The various contributions to this book record the remarkable progress that has been made in the understanding and management of pancreatic diseases over the last decade. The improvement in understanding has led in some cases to better management with improved outcome for the patient, whereas in other areas the way is now clear towards a better prospect for the future.

Progress and Prospects

During the evolution of SARS-CoV-2 in humans a D614G substitution in the spike (S) protein emerged and became the predominant circulating variant (S-614G) of the COVID-19 pandemic 1 . However, whether the increasing prevalence of the S-614G variant represents a fitness advantage that improves replication and/or transmission in humans or is merely due to founder effects remains elusive. Here, we generated isogenic SARS-CoV-2 variants and demonstrate that the S-614G variant has (i) enhanced binding to human ACE2, (ii) increased replication in primary human bronchial and nasal airway epithelial cultures as well as in a novel human ACE2 knock-in mouse model, and (iii) markedly increased replication and transmissibility in hamster and ferret models of SARS-CoV-2 infection. Collectively, our data show that while the S-614G substitution results in subtle increases in binding and replication in vitro , it provides a real competitive advantage in vivo , particularly during the transmission bottle neck, providing an explanation for the global predominance of S-614G variant among the SARS-CoV-2 viruses currently circulating.

https://biorxiv.org/content/10.1101/2020.10.27.357558v1.full.pdf

SARS-CoV-2 spike D614G variant confers enhanced replication and transmissibility

One year since the first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported in China, several variants of concern (VOC) have appeared around the world, with some variants seeming to pose a greater thread to public health due to enhanced transmissibility or infectivity. This study provides a framework for molecular characterization of novel VOC and investigates the effect of mutations on the binding affinity of the receptor-binding domain (RBD) to human angiotensin-converting enzyme 2 (hACE2) using in silico approach. Notable nonsynonymous mutations in RBD of VOC include the E484K and K417N/T that can be seen in South African and Brazilian variants, and N501Y and D614G that can be seen in all VOC. Phylogenetic analyses demonstrated that although the UK-VOC and the BR-VOC fell in the clade GR, they have different mutation signatures, implying an independent evolutionary pathway. The same is true about SA-VOC and COH-VOC felling in clade GH, but different mutation signatures. Combining molecular interaction modeling and the free energy of binding (FEB) calculations for VOC, it can be assumed that the mutation N501Y has the highest binding affinity in RBD for all VOC, followed by E484K (only for BR-VOC), which favors the formation of a stable complex. However, mutations at the residue K417N/T are shown to reduce the binding affinity. Once vaccination has started, there will be selective pressure that would be in favor of the emergence of novel variants capable of escaping the immune system. Therefore, genomic surveillance should be enhanced to find and monitor new emerging SARS-CoV-2 variants before they become a public health concern.

https://www.mdpi.com/2076-2607/9/5/926/pdf

Mutation Signatures and In Silico Docking of Novel SARS-CoV-2 Variants of Concern

The breadth of animal hosts that are susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and may serve as reservoirs for continued viral transmission are not known entirely. In August 2020, an outbreak of SARS-CoV-2 occurred on five mink farms in Utah and was associated with high mink mortality (35-55% of adult mink) and rapid viral transmission between animals. The premise and clinical disease information, pathology, molecular characterization, and tissue distribution of virus within infected mink during the early phase of the outbreak are provided. Infection spread rapidly between independently housed animals and farms, and caused severe respiratory disease and death. Disease indicators were most notably sudden death, anorexia, and increased respiratory effort. Gross pathology examination revealed severe pulmonary congestion and edema. Microscopically there was pulmonary edema with moderate vasculitis, perivasculitis, and fibrinous interstitial pneumonia. Reverse transcriptase polymerase chain reaction (RT-PCR) of tissues collected at necropsy demonstrated the presence of SARS-CoV-2 viral RNA in multiple organs including nasal turbinates, lung, tracheobronchial lymph node, epithelial surfaces, and others. Localization of viral RNA by in situ hybridization revealed a more localized infection, particularly of the upper respiratory tract. Whole genome sequencing from multiple mink was consistent with published SARS-CoV-2 genomes with few polymorphisms. The Utah mink SARS-CoV-2 strains fell into Clade GH, which is unique among mink and other animal strains sequenced to date. While sharing the N501T mutation which is common in mink, the Utah strains did not share other spike RBD mutations Y453F and F486L found in nearly all mink from the United States. Mink in the outbreak reported herein had high levels of SARS-CoV-2 in the upper respiratory tract associated with symptomatic respiratory disease and death.

/pdf/an-outbreak-of-sars-cov-2-with-high-mortality-in-mink-rgr4a3xwhk.pdf

An outbreak of SARS-CoV-2 with high mortality in mink (Neovison vison) on multiple Utah farms.

The ongoing pandemic coronavirus disease COVID-19 is caused by the highly contagious single-stranded RNA virus, SARS-coronavirus 2 (SARS-CoV-2), which has a high rate of evolution like other RNA viruses. The first genome sequences of SARS-CoV-2 were available in early 2020. Subsequent whole-genome sequencing revealed that the virus had accumulated several mutations in genes associated with viral replication and pathogenesis. These variants showed enhanced transmissibility and infectivity. Soon after the first outbreak due to the wild-type strain in December 2019, a genetic variant D614G emerged in late January to early February 2020 and became the dominant genotype worldwide. Thereafter, several variants emerged, which were found to harbor mutations in essential viral genes encoding proteins that could act as drug and vaccine targets. Numerous vaccines have been successfully developed to assuage the burden of COVID-19. These have different rates of efficacy, including, although rarely, a number of vaccinated individuals exhibiting side effects like thrombosis. However, the recent emergence of the Britain strain with 70% more transmissibility and South African variants with higher resistance to vaccines at a time when several countries have approved these for mass immunization has raised tremendous concern regarding the long-lasting impact of currently available prophylaxis. Apart from studies addressing the pathophysiology, pathogenesis, and therapeutic targets of SARS-CoV-2, analysis of the gut, oral, nasopharyngeal, and lung microbiome dysbiosis has also been undertaken to find a link between the microbiome and the pathogenesis of COVID-19. Therefore, in the current scenario of skepticism regarding vaccine efficacy and challenges over the direct effects of currently available drugs looming large, investigation of alternative therapeutic avenues based on the microbiome can be a rewarding finding. This review presents the currently available understanding of microbiome dysbiosis and its association with cause and consequence of COVID-19. Taking cues from other inflammatory diseases, we propose a hypothesis of how the microbiome may be influencing homeostasis, pro-inflammatory condition, and the onset of inflammation. This accentuates the importance of a healthy microbiome as a protective element to prevent the onset of COVID-19. Finally, the review attempts to identify areas where the application of microbiome research can help in reducing the burden of the disease.

/pdf/role-of-the-microbiome-in-the-pathogenesis-of-covid-19-2z0maw6m.pdf

Role of the Microbiome in the Pathogenesis of COVID-19

The COVID-19 pandemic has been ongoing since its onset in late November 2019 in Wuhan, China. Understanding and monitoring the genetic evolution of the virus, its geographical characteristics, and its stability are particularly important for controlling the spread of the disease and especially for the development of a universal vaccine covering all circulating strains. From this perspective, we analyzed 30,983 complete SARS-CoV-2 genomes from 79 countries located in the six continents and collected from 24 December 2019, to 13 May 2020, according to the GISAID database. Our analysis revealed the presence of 3206 variant sites, with a uniform distribution of mutation types in different geographic areas. Remarkably, a low frequency of recurrent mutations has been observed; only 169 mutations (5.27%) had a prevalence greater than 1% of genomes. Nevertheless, fourteen non-synonymous hotspot mutations (>10%) have been identified at different locations along the viral genome; eight in ORF1ab polyprotein (in nsp2, nsp3, transmembrane domain, RdRp, helicase, exonuclease, and endoribonuclease), three in nucleocapsid protein, and one in each of three proteins: Spike, ORF3a, and ORF8. Moreover, 36 non-synonymous mutations were identified in the receptor-binding domain (RBD) of the spike protein with a low prevalence (<1%) across all genomes, of which only four could potentially enhance the binding of the SARS-CoV-2 spike protein to the human ACE2 receptor. These results along with intra-genomic divergence of SARS-CoV-2 could indicate that unlike the influenza virus or HIV viruses, SARS-CoV-2 has a low mutation rate which makes the development of an effective global vaccine very likely.

https://www.mdpi.com/2076-0817/9/10/829/pdf

Genomic Diversity and Hotspot Mutations in 30,983 SARS-CoV-2 Genomes: Moving Toward a Universal Vaccine for the “Confined Virus”?

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Genomic Diversity and Hotspot Mutations in 30,983 SARS-CoV-2 Genomes: Moving Toward a Universal Vaccine for the “Confined Virus”?