scholarly journals The ancient cardioprotective mechanisms of ACE2 bestow SARS-CoV-2 with a wide host range

2021 ◽  
Author(s):  
Gianni M. Castiglione ◽  
Lingli Zhou ◽  
Zhenhua Xu ◽  
Zachary Neiman ◽  
Chien-Fu Hung ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Host Range ◽  
Mammalian Species ◽  
Sequence Divergence ◽  
Extreme Caution ◽  
Viral Binding ◽  
Wide Host Range ◽  
Wide Range ◽  
Evolutionary Trajectories ◽  
Animal Reservoirs

AbstractSARS-CoV-2 infects a broader range of mammalian species than previously anticipated, suggesting there may be additional unknown hosts wherein the virus can evolve and potentially circumvent effective vaccines. We find that SARS-CoV-2 gains a wide host range by binding ACE2 sites essential for ACE2 carboxypeptidase activity. Six mutations found only in rodent species immune to SARS-CoV-2 are sufficient to abolish viral binding to human and dog ACE2. This is achieved through context-dependent mutational effects (intramolecular epistasis) conserved despite ACE2 sequence divergence between species. Across mammals, this epistasis generates sequence-function diversity, but through structures all bound by SARS-CoV-2. Mutational trajectories to the mouse conformation not bound by SARS-CoV-2 are blocked, by single mutations functionally deleterious in isolation, but compensatory in combination, explaining why human polymorphisms at these sites are virtually non-existent. Closed to humans, this path was opened to rodents via permissive cardiovascular phenotypes and ancient increases to ACE2 activity, serendipitously granting SARS-CoV-2 immunity. This reveals how ancient evolutionary trajectories are linked with unprecedented phenotypes such as COVID-19 and suggests extreme caution should be taken to monitor and prevent emerging animal reservoirs of SARS-CoV-2.One sentence summaryA conserved mechanism essential for ACE2 catalytic activity is exploited by SARS-CoV-2 binding, allowing the virus to infect a wide range of species.

Backyard Farms Represent a Source of Wide Host Range Salmonella Phages That Lysed the Most Common Salmonella Serovars

2018 ◽  
Vol 81 (2) ◽  
pp. 272-278 ◽  
Author(s):  
DÁCIL RIVERA ◽  
VIVIANA TOLEDO ◽  
FRANCISCA DI PILLO ◽  
FERNANDO DUEÑAS ◽  
RODOLFO TARDONE ◽  
...  
Keyword(s):  
Host Range ◽  
Salmonella Enteritidis ◽  
Genetic Relatedness ◽  
Production Systems ◽  
Lytic Cycle ◽  
Salmonella Infections ◽  
Wide Host Range ◽  
Wide Range ◽  
Salmonella Serovars ◽  
Phage Isolation

ABSTRACT The genus Salmonella has more than 2,600 serovars, and this trait is important when considering interventions for Salmonella control. Bacteriophages that are used for biocontrol must have an exclusively lytic cycle and the ability to lyse several Salmonella serovars under a wide range of environmental conditions. Salmonella phages were isolated and characterized from 34 backyard production systems (BPSs) with a history of Salmonella infections. BPSs were visited once, and cloacal or fecal samples were processed for phage isolation. Four hosts, Salmonella serovars Enteritidis, Heidelberg, Infantis, and Typhimurium, were used for phage isolation. The host range of the phages was later characterized with a panel of 23 Salmonella serovars (serovar diversity set) and 31 isolates obtained from the same farms (native set). Genetic relatedness for 10 phages with a wide host range was characterized by restriction fragment length polymorphism, and phages clustered based on the host range. We purified 63 phages, and 36 phage isolates were obtained on Salmonella Enteritidis, 16 on Salmonella Heidelberg, and 11 on Salmonella Infantis. Phages were classified in three clusters: (i) phages with a wide host range (cluster I), (ii) phages that lysed the most susceptible Salmonella serovars (serogroup D) and other isolates (cluster II), and (iii) phages that lysed only isolates of serogroup D (cluster III). The most susceptible Salmonella serovars were Enteritidis, Javiana, and Dublin. Seven of 34 farms yielded phages with a wide host range, and these phages had low levels of genetic relatedness. Our study showed an adaptation of the phages in the sampled BPSs to serogroup D Salmonella isolates and indicated that isolation of Salmonella phages with wide host range differs by farm. A better understanding of the factors driving the Salmonella phage host range could be useful when designing risk-based sampling strategies to obtain phages with a wide lytic host range for biocontrol purposes.

scholarly journals Evolutionary pathways to SARS-CoV-2 resistance are opened and closed by epistasis acting on ACE2

PLoS Biology ◽  
2021 ◽  
Vol 19 (12) ◽  
pp. e3001510
Author(s):  
Gianni M. Castiglione ◽  
Lingli Zhou ◽  
Zhenhua Xu ◽  
Zachary Neiman ◽  
Chien-Fu Hung ◽  
...  
Keyword(s):  
Genetic Background ◽  
Deleterious Effect ◽  
Mammalian Species ◽  
Sequence Divergence ◽  
Trade Off ◽  
Angiotensin Converting Enzyme 2 ◽  
The Road ◽  
Viral Binding ◽  
Evolutionary Pathways

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infects a broader range of mammalian species than previously predicted, binding a diversity of angiotensin converting enzyme 2 (ACE2) orthologs despite extensive sequence divergence. Within this sequence degeneracy, we identify a rare sequence combination capable of conferring SARS-CoV-2 resistance. We demonstrate that this sequence was likely unattainable during human evolution due to deleterious effects on ACE2 carboxypeptidase activity, which has vasodilatory and cardioprotective functions in vivo. Across the 25 ACE2 sites implicated in viral binding, we identify 6 amino acid substitutions unique to mouse—one of the only known mammalian species immune to SARS-CoV-2. Substituting human variants at these positions is sufficient to confer binding of the SARS-CoV-2 S protein to mouse ACE2, facilitating cellular infection. Conversely, substituting mouse variants into either human or dog ACE2 abolishes viral binding, diminishing cellular infection. However, these same substitutions decrease human ACE2 activity by 50% and are predicted as pathogenic, consistent with the extreme rarity of human polymorphisms at these sites. This trade-off can be avoided, however, depending on genetic background; if substituted simultaneously, these same mutations have no deleterious effect on dog ACE2 nor that of the rodent ancestor estimated to exist 70 million years ago. This genetic contingency (epistasis) may have therefore opened the road to resistance for some species, while making humans susceptible to viruses that use these ACE2 surfaces for binding, as does SARS-CoV-2.

scholarly journals Effect of Posttranslational Modifications on the Structure and Activity of FTO Demethylase

2021 ◽  
Vol 22 (9) ◽  
pp. 4512
Author(s):  
Michał Marcinkowski ◽  
Tomaš Pilžys ◽  
Damian Garbicz ◽  
Jan Piwowarski ◽  
Damian Mielecki ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Size Exclusion Chromatography ◽  
Posttranslational Modifications ◽  
Size Exclusion ◽  
Saxs Data ◽  
Wide Range ◽  
Exclusion Chromatography ◽  
Demethylase Activity ◽  
Structure And Activity

The FTO protein is involved in a wide range of physiological processes, including adipogenesis and osteogenesis. This two-domain protein belongs to the AlkB family of 2-oxoglutarate (2-OG)- and Fe(II)-dependent dioxygenases, displaying N6-methyladenosine (N6-meA) demethylase activity. The aim of the study was to characterize the relationships between the structure and activity of FTO. The effect of cofactors (Fe2+/Mn2+ and 2-OG), Ca2+ that do not bind at the catalytic site, and protein concentration on FTO properties expressed in either E. coli (ECFTO) or baculovirus (BESFTO) system were determined using biophysical methods (DSF, MST, SAXS) and biochemical techniques (size-exclusion chromatography, enzymatic assay). We found that BESFTO carries three phosphoserines (S184, S256, S260), while there were no such modifications in ECFTO. The S256D mutation mimicking the S256 phosphorylation moderately decreased FTO catalytic activity. In the presence of Ca2+, a slight stabilization of the FTO structure was observed, accompanied by a decrease in catalytic activity. Size exclusion chromatography and MST data confirmed the ability of FTO from both expression systems to form homodimers. The MST-determined dissociation constant of the FTO homodimer was consistent with their in vivo formation in human cells. Finally, a low-resolution structure of the FTO homodimer was built based on SAXS data.

scholarly journals Revealing biophysical properties of KfrA-type proteins as a novel class of cytoskeletal, coiled-coil plasmid-encoded proteins

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
M. Adamczyk ◽  
E. Lewicka ◽  
R. Szatkowska ◽  
H. Nieznanska ◽  
J. Ludwiczak ◽  
...  
Keyword(s):  
Dna Binding ◽  
Host Range ◽  
Coiled Coil ◽  
Amino Acid Sequences ◽  
Broad Host Range ◽  
Biophysical Properties ◽  
Dna Binding Sites ◽  
In Silico Studies ◽  
Wide Range

Abstract Background DNA binding KfrA-type proteins of broad-host-range bacterial plasmids belonging to IncP-1 and IncU incompatibility groups are characterized by globular N-terminal head domains and long alpha-helical coiled-coil tails. They have been shown to act as transcriptional auto-regulators. Results This study was focused on two members of the growing family of KfrA-type proteins encoded by the broad-host-range plasmids, R751 of IncP-1β and RA3 of IncU groups. Comparative in vitro and in silico studies on KfrAR751 and KfrARA3 confirmed their similar biophysical properties despite low conservation of the amino acid sequences. They form a wide range of oligomeric forms in vitro and, in the presence of their cognate DNA binding sites, they polymerize into the higher order filaments visualized as “threads” by negative staining electron microscopy. The studies revealed also temperature-dependent changes in the coiled-coil segment of KfrA proteins that is involved in the stabilization of dimers required for DNA interactions. Conclusion KfrAR751 and KfrARA3 are structural homologues. We postulate that KfrA type proteins have moonlighting activity. They not only act as transcriptional auto-regulators but form cytoskeletal structures, which might facilitate plasmid DNA delivery and positioning in the cells before cell division, involving thermal energy.

scholarly journals New Hepatitis B Virus of Cranes That Has an Unexpected Broad Host Range

2003 ◽  
Vol 77 (3) ◽  
pp. 1964-1976 ◽  
Author(s):  
Alexej Prassolov ◽  
Heinz Hohenberg ◽  
Tatyana Kalinina ◽  
Carola Schneider ◽  
Lucyna Cova ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Host Range ◽  
Sequence Divergence ◽  
Divergent Evolution ◽  
Broad Host Range ◽  
Virus Propagation ◽  
Direct Dna Sequencing ◽  
Duck Hepatitis ◽  
B Virus

ABSTRACT All hepadnaviruses known so far have a very limited host range, restricted to their natural hosts and a few closely related species. This is thought to be due mainly to sequence divergence in the large envelope protein and species-specific differences in host components essential for virus propagation. Here we report an infection of cranes with a novel hepadnavirus, designated CHBV, that has an unexpectedly broad host range and is only distantly evolutionarily related to avihepadnaviruses of related hosts. Direct DNA sequencing of amplified CHBV DNA as well a sequencing of cloned viral genomes revealed that CHBV is most closely related to, although distinct from, Ross' goose hepatitis B virus (RGHBV) and slightly less closely related to duck hepatitis B virus (DHBV). Phylogenetically, cranes are very distant from geese and ducks and are most closely related to herons and storks. Naturally occurring hepadnaviruses in the last two species are highly divergent in sequence from RGHBV and DHBV and do not infect ducks or do so only marginally. In contrast, CHBV from crane sera and recombinant CHBV produced from LMH cells infected primary duck hepatocytes almost as efficiently as DHBV did. This is the first report of a rather broad host range of an avihepadnavirus. Our data imply either usage of similar or identical entry pathways and receptors by DHBV and CHBV, unusual host and virus adaptation mechanisms, or divergent evolution of the host genomes and cellular components required for virus propagation.

scholarly journals The nucleoporin RanBP2 tethers the cAMP effector Epac1 and inhibits its catalytic activity

2011 ◽  
Vol 193 (6) ◽  
pp. 1009-1020 ◽  
Author(s):  
Martijn Gloerich ◽  
Marjolein J. Vliem ◽  
Esther Prummel ◽  
Lars A.T. Meijer ◽  
Marije G.A. Rensen ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Negative Regulator ◽  
Camp Signaling ◽  
Nuclear Pore ◽  
Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Wide Range

Cyclic adenosine monophosphate (cAMP) is a second messenger that relays a wide range of hormone responses. In this paper, we demonstrate that the nuclear pore component RanBP2 acts as a negative regulator of cAMP signaling through Epac1, a cAMP-regulated guanine nucleotide exchange factor for Rap. We show that Epac1 directly interacts with the zinc fingers (ZNFs) of RanBP2, tethering Epac1 to the nuclear pore complex (NPC). RanBP2 inhibits the catalytic activity of Epac1 in vitro by binding to its catalytic CDC25 homology domain. Accordingly, cellular depletion of RanBP2 releases Epac1 from the NPC and enhances cAMP-induced Rap activation and cell adhesion. Epac1 also is released upon phosphorylation of the ZNFs of RanBP2, demonstrating that the interaction can be regulated by posttranslational modification. These results reveal a novel mechanism of Epac1 regulation and elucidate an unexpected link between the NPC and cAMP signaling.

Wide host range of murine sarcoma virus

1973 ◽  
Vol 12 (3) ◽  
pp. 734-741 ◽  
Author(s):  
Johng S. Rhim ◽  
Mina L. Vernon ◽  
Fuw G. Duh ◽  
Robert J. Huebner
Keyword(s):  
Host Range ◽  
Wide Host Range ◽  
Murine Sarcoma Virus ◽  
Sarcoma Virus ◽  
Murine Sarcoma

scholarly journals In Vitro-Transcribed Chrysanthemum stunt viroid RNA Is Infectious to Chrysanthemum and Other Plants

2009 ◽  
Vol 99 (1) ◽  
pp. 58-66 ◽  
Author(s):  
Yosuke Matsushita ◽  
Kumar K. R. Penmetcha
Keyword(s):  
Host Range ◽  
Noncoding Rna ◽  
Chrysanthemum Stunt Viroid ◽  
Stunt Viroid ◽  
Wide Host Range

Chrysanthemum stunt viroid (CSVd), a noncoding RNA, is known to cause chrysanthemum stunt disease, which affects the yield of flowers. To gain insights into CSVd replication, infection, and the reasons for the spreading of CSVd disease in chrysanthemum plants, we prepared linear CSVd RNA and analyzed its ability to cause disease in chrysanthemum plants. We found that linear CSVd replicated as efficiently as CSVd RNA isolated from the infected chrysanthemum plants. Additionally, the linear CSVd RNA was evaluated for its ability to infect other plants as well, which revealed that CSVd has a wide host range for its replication. Importantly, the CSVd isolated from these hosts is infectious to chrysanthemum plants, and thus potentially contributes to the spreading of the disease to chrysanthemum plants.

Ecological interactions in the transmission of the leishmaniases

1988 ◽  
Vol 321 (1207) ◽  
pp. 389-404 ◽  
Keyword(s):  
Human Disease ◽  
Mammalian Species ◽  
Epidemiological Studies ◽  
Ecological Interactions ◽  
Environmental Barriers ◽  
Human Host ◽  
Phlebotomine Sandfly ◽  
Ecological Changes ◽  
Wide Range ◽  
Epidemiological Pattern

Epidemiological studies on the leishmaniases are disclosing a multiplicity of Leishmania species infecting a wide range of wild mammalian hosts, from marsupials to monkeys. In the primitive, silvatic habitat these parasites are transmitted by an equally wide variety of phlebotomine sandfly species (Diptera: Psychodidae: Phlebotominae). Transmission is not haphazard, however, and available evidence points to the existence of environmental barriers that normally limit the different Leishmania species to specific sandfly vectors, transmitting to certain mammalian species, within distinct ecotopes. In this situation, humans may become infected by a variety of leishmanial parasites when intruding into the different enzootics, if the sandfly vectors are anthropophilic. Many are not, however, and their parasites rarely, if ever, make contact with the human host. Natural or man-made ecological changes may result in modification of the epidemiological pattern of leishmaniasis, leading to either a reduction or an increase in the human disease.

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