Emerging and Re-emerging Viral Infections Since 2012

Emerging and re-emerging viruses pose a significant threat to public health and global economies. Moreover, outbreaks caused by emerging and re-emerging viruses continue to increase in frequency as a result of changing socio-economic, environmental, and ecological factors.[1] Notably, the zoonotic viral pathogens, severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), Ebola virus, chikungunya virus, and Zika virus, have emerged on a global scale in recent years; although less widely publicized, other emerging viral pathogens such as monkeypox virus and Andes virus have led to smaller recurrent outbreaks. A critical challenge for combating these outbreaks is often the discordant relationship between the economic status of outbreak “hotspots” and resource distribution or control capacity within these regions. In addition, the development and delivery of therapeutics for combating such outbreaks have been complicated by both the associated costs in design and development for novel antiinfective therapeutics and the requirements for regulatory approval and licensure.[2] Importantly, emerging infectious diseases present the additional inherent challenge that they are only “emerging”, and thus limited resources are made available for research until they present a significant risk. For many emerging viral pathogens, the requirement for high-containment facilities has further impeded widespread research. From the perspective of drug development, the limited knowledge and understanding of molecular pathogenesis for these agents is a daunting challenge to overcome when outbreaks emerge.

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Figure 1. Generation of kinome peptide array targets and kinome peptide arrays: (1) species-specific proteomic or genomic information from a diverse range of species can be used to identify kinase recognition motifs that are composed of a central phosphorylation target and the surrounding amino acids (normally +4 and −4 amino acids from the central phosphorylated residue); (2) peptides that comprise the kinase recognition motifs identified in (1) are synthesized and covalently linked to a glass surface. Peptide targets are spotted in replicates of three to nine spots on each array to account for intra-array variability. Individual amino acids of the peptides are represented by orange, red, purple, and green spheres.

In the face of an increasing burden of emerging and reemerging pathogens, it is necessary to overcome the barriers imposed by a paucity of information regarding molecular pathogenesis for these agents. OMICS-based approaches present a mechanism to rapidly generate large amounts of data in regard to host responses and assist in target identification for drug development efforts. In addition, OMICS-based analyses allow for the characterization of molecular events that mitigate cellular responses to viral pathogens from a global perspective across multiple levels of cellular complexity (individual cell types < tissues < organs). High-throughput global analyses of host gene expression, including microarrays and RNA-Seq, provide important information regarding transcriptional responses during infection. Although these validated approaches are among the most widespread of the OMICS-based technologies for infectious disease investigations, they do not provide a direct measure of the activation status of the cell signaling pathways that regulate underlying cellular responses. In contrast, global investigations of cellular kinase activities (the kinome) are able to provide insight into the activation status of cell signaling networks (including those that mediate pathogen recognition and innate immune activation, cell cycle activities, metabolic status, wound healing and repair, and cell death) at the level of individual kinase-mediated phosphorylation events. In addition, kinome investigations allow for potential identification of kinase drug targets.

Kinases are currently one of the top targets for drug design and development, and there is potential for repurposing of kinase inhibitors with existing regulatory approval. As emerging viral infections often result in severe illness including respiratory failure [severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and influenza] and multi-organ failure [Ebola virus disease (EVD)], understanding complex pathogenesis of these infections is required for effective vaccine and therapeutic design and for improved patient care. Healthcare providers caring for patients with severe emerging viral infections are generally focused on clinical care and biosafety as compared to the complex molecular events that underlie pathogenesis. In contrast, basic researchers typically focus on discrete aspects of pathogenesis through a variety of in vitro and in vivo analyses rather than the complex interplay between these events and the clinical, physiologic, and pathologic abnormalities observed by the clinician. Integrating basic and clinical research is needed to accelerate the translation of knowledge for emerging infections toward vaccine development and therapeutic discovery. Specifically, detailed natural history studies merging multiple data streams including OMICS approaches (high-throughput gene expression and kinomics) and focused translational investigations utilizing relevant models that can be validated to human disease are needed to clarify disease pathogenesis, advance therapeutic discovery, and facilitate regulatory approval. Although an integrated approach between basic and clinical research is ideal for investigating the connections between molecular and clinical pathogenesis, there has been a paucity of investigations for which this has been undertaken. A discussion is needed on emerging pathogens for which there is available information regarding the clinical course of disease, host immune responses during natural infection, and molecular information regarding the global cellular responses to infection, with particular attention on host kinome investigations. In this regard a focus is maintained on the emerging viral pathogens MERSCoV, Ebola virus (EBOV), and monkeypox virus (MPXV)

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(Figure 2). Global outbreaks of Ebola virus, MERS-CoV, and monkeypox: (a) Europe; (b) Africa; © Asia; (d) United States. Data include all transmission-related infections that have been documented. Laboratory accident-related infections and medical evacuations are not included.

After reviewing the clinical presentation and immunological and molecular features of the diseases and summarized available OMICS data informing pathogenesis of these pathogens still it not clear how the coronavirus originated in China this time around?

[1] Jones, K. E., Patel, N. G., Levy, M. A., Storeygard, A., Balk, D., Gittleman, J. L., and Daszak, P. (2008) Global trends in emerging infectious diseases. Nature 451, 990−993.

[2] Arias, C. A., and Murray, B. E. (2015) A new antibiotic and the evolution of resistance. N. Engl. J. Med. 372, 1168−1170

keywords: emerging pathogens, kinomics, cell signaling, virology, kinases, high-consequence pathogens

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