Strategies for search of pharmacological drugs against SARS-CoV-2 on the base of studying the structural-genetic features of coronaviruses SARS-CoV, MERS-CoV and SARS-CoV-2

2020 ◽  
Vol 18 (4) ◽  
pp. 269-296
Author(s):  
Vladimir I. Vashchenko ◽  
Vladimir N. Vilyaninov ◽  
Petr D. Shabanov
Keyword(s):  
Immune Response ◽  
Molecular Mechanisms ◽  
Vaccine Development ◽  
Inflammatory Responses ◽  
Host Immune Response ◽  
Medication Cost ◽  
Atypical Pneumonia ◽  
Therapeutic Approaches ◽  
Mathematical Methods ◽  
Coronavirus Infection

A sudden outbreak of COVID-19 caused by a novel coronavirus, SARS-CoV-2, in Wuhan, China in December 2019 quickly grew into a global pandemic, putting at risk not only the global healthcare system, but also the world economy. As the disease continues to spread rapidly, the development of prophylactic and therapeutic approaches is urgently required. Although some progress has been made in understanding the viral structure and invasion mechanism of coronaviruses that may cause severe cases of the syndrome, due to the limited understanding of the immune effects caused by SARS-CoV-2, it is difficult for us to prevent patients from developing acute respiratory distress syndrome (ARDS) and pulmonary fibrosis (PF), the major complications of coronavirus infection. Therefore, any potential treatments should focus not only on direct killing of coronaviruses and prevention strategies by vaccine development, but also on keeping in check the acute immune/inflammatory responses, resulting in ARDS and PF. In addition, potential treatments currently under clinical trials focusing on killing coronaviruses or on developing vaccines preventing coronavirus infection largely ignore the host immune response. However, taking care of SARS-CoV-2 infected patients with ARDS and PF is considered to be the major difficulty. Therefore, further understanding of the host immune response to SARS-CoV-2 is extremely important for clinical resolution and saving medication cost. In addition to a breif overview of the structure, infection mechanism, and possible therapeutic approaches, we summarized and compared the hematopathologic effect and immune responses to SARS-CoV, MERS-CoV, and SARS-CoV-2. Also the basic molecular mechanisms of an atypical pneumonia and molecular targets SARS-CoV-2 that allows to allocate 8 basic directions of search of pharmacological agents for struggle with SARS-CoV-2 are discussed. Mathematical methods of search of perspective preparations for struggle with COVID-19 are in detail discussed. The pathophysiological mechanisms of an infection inducing a lymphopenia or cytokine storm that allows to allocate a special direction of search of pharmacological preparations for struggle against new coronaviruse SARS-CoV-2 are discussed.

scholarly journals SARS-CoV-2: From Structure to Pathology, Host Immune Response and Therapeutic Management

2020 ◽  
Vol 8 (10) ◽  
pp. 1468
Author(s):  
Grigore Mihaescu ◽  
Mariana Carmen Chifiriuc ◽  
Ciprian Iliescu ◽  
Corneliu Ovidiu Vrancianu ◽  
Lia-Mara Ditu ◽  
...  
Keyword(s):  
Immune Response ◽  
Molecular Mechanisms ◽  
Prolonged Exposure ◽  
Vaccine Development ◽  
Host Immune Response ◽  
Physical Factors ◽  
Respiratory Pathogens ◽  
Inflammatory Conditions ◽  
Multiplication Cycle ◽  
Wide Range

Coronaviruses are large, enveloped viruses with a single-stranded RNA genome, infecting both humans and a wide range of wild and domestic animals. SARS-CoV-2, the agent of the COVID-19 pandemic, has 80% sequence homology with SARS-CoV-1 and 96–98% homology with coronaviruses isolated from bats. The spread of infection is favored by prolonged exposure to high densities of aerosols indoors. Current studies have shown that SARS-CoV-2 is much more stable than other coronaviruses and viral respiratory pathogens. The severe forms of infection are associated with several risk factors, including advanced age, metabolic syndrome, diabetes, obesity, chronic inflammatory or autoimmune disease, and other preexisting infectious diseases, all having in common the pre-existence of a pro-inflammatory condition. Consequently, it is essential to understand the relationship between the inflammatory process and the specific immune response in SARS-CoV-2 infection. In this review, we present a general characterization of the SARS-CoV-2 virus (origin, sensitivity to chemical and physical factors, multiplication cycle, genetic variability), the molecular mechanisms of COVID-19 pathology, the host immune response and discuss how the inflammatory conditions associated with different diseases could increase the risk of COVID-19. Last, but not least, we briefly review the SARS-CoV-2 diagnostics, pharmacology, and future approaches toward vaccine development.

scholarly journals Key Limitations and New Insights Into the Toxoplasma gondii Parasite Stage Switching for Future Vaccine Development in Human, Livestock, and Cats

2020 ◽  
Vol 10 ◽  
Author(s):  
Marie-Noëlle Mévélec ◽  
Zineb Lakhrif ◽  
Isabelle Dimier-Poisson
Keyword(s):  
Immune Response ◽  
Molecular Mechanisms ◽  
Vaccine Development ◽  
Host Immune Response ◽  
Oral Route ◽  
Effective Vaccine ◽  
Naked Dna ◽  
Protection Mechanisms ◽  
Immunogenic Proteins ◽  
Cellular Immune

Toxoplasmosis is a parasitic disease affecting human, livestock and cat. Prophylactic strategies would be ideal to prevent infection. In a One Health vaccination approach, the objectives would be the prevention of congenital disease in both women and livestock, prevention/reduction of T. gondii tissue cysts in food-producing animals; and oocyst shedding in cats. Over the last few years, an explosion of strategies for vaccine development, especially due to the development of genetic-engineering technologies has emerged. The field of vaccinology has been exploring safer vaccines by the generation of recombinant immunogenic proteins, naked DNA vaccines, and viral/bacterial recombinants vectors. These strategies based on single- or few antigens, are less efficacious than recombinant live-attenuated, mostly tachyzoite T. gondii vaccine candidates. Reflections on the development of an anti-Toxoplasma vaccine must focus not only on the appropriate route of administration, capable of inducing efficient immune response, but also on the choice of the antigen (s) of interest and the associated delivery systems. To answer these questions, the choice of the animal model is essential. If mice helped in understanding the protection mechanisms, the data obtained cannot be directly transposed to humans, livestock and cats. Moreover, effectiveness vaccines should elicit strong and protective humoral and cellular immune responses at both local and systemic levels against the different stages of the parasite. Finally, challenge protocols should use the oral route, major natural route of infection, either by feeding tissue cysts or oocysts from different T. gondii strains. Effective Toxoplasma vaccines depend on our understanding of the (1) protective host immune response during T. gondii invasion and infection in the different hosts, (2) manipulation and modulation of host immune response to ensure survival of the parasites able to evade and subvert host immunity, (3) molecular mechanisms that define specific stage development. This review presents an overview of the key limitations for the development of an effective vaccine and highlights the contributions made by recent studies on the mechanisms behind stage switching to offer interesting perspectives for vaccine development.

scholarly journals Panorama de la pandemia COVID-19

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Obert Marín Sánchez ◽  
Ana Juliet Rodriguez Landauro ◽  
Olegario Marín Machuca ◽  
Ulert Marín Sánchez ◽  
Betty E. Gamero C. ◽  
...  
Keyword(s):  
Immune Response ◽  
Molecular Mechanisms ◽  
Vaccine Development ◽  
Epidemiological Studies ◽  
World Health ◽  
Molecular Evidence ◽  
Atypical Pneumonia ◽  
Serological Tests ◽  
Republic Of China ◽  
Health Organization

<p>La Organización Mundial de la Salud recibió un informe de la República Popular China sobre neumonía atípica en la ciudad de Wuhan, el 31 de diciembre de 2019. Desde el primer reporte han pasado 105 días (30 de abril), y es poco lo que se conoce sobre el nuevo coronavirus (SARS-CoV2) y la enfermedad COVID-19. Los estudios epidemiológicos de los últimos años ya alertaban sobre nuevos brotes de coronavirus, pero no fueron tomados en consideración, y esto dio lugar a que SARS-CoV2 sea el primer beta-coronavirus que alcanza el estado de pandemia. El diagnóstico está basado en pruebas moleculares para detección del virus y, en pruebas serológicas para la enfermedad. Adicionalmente, se conoce poco sobre los mecanismos de contagio y de transmisión. Aún se está investigando los mecanismos celulares y moleculares que emplea el virus para la infección, adicionando los procesos similares de la respuesta inmune en humanos. Finalmente, los esfuerzos actuales están enfocados en tratamientos eficaces y en el desarrollo de vacunas; pero por el momento sólo se tienen candidatos vacunales que aún están en fase de investigación clínica y aún requieren más tiempo para aprobarse su uso en la población humana.</p><p>Palabras clave: coronavirus, transmisión, respuesta inmune, diagnóstico, vacuna.</p><p> </p><p><strong>ABSTRACT</strong></p><p>The World Health Organization received a report from the People's Republic of China on atypical pneumonia in Wuhan City on December 31, 2019. Since the first report to date (April 30th), it has been 105 days, and little we know about the new coronavirus (SARS-CoV2) and COVID-19 disease. Epidemiological studies in recent years were already alerting about new coronavirus outbreaks, but were not taken into consideration, and this resulted in SARS-CoV2 being the first beta-coronavirus to reach pandemic status. Diagnosis is based on molecular evidence against the virus and serological tests for the disease. In addition, little is known about the mechanisms of contagion and transmission, and in turn the cellular and molecular mechanisms used by the virus for infection, and about immune response mechanisms are known. Finally, current efforts are focused on effective treatments and vaccine development; but now there are only vaccine candidates which are still in the clinical research phase and still require more time to be approved their use in the human population.</p><p>Keywords: coronavirus, transmission, immune response, diagnostic, vaccine.</p>

scholarly journals Genome assembly and transcriptome analysis provide insights into the anti-schistosome mechanism of Microtus fortis

2020 ◽  
Author(s):  
Hong Li ◽  
Zhen Wang ◽  
Shumei Chai ◽  
Xiong Bai ◽  
Guohui Ding ◽  
...  
Keyword(s):  
Immune Response ◽  
Genome Assembly ◽  
Post Infection ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Inflammatory Responses ◽  
Gene Annotation ◽  
Intrinsic Resistance ◽  
Schistosome Infection ◽  
Susceptible Host

ABSTRACTMicrotus fortis (M. fortis) so far is the only mammal host that exhibits intrinsic resistance against Schistosoma japonicum infection. However, the underlying molecular mechanisms of this intrinsic resistance are not yet known. Here we performed the first de novo genome assembly of M. fortis, comprehensive gene annotation and evolution analysis. Furthermore, we compared the recovery rate of schistosome, pathological change and liver transcriptome between non-permissive host M. fortis and susceptible host mouse at different time points after Schistosome infection. We reveal that Immune response of M. fortis and mouse is different in time and type. M. fortis activates immune and inflammatory responses on the 10th days post infection, involving in multiple pathways, such as leukocyte extravasation, antibody activation (especially IgG3), Fc-gamma receptor mediated phagocytosis, and interferon signaling cascade. The strong immune responses of M. fortis in early stages of infection play important roles in preventing the development of schistosome. On the contrary, intense immune response occurred in mouse in late stages of infection (28~42 days post infection), and cannot eliminate schistosome. Infected mouse suffers severe pathological injury and continuous decrease of important functions such as cell cycle and lipid metabolism. Our findings offer new insights to the intrinsic resistance mechanism of M. fortis against schistosome infection. The genome sequence also provides bases for future studies of other important traits in M. fortis.

scholarly journals Targeting Macrophages as a Therapeutic Option in Coronavirus Disease 2019

2020 ◽  
Vol 11 ◽  
Author(s):  
Maria Gracia-Hernandez ◽  
Eduardo M. Sotomayor ◽  
Alejandro Villagra
Keyword(s):  
Immune Response ◽  
Tissue Repair ◽  
Inflammatory Responses ◽  
Therapeutic Option ◽  
Interferon Signaling ◽  
Therapeutic Approaches ◽  
Antiviral Immune Response ◽  
Antiviral Responses ◽  
Alternative Approaches ◽  
Pathogen Clearance

Immune cells of the monocyte/macrophage lineage are characterized by their diversity, plasticity, and variety of functions. Among them, macrophages play a central role in antiviral responses, tissue repair, and fibrosis. Macrophages can be reprogrammed by environmental cues, thus changing their phenotype during an antiviral immune response as the viral infection progresses. While M1-like macrophages are essential for the initial inflammatory responses, M2-like macrophages are critical for tissue repair after pathogen clearance. Numerous reports have evaluated the detrimental effects that coronaviruses, e.g., HCoV-229E, SARS-CoV, MERS-CoV, and SARS-CoV-2, have on the antiviral immune response and macrophage functions. In this review, we have addressed the breadth of macrophage phenotypes during the antiviral response and provided an overview of macrophage-coronavirus interactions. We also discussed therapeutic approaches to target macrophage-induced complications, currently under evaluation in clinical trials for coronavirus disease 2019 patients. Additionally, we have proposed alternative approaches that target macrophage recruitment, interferon signaling, cytokine storm, pulmonary fibrosis, and hypercoagulability.

scholarly journals Murine Coronavirus Infection Activates the Aryl Hydrocarbon Receptor in an Indoleamine 2,3-Dioxygenase-Independent Manner, Contributing to Cytokine Modulation and Proviral TCDD-Inducible-PARP Expression

2019 ◽  
Vol 94 (3) ◽  
Author(s):  
Matthew E. Grunewald ◽  
Mohamed G. Shaban ◽  
Samantha R. Mackin ◽  
Anthony R. Fehr ◽  
Stanley Perlman
Keyword(s):  
Immune Response ◽  
Viral Replication ◽  
Aryl Hydrocarbon Receptor ◽  
Hepatitis Virus ◽  
Mouse Hepatitis Virus ◽  
Host Immune Response ◽  
Indoleamine 2,3 Dioxygenase ◽  
Aryl Hydrocarbon ◽  
Coronavirus Infection ◽  
In Cells

ABSTRACT The aryl hydrocarbon receptor (AhR) is a cytoplasmic receptor/transcription factor that modulates several cellular and immunological processes following activation by pathogen-associated stimuli, though its role during virus infection is largely unknown. Here, we show that AhR is activated in cells infected with mouse hepatitis virus (MHV), a coronavirus (CoV), and contributes to the upregulation of downstream effector TCDD-inducible poly(ADP-ribose) polymerase (TiPARP) during infection. Knockdown of TiPARP reduced viral replication and increased interferon expression, suggesting that TiPARP functions in a proviral manner during MHV infection. We also show that MHV replication induced the expression of other genes known to be downstream of AhR in macrophages and dendritic cells and in livers of infected mice. Further, we found that chemically inhibiting or activating AhR reciprocally modulated the expression levels of cytokines induced by infection, specifically, interleukin 1β (IL-1β), IL-10, and tumor necrosis factor alpha (TNF-α), consistent with a role for AhR activation in the host response to MHV infection. Furthermore, while indoleamine 2,3-dioxygenase (IDO1) drives AhR activation in other settings, MHV infection induced equal expression of downstream genes in wild-type (WT) and IDO1−/− macrophages, suggesting an alternative pathway of AhR activation. In summary, we show that coronaviruses elicit AhR activation by an IDO1-independent pathway, contributing to upregulation of downstream effectors, including the proviral factor TiPARP, and to modulation of cytokine gene expression, and we identify a previously unappreciated role for AhR signaling in CoV pathogenesis. IMPORTANCE Coronaviruses are a family of positive-sense RNA viruses with human and agricultural significance. Characterizing the mechanisms by which coronavirus infection dictates pathogenesis or counters the host immune response would provide targets for the development of therapeutics. Here, we show that the aryl hydrocarbon receptor (AhR) is activated in cells infected with a prototypic coronavirus, mouse hepatitis virus (MHV), resulting in the expression of several effector genes. AhR is important for modulation of the host immune response to MHV and plays a role in the expression of TiPARP, which we show is required for maximal viral replication. Taken together, our findings highlight a previously unidentified role for AhR in regulating coronavirus replication and the immune response to the virus.

scholarly journals Capsular polysaccharide correlates with immune response to the human gut microbe Ruminococcus gnavus

2021 ◽  
Vol 118 (20) ◽  
pp. e2007595118
Author(s):  
Matthew T. Henke ◽  
Eric M. Brown ◽  
Chelsi D. Cassilly ◽  
Hera Vlamakis ◽  
Ramnik J. Xavier ◽  
...  
Keyword(s):  
Immune Response ◽  
Molecular Mechanisms ◽  
Capsular Polysaccharide ◽  
Inflammatory Responses ◽  
Cell Wall Polysaccharide ◽  
Proinflammatory Responses ◽  
Gut Microbe ◽  
Inflammatory Bowel

Active inflammatory bowel disease (IBD) often coincides with increases of Ruminococcus gnavus, a gut microbe found in nearly everyone. It was not known how, or if, this correlation contributed to disease. We investigated clinical isolates of R. gnavus to identify molecular mechanisms that would link R. gnavus to inflammation. Here, we show that only some isolates of R. gnavus produce a capsular polysaccharide that promotes a tolerogenic immune response, whereas isolates lacking functional capsule biosynthetic genes elicit robust proinflammatory responses in vitro. Germ-free mice colonized with an isolate of R. gnavus lacking a capsule show increased measures of gut inflammation compared to those colonized with an encapsulated isolate in vivo. These observations in the context of our earlier identification of an inflammatory cell-wall polysaccharide reveal how some strains of R. gnavus could drive the inflammatory responses that characterize IBD.

scholarly journals Time-series transcriptomic analysis of bronchoalveolar lavage cells from virulent and low virulent PRRSV-1-infected piglets

2021 ◽  
Author(s):  
J. M. Sánchez-Carvajal ◽  
I. M. Rodríguez-Gómez ◽  
I. Ruedas-Torres ◽  
S. Zaldívar-López ◽  
F. Larenas-Muñoz ◽  
...  
Keyword(s):  
Immune Response ◽  
Time Series ◽  
T Cell ◽  
Bacterial Infections ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Transcriptomic Analysis ◽  
Immune Checkpoints ◽  
Respiratory Syndrome Virus

Porcine reproductive and respiratory syndrome virus (PRRSV) has evolved to escape the immune surveillance for a survival advantage leading to a strong modulation of host’s immune responses and favoring secondary bacterial infections. However, limited data are available on how the immunological and transcriptional responses elicited by virulent and low virulent PRRSV-1 strains are comparable and how are them conserved along the infection. To explore the kinetic transcriptional signature associated with the modulation of host immune response at lung level a time-series transcriptomic analysis was performed in bronchoalveolar lavage cells upon experimental in vivo infection with two PRRSV-1 strains of different virulence, virulent subtype 3 Lena strain or the low virulent subtype 1 3249 strain. The time-series analysis revealed overlapping patterns of dysregulated genes enriched in T-cell signaling pathways among both virulent and low-virulent strains, highlighting an up-regulation of co-stimulatory and co-inhibitory immune checkpoints which were disclosed as Hub genes. On the other hand, virulent Lena infection induced an early and more marked “negative regulation of immune system process” with an overexpression of co-inhibitory receptors genes related to T-cell and NK cell functions, in association with more severe lung lesion, lung viral load and BAL cell kinetics. These results underline a complex network of molecular mechanisms governing PRRSV-1 immunopathogenesis at lung level, revealing a pivotal role of co-inhibitory and co-stimulatory immune checkpoints in the pulmonary disease, which may have an impact on T-cell activation and related-pathways. These immune checkpoints together with the regulation of cytokine-signaling pathways, modulated in a virulence-dependent fashion, orchestrate an interplay among pro- and anti-inflammatory responses. Importance: Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the major threats to swine health and global production, causing substantial economic losses. We explore the mechanisms involved in the modulation of host immune response at lung level performing a time-series transcriptomic analysis upon experimental infection with two PRRSV-1 strains of different virulence. A complex network of molecular mechanisms was revealed to control the immunopathogenesis of PRRSV-1 infection, highlighting an interplay among pro- and anti-inflammatory responses as a potential mechanism to restrict inflammation-induced lung injury. Moreover, a pivotal role of co-inhibitory and co-stimulatory immune checkpoints was evidenced, which may lead to progressive dysfunction of T cells, impairing viral clearance and leading to persistent infection, favoring as well secondary bacterial infections or viral rebound. Although further studies should be conducted to evaluate the functional role of immune checkpoints in advanced stages of PRRSV infection and explore a possible T-cell exhaustion state.

scholarly journals Identification of Sulfavant A as the First Synthetic TREM2 Ligand Discloses a Homeostatic Response of Dendritic Cells After Receptor Engagement

2022 ◽  
Author(s):  
Carmela Gallo ◽  
Emiliano Manzo ◽  
Giusi Barra ◽  
Laura Fioretto ◽  
Marcello Ziaco ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Mhc Class Ii ◽  
Molecular Mechanisms ◽  
Vaccine Development ◽  
Class Ii ◽  
Receptor Activation ◽  
T Cell Response ◽  
Adjuvant Effect ◽  
Adjuvant Activity

Abstract The immune response arises from a fine balance of cellular and molecular mechanisms that provide for surveillance, tolerance, and elimination of dangers as pathogens. Improving the quality of the immune response remains a major goal in immunotherapy and vaccine development. Sulfavant A (SULF A) is a sulfolipid that has shown promising adjuvant activity in a cancer vaccine model. Here we report that SULF A is the first synthetic small molecule binding to the Triggering Receptor Expressed on Myeloid cells-2 (TREM2). The receptor engagement initiates an unconventional maturation of Dendritic cells (DCs) leading to upregulation of the Major Histocompatibility Complex class II (MHC Class II) and costimulatory molecules (CD83, CD86, DC54) without release of T helper type 1 (Th1) or 2 (Th2) cytokines. According to a TREM2 mechanism, this response is mediated by SYK-NFAT axis and is compromised by blockade and gene silencing of the receptor. Activation by SULF A preserved the DC functions to excite the allogeneic T cell response, and induced interleukin-10 (IL-10) release after lipopolysaccharide (LPS) stimulation. These results well support the adjuvant effect of SULF A and offer novel insights into the role of TREM2 in the differentiation of an unprecedented DC phenotype (homeDCs) that contributes to the maintenance of immune homeostasis without compromising lymphocyte activation and immunogenic response. The biological function of SULF-A may be of interest in various physiological and pathological processes involving the immune system.

Sign in / Sign up

Export Citation Format

Share Document