Response Of Innate Immune System Research Articles

Development and evaluation of polymeric nanoparticles as a delivery system for snake envenoming prevention

Polymer-based nanoparticles have become an appealing carrier for improving vaccine delivery efficiency. In this study, we investigated an interesting approach based on PLGA nanoparticles encapsulating Cerastes cerastes venom as an intranasal vaccine delivery system for snake envenomation prevention. Particles were synthesized by double emulsion solvent evaporation method and characterized for their size, morphology, distribution, and venom-nanoparticles interactions. An immunization trial was performed in mice by the intranasal route to evaluate the immune response, the reactogenicity, and the protective effect of this nanovaccine.The physicochemical and structural characteristics of Cc-loaded PLGA NPs revealed that the particles exhibited a spherical shape with a diameter of 370 nm, and a negatively charged surface with a zeta potential value of 19,9 mV.The immunization with Cc-PLGA NPs can induce a systemic innate and humoral immune response and confers protection against Cerastes cerastes venom (Cc) over than 6 LD50 with a cross-protection against Vipera lebetina venom (Vl) over than 5 LD50. Nano-encapsulation of Cc venom reduced its toxicity and the induced tissue alterations.Our results confirm that the nano-formulation Cc-PLGA NPs is a potent adjuvant system that improve the humoral immune response and provide protection against high lethal doses of viper venoms.

Enzymatically Inactive Tissue-Type Plasminogen Activator Reverses Disease Progression in the Dextran Sulfate Sodium Mouse Model of Inflammatory Bowel Disease

Enzymatically inactive tissue-type plasminogen activator (EI-tPA) does not activate fibrinolysis, but interacts with the N-methyl-d-aspartate receptor (NMDA-R) and low-density lipoprotein receptor-related protein-1 (LRP1) in macrophages to block innate immune system responses mediated by toll-like receptors. Herein, we examined the ability of EI-tPA to treat colitis in mice, induced by dextran sulfate sodium. In two separate studies, designed to generate colitis of differing severity, a single dose of EI-tPA administered after inflammation established significantly improved disease parameters. EI-tPA-treated mice demonstrated improved weight gain. Stools improved in character and became hemoccult negative. Abdominal tenderness decreased. Colon shortening significantly decreased in EI-tPA-treated mice, suggesting attenuation of irreversible tissue damage and remodeling. Furthermore, histopathologic evidence of disease decreased in the distal 25% of the colon in EI-tPA-treated mice. EI-tPA did not decrease the number of CD45-positive leukocytes or F4/80-positive macrophage-like cells detected in extracts of colons from dextran sulfate sodium-treated mice as assessed by flow cytometry. However, multiple colon cell types expressed the NMDA-R, suggesting the ability of diverse cells, including CD3-positive cells, CD103-positive cells, Ly6G-positive cells, and epithelial cell adhesion molecule-positive epithelial cells to respond to EI-tPA. Mesenchymal cells that line intestinal crypts and provide barrier function expressed LRP1, thereby representing another potential target for EI-tPA. These results demonstrate that the NMDA-R/LRP1 receptor system may be a target for drug development in diseases characterized by tissue damage and chronic inflammation.

Inflammatory biomarkers as a part of diagnosis in diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN), a chronic neurological complication of diabetes mellitus, remains scantily addressed area of research. Many lacunae in the temporal sequence between cause and effect of DPN still remain unfilled and therefore treatment of DPN remains unsatisfactory. This is largely due to the conventional glucocentric focus to resolve the problem. This focus over hyperglycemia should be shifted to consider, chronic low grade inflammation as the major determinant in DPN. Rapidly emerging evidences from recent studies suggest that chronic low grade inflammation leads to the activation of innate immune system response, loss of insulin signaling and insulin resistance, endoplasmic reticulum stress, mitochondrial stress, leading to production of kinases like protein kinase C, mitogen activated protein kinase and jun-N-terminal kinase, pro-inflammatory cytokines and inter leukins-1b, 2, 6 and 8, tumour necrosis factor-alpha and other chemokines, leading to DPN. These biomarkers can be early predictors of DPN and therefore should be the focus of work testing their clinical utility to identify high-risk individuals as well as perhaps to target interventions. In this paper, we would like to review all the aspects of DPN, laying greater emphasis on inflammatory biomarkers as a tool for early diagnosis of DPN and the possible research approaches to address it satisfactorily.

Milk supplemented with dried seaweed affects the systemic innate immune response in preweaning dairy calves

Intact seaweed or seaweed extracts are used as feed supplements to improve the gut microbiome in young animals. Seaweeds provide functional polysaccharides, and they are a good source of vitamins, minerals, and phenolic compounds, all of which are relevant for immune system development. However, literature on the effects of dried seaweed supplementation on immune system development is limited, especially in calves. This experiment aimed to study the effect of feeding milk supplemented with Ulva lactuca, Ascophyllum nodosum, or Saccharina latissima on the systemic immune status of preweaning dairy calves. Forty male Holstein calves with birth body weight 41 ± 4 kg and plasma Brix percentage ≥8.7% at d 2 after birth were used in this study. Calves were fed 4 L of cow milk twice a day (total 8 L/d). From d 2 to d 28, calves in the control group (n = 10) received milk without seaweed supplementation. Over the same period, experimental calves received milk supplemented with Ulva lactuca (SW1; n = 10), Ascophyllum nodosum (SW2; n = 10), or Saccharina latissima (SW3, n = 10). Dried and ground seaweeds were offered at a daily allowance of 50 g/8 L of milk (i.e., approximately 5% inclusion rate on a dry matter basis). Blood samples were collected from a jugular vein on d 2, 4, 7, 14, 21, and 28 after birth. Plasma concentrations of total protein, albumin, immunoglobulins, and acute-phase proteins (i.e., serum amyloid A, fibrinogen, and haptoglobin) were measured. We detected no differences in average daily gain, plasma immunoglobulins, albumin, or total protein. However, the contrast analysis revealed that plasma concentrations of fibrinogen (SW1 and SW2) and serum amyloid A (SW2 and SW3) were significantly higher in the seaweed groups compared with the control group. We also found a tendency for high plasma haptoglobin in the seaweed groups (SW1 and SW2) compared with the control group. Differences in acute-phase protein concentrations could be partially explained by the large differences in micromineral intake between control and seaweed-supplemented calves. Feeding milk supplemented with dried seaweed increased plasma concentrations of variables related to the innate immune response in preweaning dairy calves.

Expanded Scope of Bacillus Calmette-Guerin (BCG) Vaccine Applicability in Disease Prophylaxis, Diagnostics, and Immunotherapeutics.

Following the discovery of the Bacillus Calmette-Guerin (BCG) vaccine, its efficacy against Mycobacterium tuberculosis was soon established, with several countries adopting universal BCG vaccination schemes for their populations. Soon, however, studies aimed to further establish the efficacy of the vaccine in different populations discovered that the vaccine has a larger effect in reducing mortality rate than could be explained by its effect on tuberculosis alone, which sparked suggestions that the BCG vaccine could have effects on other unrelated or non-mycobacterial pathogens causing diseases in humans. These effects were termed heterologous, non-specific or off-target effects and have been shown to be due to both innate and adaptive immune system responses. Experiments carried out in a bid to further understand these effects led to many more discoveries about the applicability of the BCG vaccine for the prevention, diagnosis, and treatment of certain disease conditions. As we approach the second century since the discovery of the vaccine, we believe it is timely to review these interesting applications of the BCG vaccine, such as in the prevention of diabetes, atherosclerosis, and leukemia; the diagnosis of Kawasaki disease; and the treatment of multiple sclerosis, non-muscle invading bladder cancer, and stage III melanoma. Furthermore, complications associated with the administration of the BCG vaccine to certain groups of patients, including those with severe combined immunodeficiency and HIV, have been well described in literature, and we conclude by describing the mechanisms behind these complications and discuss their implications on vaccination strategies, especially in low-resource settings.

Paroxysmal nocturnal hemoglobinuria: role of the complement system, pathogenesis, and pathophysiology.

The complement system is part of the innate immune response system, which comprises more than 50 distinct plasma and serum proteins that interact to opsonize pathogens (i.e., mark pathogens for destruction) and induce inflammatory responses to fight infection. The role of the complement system is 2-fold: immune surveillance and host defense. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic, acquired, hematologic disease caused by somatic mutations in the gene PIGA in the hematopoietic stem cells. These stem cells produce abnormal clone blood cells that lack the complement regulatory proteins CD55 and CD59, causing the body to recognize these otherwise healthy red blood cells as damaged. The complement system destroys cells without these protective proteins, resulting in general hemolysis. PNH is characterized by fatigue; hemolytic anemia that can be severe and debilitating; increased lactic dehydrogenase level, reticulocyte count, and bilirubin level; propensity for thrombotic events; and renal dysfunction. Epidemiologic data, while sparse, suggest that an estimated 5,000-6,000 individuals in the United States are affected by PNH. If left untreated, PNH has a 10-year mortality rate of 29%, although the natural history of this disease has been recently altered by the introduction of complement inhibitors for the treatment of PNH. DISCLOSURES: This research was developed under a research contract between RTI Health Solutions and Apellis Pharmaceuticals and was funded by Apellis Pharmaceuticals. Bektas, Copley-Merriman, and Khan are employees of RTI Health Solutions. Sarda is an employee of Apellis Pharmaceuticals. Shammo consults for Apellis Pharmaceuticals.

Prophylactic Use of Chloroquine May Impair Innate Immune System Response against SARS-Cov-2

The debilitating effects of the innate immune system by the prophylactic use of chloroquine are discussed in this paper. TLRs require the acidic environment of endosomes to produce antiviral effects. Chloroquine antiviral actions partially attributed to increment in pH of endosomes. Therefore, we suppose that use of chloroquine for prophylaxis of COVID-19 can facilitate initiation and development of COVID-19.

Very Early Involvement of Innate Immunity in Peripheral Nerve Degeneration in SOD1-G93A Mice.

Recent preclinical and clinical evidence suggest that immune system has a role in the progression and prognosis of Amyotrophic Lateral Sclerosis (ALS), but the identification of a clear mechanism and immune players remains to be elucidated. Here, we have investigated, in 30 and 60 days (presymptomatic) and 120 days (symptomatic) old SOD1-G93A mice, systemic, peripheral, and central innate and adaptive immune and inflammatory response, correlating it with the progression of the neurodegeneration in neuromuscular junction, sciatic nerves, and spinal cord. Surprisingly, we found a very initial (45–60 days) presence of IgG in sciatic nerves together with a gradual enhancement of A20/TNFAIP3 (protein controlling NF-κB signalling) and a concomitantly significant increase and activation of circulating mast cells (MCs) as well as MCs and macrophages in sciatic nerve and an enhancement of IL-6 and IL-10. This immunological frame coincided with a myelin aggregation. The 30–60 days old SOD1-G93A mice didn’t show real elements of neuroinflammation and neurodegeneration in spinal cord. In 120 days old mice macrophages and monocytes are widely diffused in sciatic nerves, peripheral neurodegeneration reaches the tip, high circulating levels of TNFα and IL-2 were found and spinal cord exhibits clear signs of neural damage and infiltrating immune cells. Our results underpin a clear immunological disorder at the origin of ALS axonopathy, in which MCs are involved in the initiation and sustaining of inflammatory events. These data cannot be considered a mere epiphenomenon of motor neuron degeneration and reveal new potential selective immune targets in ALS therapy.

Photochemotherapy Induces Interferon Type III Expression via STING Pathway.

DNA-damaging cancer therapies induce interferon expression and stimulate the immune system, promoting therapy responses. The immune-activating STING (Stimulator of Interferon Genes) pathway is induced when DNA or double-stranded RNA (dsRNA) is detected in the cell cytoplasm, which can be caused by viral infection or by DNA damage following chemo- or radiotherapy. Here, we investigated the responses of cutaneous T-cell lymphoma (CTCL) cells to the clinically applied DNA crosslinking photochemotherapy (combination of 8–methoxypsoralen and UVA light; 8–MOP + UVA). We showed that this treatment evokes interferon expression and that the type III interferon IFNL1 is the major cytokine induced. IFNL1 upregulation is dependent on STING and on the cytoplasmic DNA sensor cyclic GMP-AMP synthase (cGAS). Furthermore, 8–MOP + UVA treatment induced the expression of genes in pathways involved in response to the tumor necrosis factor, innate immune system and acute inflammatory response. Notably, a subset of these genes was under control of the STING–IFNL1 pathway. In conclusion, our data connected DNA damage with immune system activation via the STING pathway and contributed to a better understanding of the effectiveness of photochemotherapy.

Plasma levels of corticosterone, tumor necrosis factor receptor 1 and interleukin 6 are influenced by age, sex and chronic inflammation in mice treated with acute temperature stress.

Resiliency is the ability to respond to, adapt to and recover from stressors. Deterioration of resiliency in older adults has been hypothesized to be regulated by age-related changes in stress response systems, including the Hypothalamic Pituitary Adrenal (HPA) axis and the innate immune system response. Although age-related chronic inflammation is strongly related to lack of resiliency, the impact of chronic inflammation on acute stress response is unclear. Here we describe the impact of a five-hour exposure to cold temperature acute stressor, on immune and corticosterone response using older and younger IL-10tm/tm mice, a mouse model with chronic inflammatory pathway activation, and age and gender matched C57/Bl6 background control (WT) mice. Overall, mice exposed to 4°C for 5h had significantly higher plasma corticosterone levels compared to those that remained at room temperature (25°C), with the exception of the WT females. Cold stressed mice had lower plasma tumor necrosis factor receptor 1 (TNFR1) levels with varying significance, in all ages and phenotypes, with the exception of the old female WT mice. In contrast, the effects of cold stress on pro-inflammatory cytokine interleukin 6 (IL-6) levels were inconsistent and not significant, with the exception of the female IL-10tm/tm mice. In conclusion, these findings demonstrate that sex, age and chronic inflammatory pathway activation all influence corticosterone secretion and inflammatory processes in the face of acute cold stress.

Innate Immune System Response Against Environmental Temperature Changes as A Dangerous Abiotic Factor

<p>Innate immune system is the first line response against environmental changes in invertebrate. It protects the animal from environmental changes such as temperature change, PH and salinity as well as pathogens such as bacteria and viruses through different biochemical pathways. In fact, the innate immune system relies on different biochemical reactions which are protecting the animal under adverse environmental circumstances. Among all of the environmental factors, temperature is a dangerous abiotic factor which affects organisms on its ecological level through infiltrating it’s the molecular and cellular levels. Invertebrate could survive from a wide range of environmental effects and possesses innate immunity as its defense systems. This review paper aimed at presenting the main innate immune pathways that are activated against the most abiotic environmental changes. We reviewed fundamental aspects of invertebrates’ defense process by focusing on the important innate immune pathways including: Pattern recognition receptors (PRRs), Antimicrobial peptide (AMP), Pro-PO activating system, Melanization Pathway, Lectin Pathway, Apoptosis Pathway, Plasma clotting protein.</p>

Macrophage polarization contributes to the efficacy of an oncolytic HSV-1 targeting human uveal melanoma in a murine xenograft model

Uveal melanoma (UM), the most common primary malignant tumor of the eye in adults, is difficult-to-treat. UM has a relatively high mortality secondary to distant metastasis and poor overall survival with existing therapies. The oncolytic virus herpes simplex virus type-1 (HSV-1) has been approved for clinical use in melanoma. This double-stranded DNA virus was suspected to directly activate lysis specifically in neoplastic cells. We tested the antitumor efficacy of recombinant oncolytic HSV-1-EGFP (oHSV-EGFP) in UM and characterized the local and systemic antitumor innate immune response in a murine xenograft model. We first determined the efficacy of the oncolytic virus in 92.1, MUM2B and MP41 cell lines. In murine xenograft models, oHSV-EGFP reduced intraocular tumors as well as systemic subcutaneous tumors. A significant change in cytokines was observed in viral infected cells, especially a rise in IFNγ. In vivo analyses showed increased anti-tumorigenic M1 macrophages and decreased pro-tumorigenic M2 macrophages in peripheral blood, and intraocular and distant tumors after intravitreal viral treatment. Increased infiltration of natural killer cells and mature dendritic cells was also detected after viral treatment. In addition, no virus was detected in major organs after the treatment. Our data support that oHSV-EGFP is effective, neoplasm specific, immune active and safe, providing possible clinical translatable options to treat ocular and metastatic UM.

Cancer metastasis and the immune system response: modeling the micro-environment by Ising hamiltonian

To overcome the cancer seeding and late metastasis, the immune system opportune response is essential. Recently, the system biology approach is relevant for better understanding the highly complex process of cancer metastasis and the immune system response CM-IS. Diversemathematical modeling and algorithmic simulations has been introduced in the tumor immune research. In spite of that the comprehension is far away to be satisfactory. In this paper we introduce an Ising Hamiltonian energy function to model the micro-environment of CM-IS,focus on the innate immune system response.

Genetic and epigenetic modification of human primary NK cells for enhanced antitumor activity

Cancer immunotherapy using genetically modified immune cells such as those expressing chimeric antigen receptors has shown dramatic outcomes in patients with refractory and relapsed malignancies. Natural killer (NK) cells as a member of the innate immune system, possessing both anticancer (cytotoxic) and proinflammatory (cytokine) responses to cancers and rare off-target toxicities have great potential for a wide range of cancer therapeutic settings. Therefore, improving NK cell antitumor activity through genetic modification is of high interest in the field of cancer immunotherapy. However, gene manipulation in primary NK cells has been challenging because of broad resistance to many genetic modification methods that work well in T cells. Here we review recent successful approaches for genetic and epigenetic modification of NK cells including epigenetic remodeling, transposons, mRNA-mediated gene delivery, lentiviruses, and CRISPR gene targeting.

EP01 Post COVID-19 reactive arthritis

Case report - IntroductionWe present what we believe to be the first reported case of post COVID-19 reactive arthritis, in a previously medically well 16-year-old with no past or family history of inflammatory arthritis.Case report - Case descriptionOur patient was a previously medically fit 16-year-old of Caucasian origin who tested positive for COVID-19 in late March 2020. She developed with a 4-day illness with fever, cough, and myalgia from which she made a full and uncomplicated recovery.Ten days later she developed a new erythematous itchy rash on her legs, trunk, and face and a progressive polyarthralgia affecting her MCPs, wrists, shoulders, hips, and knees. The rash typically lasted for 2 days at one site and was non-scarring. This was associated with a low-grade fever. There were no associated mouth ulcers, photosensitivity, alopecia, Raynaud’s, GI disturbance or respiratory symptoms. She had no relevant family history of autoimmunity, psoriasis or inflammatory bowel disease or travel history and had been prescribed no new medications.On examination, she had an erythematous rash on the face in a non malar distribution. She had multiple tender joints without definite synovitis. Cardiovascular, respiratory, gastroenterology and neurological examinations were unremarkable.Investigations revealed a normal full blood count and CRP<1 with normal liver and renal function tests. Her urinalysis was unremarkable. Immunology was negative for ANA, ANCA and rheumatoid factor. Immunoglobulins were normal. Two weeks later her symptoms were fully resolved.Case report - DiscussionCoronaviruses are single-stranded RNA viruses with nearly 30 strains recognised to infect humans. They induce both an innate and adaptive immune system response. It is hypothesised that a dysregulated innate system response, leading to a prolonged adaptive response triggers damaging inflammation and a potential cytokine storm. This is associated with poor outcome during primary viral infection. Variations in this immune response, with different underlying HLA genotypes could lead to other post infectious immune mediated phenomena, such as Paediatric Multisystem Inflammatory Syndrome - Temporally associated with COVID-19.There is a European registry collating data about patients with known rheumatic diseases who are admitted with COVID-19. There is emerging data regarding Paediatric Inflammatory Multisystem Syndrome - Temporally associated with SARS-CoV-2 (PIMS-TS). There is a growing suggestion that a subgroup of patients is developing a COVID-19 associated post viral fatigue syndrome. We suggest that a registry to collect information on de novo autoimmune diseases presenting post COVID-19 is also commenced.Case report - Key learning pointsCOVID-19 infection is associated with a wide variety of sequalae, including rheumatological ones.Classic post viral Reactive arthritis has been seen. A registry to collect information on de novo autoimmune presentations would be highly informative.

Mitochondria: In the Cross Fire of SARS-CoV-2 and Immunity.

SummaryThe pathophysiology, immune reaction, and differential vulnerability of different population groups and viral host immune system evasion strategies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are not yet well understood. Here, we reviewed the multitude of known strategies of coronaviruses and other viruses to usurp mitochondria-associated mechanisms involved in the host innate immune response and put them in context with the current knowledge on SARS-CoV-2. We argue that maintenance of mitochondrial integrity is essential for adequate innate immune system responses and to blunt mitochondrial modulation by SARS-CoV-2. Mitochondrial health thus may determine differential vulnerabilities to SARS-CoV-2 infection rendering markers of mitochondrial functions promising potential biomarkers for SARS-CoV-2 infection risk and severity of outcome. Current knowledge gaps on our understanding of mitochondrial involvement in SARS-CoV-2 infection, lifestyle, and pharmacological strategies to improve mitochondrial integrity and potential reciprocal interactions with chronic and age-related diseases, e.g., Parkinson disease, are pointed out.

Cell-autonomous hepatocyte-specific GP130 signaling is sufficient to trigger a robust innate immune response in mice

Interleukin (IL)-6 cytokine family members contribute to inflammatory and regenerative processes. Engagement of the signaling receptor subunit gp130 is common to almost all members of the family. In the liver, all major cell types respond to IL-6-type cytokines, making it difficult to delineate cell type-specific effects. We therefore generated mouse models for liver cell type-specific analysis of IL-6 signaling. We produced mice with a Cre-inducible expression cassette encoding a designed pre-dimerized constitutive active gp130 variant. We bred these mice to different Cre-drivers to induce transgenic gp130 signaling in distinct liver cell types: hepatic stellate cells, cholangiocytes/liver progenitor cells or hepatocytes. We phenotyped these mice using multi-omics approaches, immunophenotyping and a bacterial infection model. Hepatocyte-specific gp130 activation led to the upregulation of innate immune system components, including acute-phase proteins. Consequently, we observed peripheral mobilization and recruitment of myeloid cells to the liver. Hepatic myeloid cells, including liver-resident Kupffer cells were instructed to adopt a bactericidal phenotype which ultimately conferred enhanced resistance to bacterial infection in these mice. We demonstrate that persistent hepatocyte-specific gp130 activation resulted in amyloid A amyloidosis in aged mice. In contrast, we did not observe overt effects of hepatic stellate cell- or cholangiocyte/liver progenitor cell-specific transgenic gp130 signaling. Hepatocyte-specific gp130 activation alone is sufficient to trigger a robust innate immune response in the absence of NF-κB activation. We therefore conclude that gp130 engagement, e.g. by IL-6 trans-signaling, represents a safe-guard mechanism in innate immunity. Members of the interleukin-6 cytokine family signal via the receptor subunit gp130 and are involved in multiple processes in the liver. However, as several liver cell types respond to interleukin-6 family cytokines, it is difficult to delineate cell type-specific effects. Using a novel mouse model, we provide evidence that hepatocyte-specific gp130 activation is sufficient to trigger a robust systemic innate immune response.

The novel coronavirus Disease-2019 (COVID-19): Mechanism of action, detection and recent therapeutic strategies

Novel coronavirus SARS-CoV-2, designated as COVID-19 by the World Health Organization (WHO) on the February 11, 2020, is one of the highly pathogenic β‐coronaviruses which infects human. Early diagnosis of COVID-19 is the most critical step to treat infection. The diagnostic tools are generally molecular methods, serology and viral culture. Recently CRISPR-based method has been investigated to diagnose and treat coronavirus infection. The emergence of 2019-nCoV during the influenza season, has led to the extensive use of antibiotics and neuraminidase enzyme inhibitors, taken orally and intravenously.Currently, antiviral inhibitors of SARS and MERS spike proteins, neuraminidase inhibitors, anti-inflammatory drugs and EK1 peptide are the available therapeutic options for SARS-CoV-2 infected individuals. In addition, Chloroquine, which was previously used for malarial and autoimmune disease, has shown efficacy in the 2019-nCoV infection treatment. In severe hypoxaemia, a combination of antibiotics, α-interferon, lopinavir and mechanical ventilation can effectively mitigate the symptoms. Comprehensive knowledge on the innate and adaptive immune responses, will make it possible to propose potent antiviral drugs with their effective therapeutic measures for the prevention of viral infection. This therapeutic strategy will help patients worldwide to protect themselves against severe and fatal viral infections, that potentially can evolve and develop drug resistance, and to reduce mortality rates.

Systemic innate and adaptive immune responses to SARS-CoV-2 as it relates to other coronaviruses

ABSTRACT The deadly pandemic caused by the novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) represents one of the greatest threats humanity has faced in the last century. Infection with this easily transmissible virus can run the gamut from asymptomatic to fatal, and the disease caused by SARS-CoV-2 has been termed Coronavirus Disease 2019 (COVID-19). What little research that has already been conducted implicates pathological responses by the immune system as the leading culprit responsible for much of the morbidity and mortality caused by COVID-19. In this review we will summarize what is currently known about the systemic immune response to SARS-CoV-2 and potential immunotherapeutic approaches.

Emerging of a SARS-CoV-2 viral strain with a deletion in nsp1

BackgroundThe new Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), which was first detected in Wuhan (China) in December of 2019 is responsible for the current global pandemic. Phylogenetic analysis revealed that it is similar to other betacoronaviruses, such as SARS-CoV and Middle-Eastern Respiratory Syndrome, MERS-CoV. Its genome is ∼ 30 kb in length and contains two large overlapping polyproteins, ORF1a and ORF1ab that encode for several structural and non-structural proteins. The non-structural protein 1 (nsp1) is arguably the most important pathogenic determinant, and previous studies on SARS-CoV indicate that it is both involved in viral replication and hampering the innate immune system response. Detailed experiments of site-specific mutagenesis and in vitro reconstitution studies determined that the mechanisms of action are mediated by (a) the presence of specific amino acid residues of nsp1 and (b) the interaction between the protein and the host’s small ribosomal unit. In fact, substitution of certain amino acids resulted in reduction of its negative effects.MethodsA total of 17,928 genome sequences were obtained from the GISAID database (December 2019 to July 2020) from patients infected by SARS-CoV-2 from different areas around the world. Genomes alignment was performed using MAFFT (REFF) and the nsp1 genomic regions were identified using BioEdit and verified using BLAST. Nsp1 protein of SARS-CoV-2 with and without deletion have been subsequently modelled using I-TASSER.ResultsWe identified SARS-CoV-2 genome sequences, from several Countries, carrying a previously unknown deletion of 9 nucleotides in position 686-694, corresponding to the AA position 241-243 (KSF). This deletion was found in different geographical areas. Structural prediction modelling suggests an effect on the C-terminal tail structure.ConclusionsModelling analysis of a newly identified deletion of 3 amino acids (KSF) of SARS-CoV-2 nsp1 suggests that this deletion could affect the structure of the C-terminal region of the protein, important for regulation of viral replication and negative effect on host’s gene expression. In addition, substitution of the two amino acids (KS) from nsp1 of SARS-CoV was previously reported to revert loss of interferon-alpha expression. The deletion that we describe indicates that SARS-CoV-2 is undergoing profound genomic changes. It is important to: (i) confirm the spreading of this particular viral strain, and potentially of strains with other deletions in the nsp1 protein, both in the population of asymptomatic and pauci-symptomatic subjects, and (ii) correlate these changes in nsp1 with potential decreased viral pathogenicity.