scholarly journals Organ-specific genome diversity of replication-competent SARS-CoV-2

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jolien Van Cleemput ◽  
Willem van Snippenberg ◽  
Laurens Lambrechts ◽  
Amélie Dendooven ◽  
Valentino D’Onofrio ◽  
...  
Keyword(s):  
Virus Infectivity ◽  
Immunocompromised Patients ◽  
Genome Diversity ◽  
Single Nucleotide Variants ◽  
Disease Evolution ◽  
Viral Loads ◽  
Multiple Organs ◽  
Hygiene Measures ◽  
Organ Specific ◽  
Host Evolution

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is not always confined to the respiratory system, as it impacts people on a broad clinical spectrum from asymptomatic to severe systemic manifestations resulting in death. Further, accumulation of intra-host single nucleotide variants during prolonged SARS-CoV-2 infection may lead to emergence of variants of concern (VOCs). Still, information on virus infectivity and intra-host evolution across organs is sparse. We report a detailed virological analysis of thirteen postmortem coronavirus disease 2019 (COVID-19) cases that provides proof of viremia and presence of replication-competent SARS-CoV-2 in extrapulmonary organs of immunocompromised patients, including heart, kidney, liver, and spleen (NCT04366882). In parallel, we identify organ-specific SARS-CoV-2 genome diversity and mutations of concern N501Y, T1027I, and Y453F, while the patient had died long before reported emergence of VOCs. These mutations appear in multiple organs and replicate in Vero E6 cells, highlighting their infectivity. Finally, we show two stages of fatal disease evolution based on disease duration and viral loads in lungs and plasma. Our results provide insights about the pathogenesis and intra-host evolution of SARS-CoV-2 and show that COVID-19 treatment and hygiene measures need to be tailored to specific needs of immunocompromised patients, even when respiratory symptoms cease.

scholarly journals Organ-specific genome diversity of replication-competent SARS-CoV-2

2021 ◽  
Author(s):  
Jolien Van Cleemput ◽  
Willem van Snippenberg ◽  
Laurens Lambrechts ◽  
Amélie Dendooven ◽  
Valentino D’Onofrio ◽  
...  
Keyword(s):  
Genome Diversity ◽  
Disease Evolution ◽  
Viral Loads ◽  
Multiple Organs ◽  
Virulent Strains ◽  
Hygiene Measures ◽  
Organ Specific ◽  
Systemic Manifestations ◽  
Two Stages ◽  
Host Evolution

Abstract The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has gripped the world for over a year1,2. SARS-CoV-2 impacts people on a broad clinical spectrum from asymptomatic to severe respiratory and systemic manifestations resulting in death3. In addition, intra-host SARS-CoV-2 genomic plasticity periodically leads to emergence of new virus variants with higher transmission capacities4–6. Autopsy series have revealed several pathways to death in COVID-19 patients, including respiratory and multi-organ failure, and evidence of SARS-CoV-2 in various organs besides the lungs7,8. However, these studies did not demonstrate the presence of infectious virus in extrapulmonary sites nor did they investigate viral intra-host evolution across multiple organs. Here we report a detailed virological analysis of thirteen postmortem COVID-19 cases that confirms two stages of fatal disease evolution based on disease duration and viral loads in lungs and plasma9. More importantly, the study is the first to provide proof of viremia and presence of replication-competent SARS-CoV-2 in extrapulmonary organs of an immunocompromised patient, accompanied by tissue-specific patterns of genome diversity in organ-resident SARS-CoV-2 populations. In parallel, potentially more transmissible and virulent strains were detected in multiple organs, including identification of mutations N501Y, T1027I, and Y453F in spike (S) protein. These mutations are hallmarks of more contagious United Kingdom (lineage B.1.1.7), South African (lineage B.1.351), Brazilian (lineage P1 and B.1.1.248) or mink variants4,10. Our results provide novel insights about the pathogenesis of SARS-CoV-2 and highlight that COVID-19 treatment and hygiene measures need to be tailored to specific needs of immunocompromised patients.

scholarly journals An Extensive Genetic Program Occurring during Postnatal Growth in Multiple Tissues

Endocrinology ◽  
2008 ◽  
Vol 150 (4) ◽  
pp. 1791-1800 ◽  
Author(s):  
Gabriela P. Finkielstain ◽  
Patricia Forcinito ◽  
Julian C. K. Lui ◽  
Kevin M. Barnes ◽  
Rose Marino ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Pattern ◽  
Somatic Growth ◽  
Postnatal Growth ◽  
Genetic Program ◽  
Male Rats ◽  
Postnatal Life ◽  
Multiple Organs ◽  
Organ Specific ◽  
Parenchymal Cells

Mammalian somatic growth is rapid in early postnatal life but then slows and eventually ceases in multiple tissues. We hypothesized that there exists a postnatal gene expression program that is common to multiple tissues and is responsible for this coordinate growth deceleration. Consistent with this hypothesis, microarray analysis identified more than 1600 genes that were regulated with age (1 vs. 4 wk) coordinately in kidney, lung, and heart of male mice, including many genes that regulate proliferation. As examples, we focused on three growth-promoting genes, Igf2, Mest, and Peg3, that were markedly down-regulated with age. In situ hybridization revealed that expression occurred in organ-specific parenchymal cells and suggested that the decreasing expression with age was due primarily to decreased expression per cell rather than a decreased number of expressing cells. The declining expression of these genes was slowed during hypothyroidism and growth inhibition (induced by propylthiouracil at 0–5 wk of age) in male rats, suggesting that the normal decline in expression is driven by growth rather than by age per se. We conclude that there exists an extensive genetic program occurring during postnatal life. Many of the involved genes are regulated coordinately in multiple organs, including many genes that regulate cell proliferation. At least some of these are themselves apparently regulated by growth, suggesting that, in the embryo, a gene expression pattern is established that allows for rapid somatic growth of multiple tissues, but then, during postnatal life, this growth leads to negative-feedback changes in gene expression that in turn slow and eventually halt somatic growth, thus imposing a fundamental limit on adult body size.

scholarly journals Salivary Gland Pathology in IgG4-Related Disease: A Comprehensive Review

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Ilaria Puxeddu ◽  
Riccardo Capecchi ◽  
Filippo Carta ◽  
Antonio Gaetano Tavoni ◽  
Paola Migliorini ◽  
...  
Keyword(s):  
Salivary Glands ◽  
Imaging Techniques ◽  
Elevated Serum ◽  
Clinical Aspects ◽  
Related Disease ◽  
Multiple Organs ◽  
Igg4 Related Disease ◽  
Serum Igg4 ◽  
Organ Specific ◽  
Clinical Pictures

IgG4-related disease (IgG4-RD) is a rare fibroinflammatory condition that can affect almost any organ, characterized by swollen lesions and often by eosinophilia and elevated serum IgG4 concentrations. The diagnosis of IgG4-RD is a challenging task: in fact, single or multiple organs can be affected and clinical, serological, and histological findings can be heterogeneous. In IgG4-RD, the involvement of salivary glands is observed in 27% to 53% of patients. Several organ-specific conditions, now recognized as different manifestations of IgG4-related sialadenitis (IgG4-RS), were viewed in the past as individual disease entities. The study of salivary glands may sometimes be complex, because of the number of pathological conditions that may affect them, often with overlapping clinical pictures. Integration of different imaging techniques is often required in the case of swelling of salivary glands, even though biopsy remains the gold standard for a definite diagnosis of IgG4-RS. Thus, in this review, we discuss new insights in the pathogenesis of IgG4-RD, focusing on its clinical aspects and the tools that are currently available for a correct differential diagnosis when the salivary glands are involved.

scholarly journals Within-host evolution of Enterococcus faecium during longitudinal carriage and transition to bloodstream infection in immunocompromised patients

2017 ◽  
Vol 9 (1) ◽  
Author(s):  
Danesh Moradigaravand ◽  
Theodore Gouliouris ◽  
Beth Blane ◽  
Plamena Naydenova ◽  
Catherine Ludden ◽  
...  
Keyword(s):  
Bloodstream Infection ◽  
Enterococcus Faecium ◽  
Immunocompromised Patients ◽  
Host Evolution

scholarly journals SARS-CoV-2 B.1.617.2 Delta variant emergence and vaccine breakthrough

2021 ◽  
Author(s):  
Petra Mlcochova ◽  
Steven Kemp ◽  
Mahesh Shanker Dhar ◽  
Guido Papa ◽  
Bo Meng ◽  
...  
Keyword(s):  
Severe Disease ◽  
Control Measures ◽  
Virus Infectivity ◽  
Neutralising Antibodies ◽  
Post Vaccination ◽  
Viral Loads ◽  
Infection Control Measures ◽  
Alpha Variant ◽  
In Vitro Data

Abstract The SARS-CoV-2 B.1.617.2 (Delta) variant was first identified in the state of Maharashtra in late 2020 and has spread throughout India, displacing the B.1.1.7 (Alpha) variant and other pre-existing lineages. Mathematical modelling indicates that the growth advantage is most likely explained by a combination of increased transmissibility and immune evasion. Indeed in vitro, the delta variant is less sensitive to neutralising antibodies in sera from recovered individuals, with higher replication efficiency as compared to the Alpha variant. In an analysis of vaccine breakthrough in over 100 healthcare workers across three centres in India, the Delta variant not only dominates vaccine-breakthrough infections with higher respiratory viral loads compared to non-delta infections (Ct value of 16.5 versus 19), but also generates greater transmission between HCW as compared to B.1.1.7 or B.1.617.1 (p=0.02). In vitro, the Delta variant shows 8 fold approximately reduced sensitivity to vaccine-elicited antibodies compared to wild type Wuhan-1 bearing D614G. Serum neutralising titres against the SARS-CoV-2 Delta variant were significantly lower in participants vaccinated with ChadOx-1 as compared to BNT162b2 (GMT 3372 versus 654, p<0001). These combined epidemiological and in vitro data indicate that the dominance of the Delta variant in India has been most likely driven by a combination of evasion of neutralising antibodies in previously infected individuals and increased virus infectivity. Whilst severe disease in fully vaccinated HCW was rare, breakthrough transmission clusters in hospitals associated with the Delta variant are concerning and indicate that infection control measures need continue in the post-vaccination era.

scholarly journals Stochastic processes constrain the within and between host evolution of influenza virus

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
John T McCrone ◽  
Robert J Woods ◽  
Emily T Martin ◽  
Ryan E Malosh ◽  
Arnold S Monto ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Stochastic Processes ◽  
Positive Selection ◽  
Evolutionary Dynamics ◽  
Sequence Data ◽  
Influenza Viruses ◽  
Single Nucleotide Variants ◽  
Individual Host ◽  
The Individual ◽  
Host Evolution

The evolutionary dynamics of influenza virus ultimately derive from processes that take place within and between infected individuals. Here we define influenza virus dynamics in human hosts through sequencing of 249 specimens from 200 individuals collected over 6290 person-seasons of observation. Because these viruses were collected from individuals in a prospective community-based cohort, they are broadly representative of natural infections with seasonal viruses. Consistent with a neutral model of evolution, sequence data from 49 serially sampled individuals illustrated the dynamic turnover of synonymous and nonsynonymous single nucleotide variants and provided little evidence for positive selection of antigenic variants. We also identified 43 genetically-validated transmission pairs in this cohort. Maximum likelihood optimization of multiple transmission models estimated an effective transmission bottleneck of 1–2 genomes. Our data suggest that positive selection is inefficient at the level of the individual host and that stochastic processes dominate the host-level evolution of influenza viruses.

scholarly journals Intra-host evolution provides for continuous emergence of SARS-CoV-2 variants

2021 ◽  
Author(s):  
Justin Landis ◽  
Razia Moorad ◽  
Linda J. Pluta ◽  
Carolina Caro-Vegas ◽  
Ryan P. McNamara ◽  
...  
Keyword(s):  
Public Health ◽  
Sequence Evolution ◽  
Clinical Progression ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Viral Genomes ◽  
Synonymous Mutations ◽  
Health Measures ◽  
Broad Public Health ◽  
Host Evolution

Variants of concern (VOC) in SARS-CoV-2 refer to viral genomes that differ significantly from the ancestor virus and that show the potential for higher transmissibility and/or worse clinical progression. VOC have the potential to disrupt ongoing public health measures and vaccine efforts. Yet, little is known regarding how frequently different viral variants emerge and under what circumstances. We report a longitudinal study to determine the degree of SARS-CoV-2 sequence evolution in 94 COVID-19 cases and to estimate the frequency at which highly diverse variants emerge. 2 cases accumulated 9 single-nucleotide variants (SNVs) over a two-week period and 1 case accumulated 23 SNVs over a three-week period, including three non-synonymous mutations in the Spike protein (D138H, E554D, D614G). We estimate that in 2% of COVID cases, viral variants with multiple mutations, including in the Spike glycoprotein, can become the dominant strains in as little as one month of persistent in patient virus replication. This suggests the continued local emergence of VOC independent of travel patterns. Surveillance by sequencing for (i) viremic COVID-19 patients, (ii) patients suspected of re-infection, and (iii) patients with diminished immune function may offer broad public health benefits.

scholarly journals Viral infection and transmission in a large, well-traced outbreak caused by the SARS-CoV-2 Delta variant

2021 ◽  
Author(s):  
Jing Lu ◽  
Baisheng Li ◽  
Aiping Deng ◽  
Kuibiao Li ◽  
Yao Hu ◽  
...  
Keyword(s):  
Mainland China ◽  
Population Level ◽  
Epidemiological Data ◽  
Single Nucleotide Variants ◽  
Symptomatic Infection ◽  
Single Nucleotide ◽  
Viral Loads ◽  
Rapid Spread ◽  
B Lineage ◽  
Local Transmission

Abstract We report the first local transmission of the SARS-CoV-2 Delta variant in mainland China. All 167 infections could be traced back to the first index case. Daily sequential PCR testing of the quarantined subjects indicated that the viral loads of Delta infections, when they first become PCR+, were on average ~1000 times greater compared to A/B lineage infections during initial epidemic wave in China in early 2020, suggesting potentially faster viral replication and greater infectiousness of Delta during early infection. We performed high-quality sequencing on samples from 126 individuals. Reliable epidemiological data meant that, for 111 transmission events, the donor and recipient cases were known. The estimated transmission bottleneck size was 1-3 virions with most minor intra-host single nucleotide variants (iSNVs) failing to transmit to the recipients. However, transmission heterogeneity of SARS-CoV-2 was also observed. The transmission of minor iSNVs resulted in at least 4 of the 30 substitutions identified in the outbreak, highlighting the contribution of intra-host variants to population level viral diversity during rapid spread. Disease control activities, such as the frequency of population testing, quarantine during pre-symptomatic infection, and level of virus genomic surveillance should be adjusted in order to account for the increasing prevalence of the Delta variant worldwide.

A 3-D mathematical model to identify organ-specific risks in rats during thermal stress

2013 ◽  
Vol 115 (12) ◽  
pp. 1822-1837 ◽  
Author(s):  
Vineet Rakesh ◽  
Jonathan D. Stallings ◽  
Bryan G. Helwig ◽  
Lisa R. Leon ◽  
David A. Jackson ◽  
...  
Keyword(s):  
Heat Stress ◽  
Core Temperature ◽  
Three Dimensional ◽  
Blood Perfusion ◽  
Adverse Outcomes ◽  
Maximum Temperature ◽  
Blood Temperature ◽  
Multiple Organs ◽  
Organ Specific

Early prediction of the adverse outcomes associated with heat stress is critical for effective management and mitigation of injury, which may sometimes lead to extreme undesirable clinical conditions, such as multiorgan dysfunction syndrome and death. Here, we developed a computational model to predict the spatiotemporal temperature distribution in a rat exposed to heat stress in an attempt to understand the correlation between heat load and differential organ dysfunction. The model includes a three-dimensional representation of the rat anatomy obtained from medical imaging and incorporates the key mechanisms of heat transfer during thermoregulation. We formulated a novel approach to estimate blood temperature by accounting for blood mixing from the different organs and to estimate the effects of the circadian rhythm in body temperature by considering day-night variations in metabolic heat generation and blood perfusion. We validated the model using in vivo core temperature measurements in control and heat-stressed rats and other published experimental data. The model predictions were within 1 SD of the measured data. The liver demonstrated the greatest susceptibility to heat stress, with the maximum temperature reaching 2°C higher than the measured core temperature and 95% of its volume exceeding the targeted experimental core temperature. Other organs also attained temperatures greater than the core temperature, illustrating the need to monitor multiple organs during heat stress. The model facilitates the identification of organ-specific risks during heat stress and has the potential to aid in the development of improved clinical strategies for thermal-injury prevention and management.

scholarly journals Characterization of a mobilization-competent simian immunodeficiency virus (SIV) vector containing a ribozyme against SIV polymerase

2004 ◽  
Vol 85 (6) ◽  
pp. 1489-1496 ◽  
Author(s):  
Kevin V. Morris ◽  
Robert A. Grahn ◽  
David J. Looney ◽  
Niels C. Pedersen
Keyword(s):  
Gene Therapy ◽  
Simian Immunodeficiency Virus ◽  
Viral Gene ◽  
Virus Infectivity ◽  
Gene Therapy Vector ◽  
Viral Loads ◽  
Macaque Model ◽  
Immunodeficiency Virus ◽  
Feasible Alternative ◽  
Infected Cells

Exploitation of the intracellular virus machinery within infected cells to drive an anti-viral gene therapy vector may prove to be a feasible alternative to reducing viral loads or overall virus infectivity while propagating the spread of a therapeutic vector. Using a simian immunodeficiency virus (SIV)-based system, it was shown that the pre-existing retroviral biological machinery within SIV-infected cells can drive the expression of an anti-SIV pol ribozyme and mobilize the vector to transduce neighbouring cells. The anti-SIV pol ribozyme vector was derived from the SIV backbone and contained the 5′- and 3′LTR including transactivation-response, Ψ and Rev-responsive elements, thus requiring Tat and Rev and therefore limiting expression to SIV-infected cells. The data presented here show an early reduction in SIV p27 levels in the presence of the anti-SIV pol ribozyme, as well as successful mobilization (vector RNA constituted ∼17 % of the total virus pool) and spread of the vector containing this ribozyme. These findings provide direct evidence that mobilization of an anti-retroviral SIV gene therapy vector is feasible in the SIV/macaque model.

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