scholarly journals Priming of SARS-CoV-2 S protein by several membrane-bound serine proteinases could explain enhanced viral infectivity and systemic COVID-19 infection

2020 ◽  
pp. jbc.REV120.015980
Author(s):  
Pablo Fuentes-Prior
Keyword(s):  
Positive Impact ◽  
Transmission Rate ◽  
Neurological Complications ◽  
Host Cells ◽  
Serine Proteinases ◽  
Direct Role ◽  
Clinical Observations ◽  
Membrane Bound ◽  
Exclusive Or ◽  
Function Information

The ongoing COVID-19 pandemic has already caused over a million deaths worldwide, and this death toll will be much higher before effective treatments and vaccines are available. The causative agent of the disease, the coronavirus SARS-CoV-2, shows important similarities with the previously emerged SARS-CoV-1, but also striking differences. First, SARS-CoV-2 possesses a significantly higher transmission rate and infectivity than SARS-CoV-1 and has infected in a few months over 60 million people. Moreover, COVID-19 has a systemic character, as in addition to the lungs it also affects heart, liver, and kidneys among other organs of the patients, and causes frequent thrombotic and neurological complications. In fact, the term “viral sepsis” has been recently coined to describe the clinical observations. Here I review current structure-function information on the viral spike proteins and the membrane fusion process to provide plausible explanations for these observations. I hypothesize that several membrane-associated serine proteinases (MASPs), in synergy with or in place of TMPRSS2, contribute to activate the SARS-CoV-2 spike protein. Relative concentrations of the attachment receptor, ACE2, MASPs, their endogenous inhibitors (the Kunitz-type transmembrane inhibitors, HAI-1/SPINT1 and HAI-2/SPINT2, as well as major circulating serpins) would determine the infection rate of host cells. The exclusive or predominant expression of major MASPs in specific human organs suggests a direct role of these proteinases in e.g. heart infection and myocardial injury, liver dysfunction, kidney damage, as well as neurological complications. Thorough consideration of these factors could have a positive impact on the control of the current COVID-19 pandemic.

scholarly journals Perforin-2 Protects Host Cells and Mice by Restricting the Vacuole to Cytosol Transitioning of a Bacterial Pathogen

2016 ◽  
Vol 84 (4) ◽  
pp. 1083-1091 ◽  
Author(s):  
Ryan McCormack ◽  
Wael Bahnan ◽  
Niraj Shrestha ◽  
Justin Boucher ◽  
Marcella Barreto ◽  
...  
Keyword(s):  
Bacterial Pathogen ◽  
Virulence Gene ◽  
Systemic Infection ◽  
Protective Role ◽  
Host Cells ◽  
Content Type ◽  
Virulence Gene Expression ◽  
Membrane Bound ◽  
High Level ◽  
Macpf Domain

The host-encoded Perforin-2 (encoded by the macrophage-expressed gene 1,Mpeg1), which possesses a pore-forming MACPF domain, reduces the viability of bacterial pathogens that reside within membrane-bound compartments. Here, it is shown that Perforin-2 also restricts the proliferation of the intracytosolic pathogenListeria monocytogenes. Within a few hours of systemic infection, the massive proliferation ofL. monocytogenesinPerforin-2−/−mice leads to a rapid appearance of acute disease symptoms. We go on to show in culturedPerforin-2−/−cells that the vacuole-to-cytosol transitioning ofL. monocytogenesis greatly accelerated. Unexpectedly, we found that inPerforin-2−/−macrophages,Listeria-containing vacuoles quickly (≤15 min) acidify, and that this was coincident with greater virulence gene expression, likely accounting for the more rapid translocation ofL. monocytogenesto its replicative niche in the cytosol. This hypothesis was supported by our finding that aL. monocytogenesstrain expressing virulence factors at a constitutively high level replicated equally well inPerforin-2+/+andPerforin-2−/−macrophages. Our findings suggest that the protective role of Perforin-2 against listeriosis is based on it limiting the intracellular replication of the pathogen. This cellular activity of Perforin-2 may derive from it regulating the acidification ofListeria-containing vacuoles, thereby depriving the pathogen of favorable intracellular conditions that promote its virulence gene activity.

scholarly journals Ribosomal protein RPL26 is the principal target of UFMylation

2019 ◽  
Vol 116 (4) ◽  
pp. 1299-1308 ◽  
Author(s):  
Christopher P. Walczak ◽  
Dara E. Leto ◽  
Lichao Zhang ◽  
Celeste Riepe ◽  
Ryan Y. Muller ◽  
...  
Keyword(s):  
Ribosomal Protein ◽  
Protein Translocation ◽  
Specific Protein ◽  
Loss Of Function ◽  
Direct Role ◽  
Cellular Targets ◽  
Close Proximity ◽  
Protein Biogenesis ◽  
Membrane Bound ◽  
Enzyme Complexes

Ubiquitin fold modifier 1 (UFM1) is a small, metazoan-specific, ubiquitin-like protein modifier that is essential for embryonic development. Although loss-of-function mutations in UFM1 conjugation are linked to endoplasmic reticulum (ER) stress, neither the biological function nor the relevant cellular targets of this protein modifier are known. Here, we show that a largely uncharacterized ribosomal protein, RPL26, is the principal target of UFM1 conjugation. RPL26 UFMylation and de-UFMylation is catalyzed by enzyme complexes tethered to the cytoplasmic surface of the ER and UFMylated RPL26 is highly enriched on ER membrane-bound ribosomes and polysomes. Biochemical analysis and structural modeling establish that UFMylated RPL26 and the UFMylation machinery are in close proximity to the SEC61 translocon, suggesting that this modification plays a direct role in cotranslational protein translocation into the ER. These data suggest that UFMylation is a ribosomal modification specialized to facilitate metazoan-specific protein biogenesis at the ER.

scholarly journals Chlamydia trachomatis Cellular Exit Alters Interactions with Host Dendritic Cells

2017 ◽  
Vol 85 (5) ◽  
Author(s):  
Ashley M. Sherrid ◽  
Kevin Hybiske
Keyword(s):  
Dendritic Cells ◽  
Dendritic Cell ◽  
Chlamydia Trachomatis ◽  
Innate Immune ◽  
Host Cells ◽  
Bacterial Survival ◽  
Content Type ◽  
Innate Immune Signaling ◽  
Host Membrane ◽  
Membrane Bound

ABSTRACT The strategies utilized by pathogens to exit host cells are an area of pathogenesis which has received surprisingly little attention, considering the necessity of this step for infections to propagate. Even less is known about how exit through these pathways affects downstream host-pathogen interactions and the generation of an immune response. Chlamydia trachomatis exits host epithelial cells through two equally active mechanisms: lysis and extrusion. Studies have characterized the outcome of interactions between host innate immune cells, such as dendritic cells and macrophages, and free, extracellular Chlamydia bacteria, such as those resulting from lysis. Exit via extrusion generates a distinct, host-membrane-bound compartment of Chlamydia separate from the original infected cell. In this study, we assessed the effect of containment within extrusions upon the interaction between Chlamydia and host dendritic cells. Extrusion dramatically affected the outcome of Chlamydia-dendritic cell interactions for both the bacterium and the host cell. Dendritic cells rapidly underwent apoptosis in response to engulfment of an extrusion, while uptake of an equivalent dose of free Chlamydia had no such effect. Containment within an extrusion also prolonged bacterial survival within dendritic cells and altered the initial innate immune signaling by the dendritic cell.

scholarly journals Fitness benefits of low infectivity in a spatially structured population of bacteriophages

2014 ◽  
Vol 281 (1774) ◽  
pp. 20132563 ◽  
Author(s):  
Pavitra Roychoudhury ◽  
Neelima Shrestha ◽  
Valorie R. Wiss ◽  
Stephen M. Krone
Keyword(s):  
Transmission Rate ◽  
Burst Size ◽  
Structured Populations ◽  
Host Cells ◽  
Structured Population ◽  
Spatially Structured Populations ◽  
Lysis Time ◽  
Evolution Experiment ◽  
Spatially Structured Population ◽  
And Diffusion

For a parasite evolving in a spatially structured environment, an evolutionarily advantageous strategy may be to reduce its transmission rate or infectivity. We demonstrate this empirically using bacteriophage (phage) from an evolution experiment where spatial structure was maintained over 550 phage generations on agar plates. We found that a single substitution in the major capsid protein led to slower adsorption of phage to host cells with no change in lysis time or burst size. Plaques formed by phage isolates containing this mutation were not only larger but also contained more phage per unit area. Using a spatially explicit, individual-based model, we showed that when there is a trade-off between adsorption and diffusion (i.e. less ‘sticky’ phage diffuse further), slow adsorption can maximize plaque size, plaque density and overall productivity. These findings suggest that less infective pathogens may have an advantage in spatially structured populations, even when well-mixed models predict that they will not.

scholarly journals Comprehensive Single Cell Analyses of the Nutritional Environment of Intracellular Salmonella enterica

2021 ◽  
Vol 11 ◽  
Author(s):  
Jennifer Röder ◽  
Pascal Felgner ◽  
Michael Hensel
Keyword(s):  
Host Cell ◽  
Salmonella Enterica ◽  
Nutrient Supply ◽  
Host Cells ◽  
Direct Access ◽  
Uptake System ◽  
Bacterial Proliferation ◽  
Membrane Compartments ◽  
Membrane Bound ◽  
Nutritional Environment

The facultative intracellular pathogen Salmonella enterica Typhimurium (STM) resides in a specific membrane-bound compartment termed the Salmonella-containing vacuole (SCV). STM is able to obtain all nutrients required for rapid proliferation, although being separated from direct access to host cell metabolites. The formation of specific tubular membrane compartments, called Salmonella-induced filaments (SIFs) are known to provides bacterial nutrition by giving STM access to endocytosed material and enabling proliferation. Additionally, STM expresses a range of nutrient uptake system for growth in nutrient limited environments to overcome the nutrition depletion inside the host. By utilizing dual fluorescence reporters, we shed light on the nutritional environment of intracellular STM in various host cells and distinct intracellular niches. We showed that STM uses nutrients of the host cell and adapts uniquely to the different nutrient conditions. In addition, we provide further evidence for improved nutrient supply by SIF formation or presence in the cytosol of epithelial cells, and the correlation of nutrient supply to bacterial proliferation.

scholarly journals Hypertension, a Moving Target in COVID-19

2021 ◽  
Vol 128 (7) ◽  
pp. 1062-1079
Author(s):  
Carmine Savoia ◽  
Massimo Volpe ◽  
Reinhold Kreutz
Keyword(s):  
Global Health ◽  
Angiotensin Receptor Blockers ◽  
Experimental Studies ◽  
Renin Angiotensin System ◽  
Host Cells ◽  
High Rate ◽  
Direct Role ◽  
Pressure Lowering ◽  
Ras Blockers

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) associates with a considerable high rate of mortality and represents currently the most important concern in global health. The risk of more severe clinical manifestation of COVID-19 is higher in males and steeply raised with age but also increased by the presence of chronic comorbidities. Among the latter, early reports suggested that arterial hypertension associates with higher susceptibility to SARS-CoV-2 infection, more severe course and increased COVID-19–related deaths. Furthermore, experimental studies suggested that key pathophysiological hypertension mechanisms, such as activation of the renin-angiotensin system (RAS), may play a role in COVID-19. In fact, ACE2 (angiotensin-converting-enzyme 2) is the pivotal receptor for SARS-CoV-2 to enter host cells and provides thus a link between COVID-19 and RAS. It was thus anticipated that drugs modulating the RAS including an upregulation of ACE2 may increase the risk for infection with SARS-CoV-2 and poorer outcomes in COVID-19. Since the use of RAS-blockers, ACE inhibitors or angiotensin receptor blockers, represents the backbone of recommended antihypertensive therapy and intense debate about their use in the COVID-19 pandemic has developed. Currently, a direct role of hypertension, independent of age and other comorbidities, as a risk factor for the SARS-COV-2 infection and COVID-19 outcome, particularly death, has not been established. Similarly, both current experimental and clinical studies do not support an unfavorable effect of RAS-blockers or other classes of first line blood pressure lowering drugs in COVID-19. Here, we review available data on the role of hypertension and its management on COVID-19. Conversely, some aspects as to how the COVID-19 affects hypertension management and impacts on future developments are also briefly discussed. COVID-19 has and continues to proof the critical importance of hypertension research to address questions that are important for global health.

scholarly journals Students anxiety and recruitment during Covid-19 pandemic: role of university, specialization and employment expectation

2021 ◽  
Vol 49 (1) ◽  
pp. 403-413
Author(s):  
Abdullah M. Al-Ansi ◽  
Keyword(s):  
Undergraduate Students ◽  
Natural Science ◽  
Positive Impact ◽  
Medical Science ◽  
Science Students ◽  
Direct Role ◽  
Main Method ◽  
Self Confidence ◽  
Yogyakarta City

The problem and the aim of the study. Most undergraduate students at last year of university have anxiety to seek for the future job. Looking for job and moving to new chapter of their life is often accompanied by anxiousness and generates psychological stress. The purpose of this paper is to indicate the role of university, specialization and employment expectation in decreasing the students’ anxiousness. Research methods. The main method of this research is quantitative approach by using surveys. Data were collected by surveying of 400 students at the last year of university distributed under three categories: medical science, natural science and social studies in Yogyakarta city, Indonesia. Purposive sampling was used to select students based on their specialization of study. Regression path analysis was employed to examine the role of university, specialization and possibility of employment on decreasing the students’ anxiety in finding suitable job. Results. The Results indicate that university has no direct role in helping students get job but has indirect impact on shaping students’ knowledge, skills and self-confidence to prepare them for future job and this leads to negative and significant impact on students’ anxiousness with (β = -.138 and -.260; p < 0,01) respectively. Specialization has negative and significant impact (β = -.207, -.198; p < 0,01) for medical and natural science students and low negative and significant (β = -.018; p < 0,01) for social science students on their anxiety. Finally, employment expectation for most of the students was fair and has positive impact on their anxiety (β = .012, .090 and .124; p < 0,05) respectively. Conclusion. This research revealed the increasing impact of Covid-19 pandemic to the students’ anxiety due to continuous influence of the virus during the 2020. Theoretical, social and practical implications have been discussed as part of this research as well.

scholarly journals ADP-Ribosyltransferase PARP11 Suppresses Zika Virus in Synergy with PARP12

2021 ◽  
Author(s):  
Lili Li ◽  
Yueyue Shi ◽  
Sirui Li ◽  
Junxiao Liu ◽  
Shulong Zu ◽  
...  
Keyword(s):  
Zika Virus ◽  
Neurological Complications ◽  
Host Cells ◽  
Interferon Response ◽  
Type I ◽  
Zikv Infection ◽  
Interferon Stimulated Genes ◽  
Ns3 Protein ◽  
Global Threat ◽  
Adp Ribosyltransferase

Abstract Zika virus (ZIKV) infection and ZIKV epidemic have been continuously spreading silently throughout the world and its associated microcephaly and other serious congenital neurological complications poses a significant global threat to public health. ZIKV infection stimulates type I interferon response in host cells which suppresses viral replication by inducing the expression of interferon-stimulated genes (ISGs). Here, we identified ADP-ribosyltransferase PARP11 as an anti-ZIKV ISG and found that PARP11 suppressed ZIKV independently on itself PARP enzyme activity. Furthermore, PARP11 interacted with PARP12 and promoted PARP12-mediating ZIKV NS1 and NS3 protein degradation. Homo family PARP11 and PARP12 cooperated with each other on ZIKV suppression and the anti-ZIKV function of PARP11 mostly dependent on the existence of PARP12. Our findings have broadened the understanding of the anti-viral function of PARP11, and more importantly suggest a potential therapeutics target against ZIKV infection.

scholarly journals Qualitative and Quantitative Analyses of COVID-19 Dynamics

Axioms ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 210
Author(s):  
Taye Samuel Faniran ◽  
Leontine Nkague Nkamba ◽  
Thomas Timothee Manga
Keyword(s):  
High Risk ◽  
General Public ◽  
Deterministic Model ◽  
Negative Impact ◽  
Positive Impact ◽  
Transmission Rate ◽  
Low Risk ◽  
Contact Tracing ◽  
Epidemic Curve ◽  
Underlying Diseases

COVID-19 is a highly contagious disease which has spread across the world. A deterministic model that considers an important component of individuals with vertically transmitted underlying diseases (high-risk susceptible individuals), rather than the general public, is formulated in this paper. We also consider key parameters that are concerned with the disease. An epidemiological threshold, R0, is computed using next-generation matrix approach. This is used to establish the existence and global stability of equilibria. We identify the most sensitive parameters which effectively contribute to change the disease dynamics with the help of sensitivity analysis. Our results reveal that increasing contact tracing of the exposed individuals who are tested for COVID-19 and hospitalizing them, largely has a negative impact on R0. Results further reveal that transmission rate between low-risk/high-risk susceptible individuals and symptomatic infectious individuals β and incubation rate of the exposed individuals σ have positive impact on R0. Numerical simulations show that there are fewer high-risk susceptible individuals than the general public when R0<1. This may be due to the fact that high-risk susceptible individuals may prove a bit more difficult to control than the low-risk susceptible individuals as a result of inherited underlying diseases present in them. We thus conclude that high level of tracing and hospitalizing the exposed individuals, as well as adherence to standard precautions and wearing appropriate Personal Protective Equipment (PPE) while handling emergency cases, are needed to flatten the epidemic curve.

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