In addition to CD4
T lymphocytes, myeloid cells and, particularly, differentiated macrophages are targets of human immunodeficiency virus type-1 (HIV-1) infection via the interaction of gp120Env with ...CD4 and CCR5 or CXCR4. Both T cells and macrophages support virus replication, although with substantial differences. In contrast to activated CD4
T lymphocytes, HIV-1 replication in macrophages occurs in nondividing cells and it is characterized by the virtual absence of cytopathicity both in vitro and in vivo. These general features should be considered in evaluating the role of cell-associated restriction factors aiming at preventing or curtailing virus replication in macrophages and T cells, particularly in the context of designing strategies to tackle the viral reservoir in infected individuals receiving combination antiretroviral therapy. In this regard, we will here also discuss a model of reversible HIV-1 latency in primary human macrophages and the role of host factors determining the restriction or reactivation of virus replication in these cells.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Viral invasion of target cells triggers an immediate intracellular host defense system aimed at preventing further propagation of the virus. Viral genomes or early products of viral replication are ...sensed by a number of pattern recognition receptors, leading to the synthesis and production of type I interferons (IFNs) that, in turn, activate a cascade of IFN-stimulated genes (ISGs) with antiviral functions. Among these, several members of the tripartite motif (TRIM) family are antiviral executors. This article will focus, in particular, on TRIM22 as an example of a multitarget antiviral member of the TRIM family. The antiviral activities of TRIM22 against different DNA and RNA viruses, particularly human immunodeficiency virus type 1 (HIV-1) and influenza A virus (IAV), will be discussed. TRIM22 restriction of virus replication can involve either direct interaction of TRIM22 E3 ubiquitin ligase activity with viral proteins, or indirect protein–protein interactions resulting in control of viral gene transcription, but also epigenetic effects exerted at the chromatin level.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Upon infection, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is predicted to interact with diverse cellular functions, such as the nonsense-mediated decay (NMD) pathway, as suggested ...by the identification of the core NMD factor upframeshift-1 (UPF1) in the SARS-CoV-2 interactome, and the retrograde transport from the Golgi to the endoplasmic reticulum (ER) through the endoplasmic reticulum-Golgi intermediate compartment (ERGIC), where coronavirus assembly occurs. Here, we investigated the expression and localization of the neuroblastoma-amplified sequence (NBAS) protein, a UPF1 partner for the NMD at the ER, participating also in retrograde transport, and of its functional partners, at early time points after SARS-CoV-2 infection of the human lung epithelial cell line Calu3. We found a significant decrease of DExH-Box Helicase 34 (
, suppressor with morphogenetic effect on genitalia 5 (
, and
expression at 6 h post-infection, followed by a significant increase of these genes and also
and
at 9 h post-infection. Conversely,
and other genes coding for NMD factors were not modulated. Known NMD substrates related to cell stress (Growth Arrest Specific 5,
transducin beta-like 2,
; and DNA damage-inducible transcript 3,
) were increased in infected cells, possibly as a result of alterations in the NMD pathway and of a direct effect of the infection. We also found that the expression of unconventional SNARE in the ER 1,
(p31) and Zeste White 10 homolog,
, partners of NBAS in the retrograde transport function, significantly increased over time in infected cells. Co-localization of NBAS and UPF1 proteins did not change within 24 h of infection nor did it differ in infected versus non-infected cells at 1 and 24 h after infection; similarly, the co-localization of NBAS and p31 proteins was not altered by infection in this short time frame. Finally, both NBAS and UPF1 were found to co-localize with SARS-CoV-2 S and N proteins. Overall, these data are preliminary evidence of an interaction between NBAS and NBAS-related functions and SARS-CoV-2 in infected cells, deserving further investigation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has caused a significant number of fatalities and worldwide disruption. To identify drugs to repurpose to treat SARS-CoV-2 ...infections, we established a screen to measure the dimerization of angiotensin-converting enzyme 2 (ACE2), the primary receptor for the virus. This screen identified fenofibric acid, the active metabolite of fenofibrate. Fenofibric acid also destabilized the receptor-binding domain (RBD) of the viral spike protein and inhibited RBD binding to ACE2 in enzyme-linked immunosorbent assay (ELISA) and whole cell-binding assays. Fenofibrate and fenofibric acid were tested by two independent laboratories measuring infection of cultured Vero cells using two different SARS-CoV-2 isolates. In both settings at drug concentrations, which are clinically achievable, fenofibrate and fenofibric acid reduced viral infection by up to 70%. Together with its extensive history of clinical use and its relatively good safety profile, this study identifies fenofibrate as a potential therapeutic agent requiring an urgent clinical evaluation to treat SARS-CoV-2 infection.
Viruses exploit host metabolic and defence machinery for their own replication. The flaviviruses, which include Dengue (DENV), Yellow Fever (YFV), Japanese Encephalitis (JEV), West Nile (WNV) and ...Zika (ZIKV) viruses, infect a broad range of hosts, cells and tissues. Flaviviruses are largely transmitted by mosquito bites and humans are usually incidental, dead-end hosts, with the notable exceptions of YFV, DENV and ZIKV. Infection by flaviviruses elicits cellular responses including cell death via necrosis, pyroptosis (involving inflammation) or apoptosis (which avoids inflammation). Flaviviruses exploit these mechanisms and subvert them to prolong viral replication. The different effects induced by DENV, WNV, JEV and ZIKV are reviewed. Host cell surface proteoglycans (PGs) bearing glycosaminoglycan (GAG) polysaccharides - heparan/chondroitin sulfate (HS/CS) - are involved in initial flavivirus attachment and during the expression of non-structural viral proteins play a role in disease aetiology. Recent work has shown that ZIKV-infected cells are protected from cell death by exogenous heparin (a GAG structurally similar to host cell surface HS), raising the possibility of further subtle involvement of HS PGs in flavivirus disease processes. The aim of this review is to synthesize information regarding DENV, WNV, JEV and ZIKV from two areas that are usually treated separately: the response of host cells to infection by flaviviruses and the involvement of cell surface GAGs in response to those infections.
Zika virus (ZIKV) infection during pregnancy can result in severe birth defects, such as microcephaly, as well as a range of other related health complications. Heparin, a clinical-grade ...anticoagulant, is shown to protect neural progenitor cells from death following ZIKV infection. Although heparin can be safely used during pregnancy, it retains off-target anticoagulant effects if directly employed against ZIKV infection. In this study, we investigated the effects of chemically modified heparin derivatives with reduced anticoagulant activities. These derivatives were used as experimental probes to explore the structure–activity relationships. Precursor fractions of porcine heparin, obtained during the manufacture of conventional pharmaceutical heparin with decreased anticoagulant activities, were also explored. Interestingly, these modified heparin derivatives and precursor fractions not only prevented cell death but also inhibited the ZIKV replication of infected neural progenitor cells grown as neurospheres. These effects were observed regardless of the specific sulfation position or overall charge. Furthermore, the combination of heparin with Sofosbuvir, an antiviral licensed for the treatment of hepatitis C (HCV) that also belongs to the same Flaviviridae family as ZIKV, showed a synergistic effect. This suggested that a combination therapy approach involving heparin precursors and Sofosbuvir could be a potential strategy for the prevention or treatment of ZIKV infections.
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Influenza A viruses (IAVs) can cause zoonotic infections with pandemic potential when most of the human population is immunologically naive. After a pandemic, IAVs evolve to become seasonal in the ...human host by acquiring adaptive mutations. We have previously reported that the interferon (IFN)-inducible tripartite motif 22 (TRIM22) protein restricts the replication of seasonal IAVs by direct interaction with the viral nucleoprotein (NP), leading to its polyubiquitination and proteasomal degradation. Here we show that, in contrast to seasonal H1N1 IAVs, the 2009 pandemic H1N1 strain as well as H1N1 strains from the 1930s are resistant to TRIM22 restriction. We demonstrate that arginine-to-lysine substitutions conferring an increased sensitivity to TRIM22-dependent ubiquitination accumulated progressively in the NP of seasonal influenza A (H1N1) viruses between 1918 and 2009. Our findings suggest that during long-term circulation and evolution of IAVs in humans, adaptive mutations are favored at the expense of an increased sensitivity to some components of the innate immune response.
We have uncovered that long-term circulation of seasonal influenza A viruses (IAV) in the human population resulted in the progressive acquisition of increased sensitivity to a component of the innate immune response: the type I interferon-inducible TRIM22 protein, which acts as a restriction factor by inducing the polyubiquitination of the IAV nucleoprotein (NP). We show that four arginine residues present in the NP of the 1918 H1N1 pandemic strain and early postpandemic strains were progressively substituted for by lysines between 1918 and 2009, rendering NP more susceptible to TRIM22-mediated ubiquitination. Our observations suggest that during long-term evolution of IAVs in humans, variants endowed with increased susceptibility to TRIM22 restriction emerge, highlighting the complexity of selection pressures acting on the NP.
Origin and evolution of SARS-CoV-2 Pagani, Isabel; Ghezzi, Silvia; Alberti, Simone ...
European physical journal plus,
02/2023, Volume:
138, Issue:
2
Journal Article
Peer reviewed
Open access
SARS-CoV-2 is a novel coronavirus that emerged in China at the end of 2019 causing the severe disease known as coronavirus disease 2019 (COVID-19). SARS-CoV-2, as to the previously highly pathogenic ...human coronaviruses named SARS-CoV, the etiological agent of severe acute respiratory syndrome (SARS), has a zoonotic origin, although SARS-CoV-2 precise chain of animal-to-human transmission remains undefined. Unlike the 2002–2003 pandemic caused by SARS-CoV whose extinction from the human population was achieved in eight months, SARS-CoV-2 has been spreading globally in an immunologically naïve population in an unprecedented manner. The efficient infection and replication of SARS-CoV-2 has resulted in the emergence of viral variants that have become predominant posing concerns about their containment as they are more infectious with variable pathogenicity in respect to the original virus. Although vaccine availability is limiting severe disease and death caused by SARS-CoV-2 infection, its extinction is far to be close and predictable. In this regard, the emersion of the Omicron viral variant in November 2021 was characterized by humoral immune escape and it has reinforced the importance of the global monitoring of SARS-CoV-2 evolution. Given the importance of the SARS-CoV-2 zoonotic origin, it will also be crucial to monitor the animal-human interface to be better prepared to cope with future infections of pandemic potential.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
The dependence of development and homeostasis in animals on the interaction of hundreds of extracellular regulatory proteins with the peri- and extracellular glycosaminoglycan heparan ...sulfate (HS) is exploited by many microbial pathogens as a means of adherence and invasion. Heparin, a widely used anticoagulant drug, is structurally similar to HS and is a common experimental proxy. Exogenous heparin prevents infection by a range of viruses, including S-associated coronavirus isolate HSR1. Here, we show that heparin inhibits severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) invasion of Vero cells by up to 80% at doses achievable through prophylaxis and, particularly relevant, within the range deliverable by nebulisation. Surface plasmon resonance and circular dichroism spectroscopy demonstrate that heparin and enoxaparin, a low-molecular-weight heparin which is a clinical anticoagulant, bind and induce a conformational change in the spike (S1) protein receptor-binding domain (S1 RBD) of SARS-CoV-2. A library of heparin derivatives and size-defined fragments were used to probe the structural basis of this interaction. Binding to the RBD is more strongly dependent on the presence of 2-
O
or 6-
O
sulfate groups than on
N
-sulfation and a hexasaccharide is the minimum size required for secondary structural changes to be induced in the RBD. It is likely that inhibition of viral infection arises from an overlap between the binding sites of heparin/HS on S1 RBD and that of the angiotensin-converting enzyme 2. The results suggest a route for the rapid development of a first-line therapeutic by repurposing heparin and its derivatives as antiviral agents against SARS-CoV-2 and other members of the
Coronaviridae
.
This article describes, succinctly, the research results in the field of Higher Education, developed by researchers of the UCU-Argentina and UCLV-Cuba whose main characteristic is the blender ...learning used by both universities that are distanced more than 6000 km. The exchanges started a little over two years ago, and once the topics of interest were agreed upon, the first research work on teaching styles and online research groups was proposed. During its implementation, and as it happens in the ways of the investigation, new questions arose, other problems, that allowed to raise other subjects referred on the one hand to the Educational Orientation and the strategies of learning in the university context and, on the other hand, the good practices in the superior level teaching.
The two works are proposed from a qualitative perspective, considering that it allows the understanding of the phenomenon that one wishes to study from a holistic perspective, "from within", involving the different actors of the studied context.
O presente artigo descreve, de forma breve, os resultados de pesquisas no âmbito da Educação Superior, desenvolvido por docentes pesquisadores da UCU – Argentina e UCLV- Cuba, cuja característica principal é o trabalho sob a modalidade “em linha”, uma vez que a distância entre as duas universidades é de mais de 6000 km. Os intercâmbios foram iniciados há pouco mais de dois anos, e uma vez estabelecido de comum acordo os temas de interesse, se propuseram a desenvolver o primeiro trabalho de pesquisa sobre estilos docentes e grupos de pesquisa em linha. Durante a sua implementação, e como se passa nos caminhos da pesquisa, surgem novas perguntas, outros problemas, que permitiram propor outros temas referidos por um lado à Orientação Educativa e às estratégias de aprendizagem no contexto universitário e as boas práticas na docência de nível superior. Ambos os trabalhos se desenvolvem desde um enfoque qualitativo, por considerarmos que o mesmo permite a compreensão do fenômeno que se deseja estudar desde uma perspectiva holística, “desde dentro”, envolvendo os diferentes atores do contexto estudado.
El presente artículo describe, en forma sucinta, resultados de investigaciones en el ámbito de la Educación Superior, desarrollados por docentes investigadores de la UCU- Argentina y UCLV- Cuba, cuya característica principal es el trabajo bajo la modalidad “en línea”, en tanto, la distancia entre ambas universidades difiere por más de 6000 km. Iniciado los intercambios hace un poco más de dos años, y una vez acordado los temas de interés se planteó desarrollar el primer trabajo de investigación sobre estilos docentes y grupos de investigación en línea. Durante su implementación, y tal como sucede en los caminos de la investigación, surgen nuevas preguntas, otros problemas, que permitieron plantear otros temas referidos por un lado a la Orientación Educativa y las estrategias de aprendizaje en el contexto universitario y las buenas prácticas en la docencia del nivel superior. Sendos trabajos se plantean desde un enfoque cualitativo, por considerar que el mismo permite la comprensión del fenómeno que se desea estudiar desde una perspectiva holística, “desde adentro”, involucrando a los diferentes actores del contexto estudiado.
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