is regulated during viral infection, and how it is modulated by different cancer therapies. We also highlight existing research on the development of different combination therapies with anti-PD-1/PD-L1 antibodies. This information can be used to develop better cancer immunotherapies that take into consideration the pathways involved in the PD-1/PD-L1 axis, so these molecules do not reduce their efficacy, which is currently seen with some cancer therapies. This review will also assist in understanding how the TME changes during treatment, which will provide further rationale for combination therapies.

ACS Style

Hadia Farrukh; Nader El-Sayes; Karen Mossman. Mechanisms of PD-L1 Regulation in Malignant and Virus-Infected Cells. International Journal of Molecular Sciences 2021, 22, 4893 .

AMA Style

Hadia Farrukh, Nader El-Sayes, Karen Mossman. Mechanisms of PD-L1 Regulation in Malignant and Virus-Infected Cells. International Journal of Molecular Sciences. 2021; 22 (9):4893.

Chicago/Turabian Style

Hadia Farrukh; Nader El-Sayes; Karen Mossman. 2021. "Mechanisms of PD-L1 Regulation in Malignant and Virus-Infected Cells." International Journal of Molecular Sciences 22, no. 9: 4893.

Journal article
Published: 03 May 2021 in International Journal of Molecular Sciences
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Triple negative breast cancer (TNBC) is an aggressive subtype of the disease with poor clinical outcomes and limited therapeutic options. Immune checkpoint blockade (CP) has surged to the forefront of cancer therapies with widespread clinical success in a variety of cancer types. However, the percentage of TNBC patients that benefit from CP as a monotherapy is low, and clinical trials have shown the need for combined therapeutic modalities. Specifically, there has been interest in combining CP therapy with radiation therapy where clinical studies primarily with external beam have suggested their therapeutic synergy, contributing to the development of anti-tumor immunity. Here, we have developed a therapeutic platform combining radionuclide therapy (RT) and immunotherapy utilizing a radiolabeled biomolecule and CP in an E0771 murine TNBC tumor model. Survival studies show that while neither monotherapy is able to improve therapeutic outcomes, the combination of RT + CP extended overall survival. Histologic analysis showed that RT + CP increased necrotic tissue within the tumor and decreased levels of F4/80+ macrophages. Flow cytometry analysis of the peripheral blood also showed that RT + CP suppressed macrophages and myeloid-derived suppressive cells, both of which actively contribute to immune escape and tumor relapse.

ACS Style

Alyssa Vito; Stephanie Rathmann; Natalie Mercanti; Nader El-Sayes; Karen Mossman; John Valliant. Combined Radionuclide Therapy and Immunotherapy for Treatment of Triple Negative Breast Cancer. International Journal of Molecular Sciences 2021, 22, 4843 .

AMA Style

Alyssa Vito, Stephanie Rathmann, Natalie Mercanti, Nader El-Sayes, Karen Mossman, John Valliant. Combined Radionuclide Therapy and Immunotherapy for Treatment of Triple Negative Breast Cancer. International Journal of Molecular Sciences. 2021; 22 (9):4843.

Chicago/Turabian Style

Alyssa Vito; Stephanie Rathmann; Natalie Mercanti; Nader El-Sayes; Karen Mossman; John Valliant. 2021. "Combined Radionuclide Therapy and Immunotherapy for Treatment of Triple Negative Breast Cancer." International Journal of Molecular Sciences 22, no. 9: 4843.

Article
Published: 25 April 2021 in iScience
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Summary Type I interferons (IFNs) are our first line of defense against virus infection. Recent studies have suggested the ability of SARS-CoV-2 proteins to inhibit IFN responses. Emerging data also suggest that timing and extent of IFN production is associated with manifestation of COVID-19 severity. In spite of progress in understanding how SARS-CoV-2 activates antiviral responses, mechanistic studies into wild-type SARS-CoV-2-mediated induction and inhibition of human type I IFN responses are scarce. Here we demonstrate that SARS-CoV-2 infection induces a type I IFN response in vitro and in moderate cases of COVID-19. In vitro stimulation of type I IFN expression and signaling in human airway epithelial cells is associated with activation of canonical transcriptions factors, and SARS-CoV-2 is unable to inhibit exogenous induction of these responses. Furthermore, we show that physiological levels of IFNα detected in patients with moderate COVID-19 is sufficient to suppress SARS-CoV-2 replication in human airway cells.

ACS Style

Arinjay Banerjee; Nader El-Sayes; Patrick Budylowski; Rajesh Abraham Jacob; Daniel Richard; Hassaan Maan; Jennifer A. Aguiar; Wael L. Demian; Kaushal Baid; Michael R. D'Agostino; Jann Catherine Ang; Tetyana Murdza; Benjamin J.-M. Tremblay; Sam Afkhami; Mehran Karimzadeh; Aaron T. Irving; Lily Yip; Mario Ostrowski; Jeremy A. Hirota; Robert Kozak; Terence D. Capellini; Matthew S. Miller; Bo Wang; Samira Mubareka; Allison J. McGeer; Andrew G. McArthur; Andrew C. Doxey; Karen Mossman. Experimental and natural evidence of SARS-CoV-2-infection-induced activation of type I interferon responses. iScience 2021, 102477 .

AMA Style

Arinjay Banerjee, Nader El-Sayes, Patrick Budylowski, Rajesh Abraham Jacob, Daniel Richard, Hassaan Maan, Jennifer A. Aguiar, Wael L. Demian, Kaushal Baid, Michael R. D'Agostino, Jann Catherine Ang, Tetyana Murdza, Benjamin J.-M. Tremblay, Sam Afkhami, Mehran Karimzadeh, Aaron T. Irving, Lily Yip, Mario Ostrowski, Jeremy A. Hirota, Robert Kozak, Terence D. Capellini, Matthew S. Miller, Bo Wang, Samira Mubareka, Allison J. McGeer, Andrew G. McArthur, Andrew C. Doxey, Karen Mossman. Experimental and natural evidence of SARS-CoV-2-infection-induced activation of type I interferon responses. iScience. 2021; ():102477.

Chicago/Turabian Style

Arinjay Banerjee; Nader El-Sayes; Patrick Budylowski; Rajesh Abraham Jacob; Daniel Richard; Hassaan Maan; Jennifer A. Aguiar; Wael L. Demian; Kaushal Baid; Michael R. D'Agostino; Jann Catherine Ang; Tetyana Murdza; Benjamin J.-M. Tremblay; Sam Afkhami; Mehran Karimzadeh; Aaron T. Irving; Lily Yip; Mario Ostrowski; Jeremy A. Hirota; Robert Kozak; Terence D. Capellini; Matthew S. Miller; Bo Wang; Samira Mubareka; Allison J. McGeer; Andrew G. McArthur; Andrew C. Doxey; Karen Mossman. 2021. "Experimental and natural evidence of SARS-CoV-2-infection-induced activation of type I interferon responses." iScience , no. : 102477.

Protocol
Published: 10 April 2021 in STAR Protocols
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Recent data suggest that cells respond to infection by upregulating the antiviral cytokine interferon-beta (IFN-ß) in a fraction of infected cells. Approaches are thus needed to study these responses on a single-cell level rather than bulk population. Here, we describe a protocol to analyze the IFN-ß response of individual cells using flow cytometry and immunofluorescence microscopy. We show the heterogeneous IFN-ß response to inactivated Sendai virus and human cytomegalovirus, but this protocol can be adapted to other viruses. For complete details on the use and execution of this protocol, please refer to Hare et al. (2020).

ACS Style

David N. Hare; Minomi K. Subapanditha; Karen L. Mossman. Detecting single cell interferon-beta production using a fluorescent reporter telomerase-immortalized human fibroblast cell line. STAR Protocols 2021, 2, 100436 .

AMA Style

David N. Hare, Minomi K. Subapanditha, Karen L. Mossman. Detecting single cell interferon-beta production using a fluorescent reporter telomerase-immortalized human fibroblast cell line. STAR Protocols. 2021; 2 (2):100436.

Chicago/Turabian Style

David N. Hare; Minomi K. Subapanditha; Karen L. Mossman. 2021. "Detecting single cell interferon-beta production using a fluorescent reporter telomerase-immortalized human fibroblast cell line." STAR Protocols 2, no. 2: 100436.

Review
Published: 15 February 2021 in Cancers
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Throughout the history of oncology research, tumor heterogeneity has been a major hurdle for the successful treatment of cancer. As a result of aberrant changes in the tumor microenvironment such as high mutational burden, hypoxic conditions and abnormal vasculature, several malignant subpopulations often exist within a single tumor mass. Therapeutic intervention can also increase selective pressure towards subpopulations with acquired resistance. This phenomenon is often the cause of relapse in previously responsive patients, drastically changing the expected outcome of therapy. In the case of cancer immunotherapy, tumor heterogeneity is a substantial barrier as acquired resistance often takes the form of antigen escape and immunosuppression. In an effort to combat intrinsic resistance mechanisms, therapies are often combined as a multi-pronged approach to target multiple pathways simultaneously. These multi-therapy regimens have long been a mainstay of clinical oncology with chemotherapy cocktails but are more recently being investigated in the emerging landscape of immunotherapy. Furthermore, as high throughput technology becomes more affordable and accessible, researchers continue to deepen their understanding of the factors that influence tumor heterogeneity and shape the TME over the course of treatment regimens. In this review, we will investigate the factors that give rise to tumor heterogeneity and the impact it has on the field of immunotherapy. We will discuss how tumor heterogeneity causes resistance to various treatments and review the strategies currently being employed to overcome this challenging clinical hurdle. Finally, we will outline areas of research that should be prioritized to gain a better understanding of tumor heterogeneity and develop appropriate solutions.

ACS Style

Nader El-Sayes; Alyssa Vito; Karen Mossman. Tumor Heterogeneity: A Great Barrier in the Age of Cancer Immunotherapy. Cancers 2021, 13, 806 .

AMA Style

Nader El-Sayes, Alyssa Vito, Karen Mossman. Tumor Heterogeneity: A Great Barrier in the Age of Cancer Immunotherapy. Cancers. 2021; 13 (4):806.

Chicago/Turabian Style

Nader El-Sayes; Alyssa Vito; Karen Mossman. 2021. "Tumor Heterogeneity: A Great Barrier in the Age of Cancer Immunotherapy." Cancers 13, no. 4: 806.

Insights
Published: 13 January 2021 in Cell Host & Microbe
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The emergence of alternate variants of SARS-CoV-2 due to ongoing adaptations in humans and following human-to-animal transmission has raised concern over the efficacy of vaccines against new variants. We describe human-to-animal transmission (zooanthroponosis) of SARS-CoV-2, and its implications for faunal virus persistence and vaccine-mediated immunity.

ACS Style

Arinjay Banerjee; Karen Mossman; Michelle L. Baker. Zooanthroponotic potential of SARS-CoV-2 and implications of reintroduction into human populations. Cell Host & Microbe 2021, 29, 160 -164.

AMA Style

Arinjay Banerjee, Karen Mossman, Michelle L. Baker. Zooanthroponotic potential of SARS-CoV-2 and implications of reintroduction into human populations. Cell Host & Microbe. 2021; 29 (2):160-164.

Chicago/Turabian Style

Arinjay Banerjee; Karen Mossman; Michelle L. Baker. 2021. "Zooanthroponotic potential of SARS-CoV-2 and implications of reintroduction into human populations." Cell Host & Microbe 29, no. 2: 160-164.

Journal article
Published: 01 December 2020 in Journal of General Virology
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently emerged to cause widespread infections in humans. SARS-CoV-2 infections have been reported in the Kingdom of Saudi Arabia, where Middle East respiratory syndrome coronavirus (MERS-CoV) causes seasonal outbreaks with a case fatality rate of ~37 %. Here we show that there exists a theoretical possibility of future recombination events between SARS-CoV-2 and MERS-CoV RNA. Through computational analyses, we have identified homologous genomic regions within the ORF1ab and S genes that could facilitate recombination, and have analysed co-expression patterns of the cellular receptors for SARS-CoV-2 and MERS-CoV, ACE2 and DPP4, respectively, to identify human anatomical sites that could facilitate co-infection. Furthermore, we have investigated the likely susceptibility of various animal species to MERS-CoV and SARS-CoV-2 infection by comparing known virus spike protein–receptor interacting residues. In conclusion, we suggest that a recombination between SARS-CoV-2 and MERS-CoV RNA is possible and urge public health laboratories in high-risk areas to develop diagnostic capability for the detection of recombined coronaviruses in patient samples.

ACS Style

Arinjay Banerjee; Andrew C. Doxey; Benjamin J.-M. Tremblay; Michael Mansfield; Sonu Subudhi; Jeremy A. Hirota; Matthew S. Miller; Andrew G. McArthur; Samira Mubareka; Karen Mossman. Predicting the recombination potential of severe acute respiratory syndrome coronavirus 2 and Middle East respiratory syndrome coronavirus. Journal of General Virology 2020, 101, 1251 -1260.

AMA Style

Arinjay Banerjee, Andrew C. Doxey, Benjamin J.-M. Tremblay, Michael Mansfield, Sonu Subudhi, Jeremy A. Hirota, Matthew S. Miller, Andrew G. McArthur, Samira Mubareka, Karen Mossman. Predicting the recombination potential of severe acute respiratory syndrome coronavirus 2 and Middle East respiratory syndrome coronavirus. Journal of General Virology. 2020; 101 (12):1251-1260.

Chicago/Turabian Style

Arinjay Banerjee; Andrew C. Doxey; Benjamin J.-M. Tremblay; Michael Mansfield; Sonu Subudhi; Jeremy A. Hirota; Matthew S. Miller; Andrew G. McArthur; Samira Mubareka; Karen Mossman. 2020. "Predicting the recombination potential of severe acute respiratory syndrome coronavirus 2 and Middle East respiratory syndrome coronavirus." Journal of General Virology 101, no. 12: 1251-1260.

Journal article
Published: 26 November 2020 in iScience
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Type 1 interferon (IFN) plays a critical role in early antiviral defense and priming of adaptive immunity by signaling upregulation of host antiviral IFN-stimulated genes (ISGs). Certain stimuli trigger strong activation of IFN regulatory factor 3 (IRF3) and direct upregulation of ISGs in addition to IFN. It remains unclear why some stimuli are stronger activators of IRF3 and how this leads to IFN-independent antiviral protection. We found that UV-inactivated human cytomegalovirus (HCMV) particles triggered an IFN-independent ISG signature that was absent in cells infected with UV-inactivated Sendai virus particles. HCMV particles triggered mostly uniform activation of IRF3 and low-level IFN-β production within the population while SeV particles triggered a small fraction of cells producing abundant IFN-β. These findings suggest that population-level activation of IRF3 and antiviral protection emerges from a diversity of responses occurring simultaneously in single cells. Moreover, this occurs in the absence of virus replication.

ACS Style

David N. Hare; Kaushal Baid; Anna Dvorkin-Gheva; Karen L. Mossman. Virus-Intrinsic Differences and Heterogeneous IRF3 Activation Influence IFN-Independent Antiviral Protection. iScience 2020, 23, 101864 .

AMA Style

David N. Hare, Kaushal Baid, Anna Dvorkin-Gheva, Karen L. Mossman. Virus-Intrinsic Differences and Heterogeneous IRF3 Activation Influence IFN-Independent Antiviral Protection. iScience. 2020; 23 (12):101864.

Chicago/Turabian Style

David N. Hare; Kaushal Baid; Anna Dvorkin-Gheva; Karen L. Mossman. 2020. "Virus-Intrinsic Differences and Heterogeneous IRF3 Activation Influence IFN-Independent Antiviral Protection." iScience 23, no. 12: 101864.

Journal article
Published: 04 November 2020 in Communications Biology
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Cancer immunotherapies using monoclonal antibodies to block inhibitory checkpoints are showing durable remissions in many types of cancer patients, although the majority of breast cancer patients acquire little benefit. Human melanoma and lung cancer patient studies suggest that immune checkpoint inhibitors are often potent in patients that already have intratumoral T cell infiltrate; although it remains unknown what types of interventions can result in an intratumoral T cell infiltrate in breast cancer. Using non-T cell-inflamed mammary tumors, we assessed what biological processes and downstream inflammation can overcome the barriers to spontaneous T cell priming. Here we show a specific type of combination therapy, consisting of oncolytic virus and chemotherapy, activates necroptosis and limits tumor growth in autochthonous tumors. Combination therapy activates proinflammatory cytokines; intratumoral influx of myeloid cells and cytotoxic T cell infiltrate in locally treated and distant autochthonous tumors to render them susceptible to immune checkpoint inhibitors.

ACS Style

Samuel T. Workenhe; Andrew Nguyen; David Bakhshinyan; Jiarun Wei; David N. Hare; Kelly L. MacNeill; Yonghong Wan; Andrew Oberst; Jonathan L. Bramson; Jalees A. Nasir; Alyssa Vito; Nader El-Sayes; Sheila K. Singh; Andrew G. McArthur; Karen L. Mossman. De novo necroptosis creates an inflammatory environment mediating tumor susceptibility to immune checkpoint inhibitors. Communications Biology 2020, 3, 645 .

AMA Style

Samuel T. Workenhe, Andrew Nguyen, David Bakhshinyan, Jiarun Wei, David N. Hare, Kelly L. MacNeill, Yonghong Wan, Andrew Oberst, Jonathan L. Bramson, Jalees A. Nasir, Alyssa Vito, Nader El-Sayes, Sheila K. Singh, Andrew G. McArthur, Karen L. Mossman. De novo necroptosis creates an inflammatory environment mediating tumor susceptibility to immune checkpoint inhibitors. Communications Biology. 2020; 3 (1):645.

Chicago/Turabian Style

Samuel T. Workenhe; Andrew Nguyen; David Bakhshinyan; Jiarun Wei; David N. Hare; Kelly L. MacNeill; Yonghong Wan; Andrew Oberst; Jonathan L. Bramson; Jalees A. Nasir; Alyssa Vito; Nader El-Sayes; Sheila K. Singh; Andrew G. McArthur; Karen L. Mossman. 2020. "De novo necroptosis creates an inflammatory environment mediating tumor susceptibility to immune checkpoint inhibitors." Communications Biology 3, no. 1: 645.

Journal article
Published: 15 August 2020 in Viruses
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Genome sequencing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is increasingly important to monitor the transmission and adaptive evolution of the virus. The accessibility of high-throughput methods and polymerase chain reaction (PCR) has facilitated a growing ecosystem of protocols. Two differing protocols are tiling multiplex PCR and bait capture enrichment. Each method has advantages and disadvantages but a direct comparison with different viral RNA concentrations has not been performed to assess the performance of these approaches. Here we compare Liverpool amplification, ARTIC amplification, and bait capture using clinical diagnostics samples. All libraries were sequenced using an Illumina MiniSeq with data analyzed using a standardized bioinformatics workflow (SARS-CoV-2 Illumina GeNome Assembly Line; SIGNAL). One sample showed poor SARS-CoV-2 genome coverage and consensus, reflective of low viral RNA concentration. In contrast, the second sample had a higher viral RNA concentration, which yielded good genome coverage and consensus. ARTIC amplification showed the highest depth of coverage results for both samples, suggesting this protocol is effective for low concentrations. Liverpool amplification provided a more even read coverage of the SARS-CoV-2 genome, but at a lower depth of coverage. Bait capture enrichment of SARS-CoV-2 cDNA provided results on par with amplification. While only two clinical samples were examined in this comparative analysis, both the Liverpool and ARTIC amplification methods showed differing efficacy for high and low concentration samples. In addition, amplification-free bait capture enriched sequencing of cDNA is a viable method for generating a SARS-CoV-2 genome sequence and for identification of amplification artifacts.

ACS Style

Jalees A. Nasir; Robert A. Kozak; Patryk Aftanas; Amogelang R. Raphenya; Kendrick M. Smith; Finlay Maguire; Hassaan Maan; Muhannad Alruwaili; Arinjay Banerjee; Hamza Mbareche; Brian P. Alcock; Natalie C. Knox; Karen Mossman; Bo Wang; Julian A. Hiscox; Andrew G. McArthur; Samira Mubareka. A Comparison of Whole Genome Sequencing of SARS-CoV-2 Using Amplicon-Based Sequencing, Random Hexamers, and Bait Capture. Viruses 2020, 12, 895 .

AMA Style

Jalees A. Nasir, Robert A. Kozak, Patryk Aftanas, Amogelang R. Raphenya, Kendrick M. Smith, Finlay Maguire, Hassaan Maan, Muhannad Alruwaili, Arinjay Banerjee, Hamza Mbareche, Brian P. Alcock, Natalie C. Knox, Karen Mossman, Bo Wang, Julian A. Hiscox, Andrew G. McArthur, Samira Mubareka. A Comparison of Whole Genome Sequencing of SARS-CoV-2 Using Amplicon-Based Sequencing, Random Hexamers, and Bait Capture. Viruses. 2020; 12 (8):895.

Chicago/Turabian Style

Jalees A. Nasir; Robert A. Kozak; Patryk Aftanas; Amogelang R. Raphenya; Kendrick M. Smith; Finlay Maguire; Hassaan Maan; Muhannad Alruwaili; Arinjay Banerjee; Hamza Mbareche; Brian P. Alcock; Natalie C. Knox; Karen Mossman; Bo Wang; Julian A. Hiscox; Andrew G. McArthur; Samira Mubareka. 2020. "A Comparison of Whole Genome Sequencing of SARS-CoV-2 Using Amplicon-Based Sequencing, Random Hexamers, and Bait Capture." Viruses 12, no. 8: 895.

Journal article
Published: 16 July 2020 in European Respiratory Journal
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In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged, causing the coronavirus disease 2019 (COVID-19) pandemic. SARS-CoV, the agent responsible for the 2003 SARS outbreak, utilises angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) host molecules for viral entry. ACE2 and TMPRSS2 have recently been implicated in SARS-CoV-2 viral infection. Additional host molecules including ADAM17, cathepsin L, CD147 and GRP78 may also function as receptors for SARS-CoV-2. To determine the expression and in situ localisation of candidate SARS-CoV-2 receptors in the respiratory mucosa, we analysed gene expression datasets from airway epithelial cells of 515 healthy subjects, gene promoter activity analysis using the FANTOM5 dataset containing 120 distinct sample types, single cell RNA sequencing (scRNAseq) of 10 healthy subjects, proteomic datasets, immunoblots on multiple airway epithelial cell types, and immunohistochemistry on 98 human lung samples. We demonstrate absent to low ACE2 promoter activity in a variety of lung epithelial cell samples and low ACE2 gene expression in both microarray and scRNAseq datasets of epithelial cell populations. Consistent with gene expression, rare ACE2 protein expression was observed in the airway epithelium and alveoli of human lung, confirmed with proteomics. We present confirmatory evidence for the presence of TMPRSS2, CD147 and GRP78 protein in vitro in airway epithelial cells and confirm broad in situ protein expression of CD147 and GRP78 in the respiratory mucosa. Collectively, our data suggest the presence of a mechanism dynamically regulating ACE2 expression in human lung, perhaps in periods of SARS-CoV-2 infection, and also suggest that alternative receptors for SARS-CoV-2 exist to facilitate initial host cell infection.

ACS Style

Jennifer A. Aguiar; Benjamin J-M. Tremblay; Michael J. Mansfield; Owen Woody; Briallen Lobb; Arinjay Banerjee; Abiram Chandiramohan; Nicholas Tiessen; Quynh Cao; Anna Dvorkin-Gheva; Spencer Revill; Matthew S. Miller; Christopher Carlsten; Louise Organ; Chitra Joseph; Alison John; Paul Hanson; Richard C. Austin; Bruce M. McManus; Gisli Jenkins; Karen Mossman; Kjetil Ask; Andrew C. Doxey; Jeremy A. Hirota. Gene expression and in situ protein profiling of candidate SARS-CoV-2 receptors in human airway epithelial cells and lung tissue. European Respiratory Journal 2020, 56, 2001123 .

AMA Style

Jennifer A. Aguiar, Benjamin J-M. Tremblay, Michael J. Mansfield, Owen Woody, Briallen Lobb, Arinjay Banerjee, Abiram Chandiramohan, Nicholas Tiessen, Quynh Cao, Anna Dvorkin-Gheva, Spencer Revill, Matthew S. Miller, Christopher Carlsten, Louise Organ, Chitra Joseph, Alison John, Paul Hanson, Richard C. Austin, Bruce M. McManus, Gisli Jenkins, Karen Mossman, Kjetil Ask, Andrew C. Doxey, Jeremy A. Hirota. Gene expression and in situ protein profiling of candidate SARS-CoV-2 receptors in human airway epithelial cells and lung tissue. European Respiratory Journal. 2020; 56 (3):2001123.

Chicago/Turabian Style

Jennifer A. Aguiar; Benjamin J-M. Tremblay; Michael J. Mansfield; Owen Woody; Briallen Lobb; Arinjay Banerjee; Abiram Chandiramohan; Nicholas Tiessen; Quynh Cao; Anna Dvorkin-Gheva; Spencer Revill; Matthew S. Miller; Christopher Carlsten; Louise Organ; Chitra Joseph; Alison John; Paul Hanson; Richard C. Austin; Bruce M. McManus; Gisli Jenkins; Karen Mossman; Kjetil Ask; Andrew C. Doxey; Jeremy A. Hirota. 2020. "Gene expression and in situ protein profiling of candidate SARS-CoV-2 receptors in human airway epithelial cells and lung tissue." European Respiratory Journal 56, no. 3: 2001123.

Preprint content
Published: 18 June 2020
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SUMMARY Type I interferons (IFNs) are our first line of defence against a virus. Protein over-expression studies have suggested the ability of SARS-CoV-2 proteins to block IFN responses. Emerging data also suggest that timing and extent of IFN production is associated with manifestation of COVID-19 severity. In spite of progress in understanding how SARS-CoV-2 activates antiviral responses, mechanistic studies into wildtype SARS-CoV-2-mediated induction and inhibition of human type I IFN responses are lacking. Here we demonstrate that SARS-CoV-2 infection induces a mild type I IFN response in vitro and in moderate cases of COVID-19. In vitro stimulation of type I IFN expression and signaling in human airway epithelial cells is associated with activation of canonical transcriptions factors, and SARS-CoV-2 is unable to inhibit exogenous induction of these responses. Our data demonstrate that SARS-CoV-2 is not adept in blocking type I IFN responses and provide support for ongoing IFN clinical trials.

ACS Style

Arinjay Banerjee; Nader El-Sayes; Patrick Budylowski; Daniel Richard; Hassaan Maan; Jennifer A. Aguiar; Kaushal Baid; Michael R. D’Agostino; Jann Catherine Ang; Benjamin J.-M. Tremblay; Sam Afkhami; Mehran Karimzadeh; Aaron T. Irving; Lily Yip; Mario A Ostrowski; Jeremy A. Hirota; Robert Kozak; Terence D. Capellini; Matthew S. Miller; Bo Wang; Samira Mubareka; Allison J. McGeer; Andrew G. McArthur; Andrew C. Doxey; Karen Mossman. Experimental and natural evidence of SARS-CoV-2 infection-induced activation of type I interferon responses. 2020, 1 .

AMA Style

Arinjay Banerjee, Nader El-Sayes, Patrick Budylowski, Daniel Richard, Hassaan Maan, Jennifer A. Aguiar, Kaushal Baid, Michael R. D’Agostino, Jann Catherine Ang, Benjamin J.-M. Tremblay, Sam Afkhami, Mehran Karimzadeh, Aaron T. Irving, Lily Yip, Mario A Ostrowski, Jeremy A. Hirota, Robert Kozak, Terence D. Capellini, Matthew S. Miller, Bo Wang, Samira Mubareka, Allison J. McGeer, Andrew G. McArthur, Andrew C. Doxey, Karen Mossman. Experimental and natural evidence of SARS-CoV-2 infection-induced activation of type I interferon responses. . 2020; ():1.

Chicago/Turabian Style

Arinjay Banerjee; Nader El-Sayes; Patrick Budylowski; Daniel Richard; Hassaan Maan; Jennifer A. Aguiar; Kaushal Baid; Michael R. D’Agostino; Jann Catherine Ang; Benjamin J.-M. Tremblay; Sam Afkhami; Mehran Karimzadeh; Aaron T. Irving; Lily Yip; Mario A Ostrowski; Jeremy A. Hirota; Robert Kozak; Terence D. Capellini; Matthew S. Miller; Bo Wang; Samira Mubareka; Allison J. McGeer; Andrew G. McArthur; Andrew C. Doxey; Karen Mossman. 2020. "Experimental and natural evidence of SARS-CoV-2 infection-induced activation of type I interferon responses." , no. : 1.

Review
Published: 16 April 2020 in Cells
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The tumor microenvironment is a complex ecosystem comprised of many different cell types, abnormal vasculature and immunosuppressive cytokines. The irregular growth kinetics with which tumors grow leads to increased oxygen consumption and, in turn, hypoxic conditions. Hypoxia has been associated with poor clinical outcome, increased tumor heterogeneity, emergence of resistant clones and evasion of immune detection. Additionally, hypoxia-driven cell death pathways have traditionally been thought of as tolerogenic processes. However, as researchers working in the field of immunotherapy continue to investigate and unveil new types of immunogenic cell death (ICD), it has become clear that, in some instances, hypoxia may actually induce ICD within a tumor. In this review, we will discuss hypoxia-driven immune escape that drives poor prognostic outcomes, the ability of hypoxia to induce ICD and potential therapeutic targets amongst hypoxia pathways.

ACS Style

Alyssa Vito; Nader El-Sayes; Karen Mossman. Hypoxia-Driven Immune Escape in the Tumor Microenvironment. Cells 2020, 9, 992 .

AMA Style

Alyssa Vito, Nader El-Sayes, Karen Mossman. Hypoxia-Driven Immune Escape in the Tumor Microenvironment. Cells. 2020; 9 (4):992.

Chicago/Turabian Style

Alyssa Vito; Nader El-Sayes; Karen Mossman. 2020. "Hypoxia-Driven Immune Escape in the Tumor Microenvironment." Cells 9, no. 4: 992.

Preprint content
Published: 12 April 2020
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SARS-CoV-2 emerged in December 2019 in Wuhan, China and has since infected over 1.5 million people, of which over 100,000 have died. As SARS-CoV-2 spreads across the planet, speculations remain about the evolution of the virus and the range of human cells that can be infected by SARS-CoV-2. In this study, we report the isolation of SARS-CoV-2 from two COVID-19 patients in Toronto, Canada. We determined the genomic sequences of the two isolates and identified single nucleotide changes in representative populations of our virus stocks. More importantly, we have tested a wide range of human immune cells for infectivity with SARS-CoV-2. We confirm from our studies that human primary peripheral blood mononuclear cells (PBMCs) are not permissive to SARS-CoV-2. As SARS-CoV-2 continues to spread globally, it is essential to monitor any small nucleotide polymorphisms in the virus and to continue to isolate circulating strains of the virus to determine cell susceptibility and pathogenicity using in vitro and in vivo infection models.

ACS Style

Arinjay Banerjee; Jalees A. Nasir; Patrick Budylowski; Lily Yip; Patryk Aftanas; Natasha Christie; Ayoob Ghalami; Kaushal Baid; Amogelang R. Raphenya; Jeremy A Hirota; Matthew S. Miller; Allison J McGeer; Mario A Ostrowski; Robert A. Kozak; Andrew G McArthur; Karen Mossman; Samira Mubareka. Isolation, sequence, infectivity and replication kinetics of SARS-CoV-2. 2020, 1 .

AMA Style

Arinjay Banerjee, Jalees A. Nasir, Patrick Budylowski, Lily Yip, Patryk Aftanas, Natasha Christie, Ayoob Ghalami, Kaushal Baid, Amogelang R. Raphenya, Jeremy A Hirota, Matthew S. Miller, Allison J McGeer, Mario A Ostrowski, Robert A. Kozak, Andrew G McArthur, Karen Mossman, Samira Mubareka. Isolation, sequence, infectivity and replication kinetics of SARS-CoV-2. . 2020; ():1.

Chicago/Turabian Style

Arinjay Banerjee; Jalees A. Nasir; Patrick Budylowski; Lily Yip; Patryk Aftanas; Natasha Christie; Ayoob Ghalami; Kaushal Baid; Amogelang R. Raphenya; Jeremy A Hirota; Matthew S. Miller; Allison J McGeer; Mario A Ostrowski; Robert A. Kozak; Andrew G McArthur; Karen Mossman; Samira Mubareka. 2020. "Isolation, sequence, infectivity and replication kinetics of SARS-CoV-2." , no. : 1.

Brief report
Published: 20 March 2020 in Microorganisms
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The role of bats in the enzootic cycle of Lyme disease and relapsing fever-causing bacteria is a matter of speculation. In Canada, Borrelia burgdorferi sensu stricto (ss) is the genospecies that is responsible for most cases of Lyme disease in humans. In this study, we determined if big brown bats, Eptesicus fuscus, have been exposed to spirochetes from the genus Borrelia. We collected serum from 31 bats and tested them for the presence of anti-Borrelia burgdorferi antibodies using a commercial enzyme-linked immunosorbent assay (ELISA). We detected cross-reactive antibodies to Borrelia spp. in 14 of 31 bats. We confirmed the ELISA data using a commercial immunoblot assay. Pooled sera from ELISA-positive bats also cross-reacted with Borrelia antigens coated on the immunoblot strips, whereas pooled sera from ELISA-negative bats did not bind to Borrelia spp. antigens. Furthermore, to identify if bat ectoparasites, such as mites, can carry Borrelia spp., we analyzed DNA from 142 bat ectoparasites that were collected between 2003 and 2019. We detected DNA for the Borrelia burgdorferi flaB gene in one bat mite, Spinturnix americanus. The low detection rate of Borrelia burgdorferi DNA in bat ectoparasites suggests that bats are not reservoirs of this bacterium. Data from this study also raises intriguing questions about Borrelia infections in bats, including the role of humoral immunity and the ability of bats to be infected with Borrelia burgdorferi. This study can lead to more sampling efforts and controlled laboratory studies to identify if bats can be infected with Borrelia burgdorferi and the role of bat ectoparasites, such as S. americanus, in the transmission of this spirochete. Furthermore, we outlined reagents that can be used to adapt ELISA kits and immunoblot strips for use with bat sera.

ACS Style

Arinjay Banerjee; Kaushal Baid; Taylor Byron; Alyssa Yip; Caleb Ryan; Prasobh Raveendran Thampy; Hugh Broders; Paul Faure; Karen Mossman. Seroprevalence in Bats and Detection of Borrelia burgdorferi in Bat Ectoparasites. Microorganisms 2020, 8, 440 .

AMA Style

Arinjay Banerjee, Kaushal Baid, Taylor Byron, Alyssa Yip, Caleb Ryan, Prasobh Raveendran Thampy, Hugh Broders, Paul Faure, Karen Mossman. Seroprevalence in Bats and Detection of Borrelia burgdorferi in Bat Ectoparasites. Microorganisms. 2020; 8 (3):440.

Chicago/Turabian Style

Arinjay Banerjee; Kaushal Baid; Taylor Byron; Alyssa Yip; Caleb Ryan; Prasobh Raveendran Thampy; Hugh Broders; Paul Faure; Karen Mossman. 2020. "Seroprevalence in Bats and Detection of Borrelia burgdorferi in Bat Ectoparasites." Microorganisms 8, no. 3: 440.

Journal article
Published: 01 March 2020 in iScience
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Summary Compared with other mammals, bats harbor more zoonotic viruses per species and do not demonstrate signs of disease on infection with these viruses. To counteract infections with viruses, bats have evolved enhanced mechanisms to limit virus replication and immunopathology. However, molecular and cellular drivers of antiviral responses in bats largely remain an enigma. In this study, we demonstrate that a serine residue in IRF3 is positively selected for in multiple bat species. IRF3 is a central regulator of innate antiviral responses in mammals. Replacing the serine residue in bat IRF3 with the human leucine residue decreased antiviral protection in bat cells, whereas the addition of this serine residue in human IRF3 significantly enhanced antiviral protection in human cells. Our study provides genetic and functional evidence for enhanced IRF3-mediated antiviral responses in bats and adds support to speculations that bats have positively selected for multiple adaptations in their antiviral immune responses.

ACS Style

Arinjay Banerjee; Xi Zhang; Alyssa Yip; Katharina S. Schulz; Aaron Irving; Dawn Bowdish; Brian Golding; Lin-Fa Wang; Karen Mossman. Positive Selection of a Serine Residue in Bat IRF3 Confers Enhanced Antiviral Protection. iScience 2020, 23, 100958 -100958.

AMA Style

Arinjay Banerjee, Xi Zhang, Alyssa Yip, Katharina S. Schulz, Aaron Irving, Dawn Bowdish, Brian Golding, Lin-Fa Wang, Karen Mossman. Positive Selection of a Serine Residue in Bat IRF3 Confers Enhanced Antiviral Protection. iScience. 2020; 23 (3):100958-100958.

Chicago/Turabian Style

Arinjay Banerjee; Xi Zhang; Alyssa Yip; Katharina S. Schulz; Aaron Irving; Dawn Bowdish; Brian Golding; Lin-Fa Wang; Karen Mossman. 2020. "Positive Selection of a Serine Residue in Bat IRF3 Confers Enhanced Antiviral Protection." iScience 23, no. 3: 100958-100958.

Journal article
Published: 05 July 2019 in Current Clinical Microbiology Reports
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Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in 2012 and is listed in the World Health Organization’s blueprint of priority diseases that need immediate research. Camels are reservoirs of this virus, and the virus spills over into humans through direct contact with camels. Human-to-human transmission and travel-associated cases have been identified as well. Limited studies have characterized the molecular pathogenesis of MERS-CoV. Most studies have used ectopic expression of viral proteins to characterize MERS-CoV and its ability to modulate antiviral responses in human cells. Studies with live virus are limited, largely due to the requirement of high containment laboratories. In this review, we have summarized current studies on MERS-CoV molecular pathogenesis and have mentioned some recent strategies that are being developed to control MERS-CoV infection. Multiple antiviral molecules with the potential to inhibit MERS-CoV infection by disrupting virus-receptor interactions are being developed and tested. Although human vaccine candidates are still being developed, a candidate camel vaccine is being tested for efficacy. Combination of supportive treatment with interferon and antivirals is also being explored. New antiviral molecules that inhibit MERS-CoV and host cell receptor interaction may become available in the future. Additional studies are required to identify and characterize the pathogenesis of MERS-CoV EMC/2012 and other circulating strains. An effective MERS-CoV vaccine, for humans and/or camels, along with an efficient combination antiviral therapy may help us prevent future MERS cases.

ACS Style

Arinjay Banerjee; Kaushal Baid; Karen Mossman. Molecular Pathogenesis of Middle East Respiratory Syndrome (MERS) Coronavirus. Current Clinical Microbiology Reports 2019, 6, 139 -147.

AMA Style

Arinjay Banerjee, Kaushal Baid, Karen Mossman. Molecular Pathogenesis of Middle East Respiratory Syndrome (MERS) Coronavirus. Current Clinical Microbiology Reports. 2019; 6 (3):139-147.

Chicago/Turabian Style

Arinjay Banerjee; Kaushal Baid; Karen Mossman. 2019. "Molecular Pathogenesis of Middle East Respiratory Syndrome (MERS) Coronavirus." Current Clinical Microbiology Reports 6, no. 3: 139-147.