scholarly journals Defective ORF8 dimerization in delta variant of SARS CoV2 leads to abrogation of ORF8 MHC-I interaction and overcome suppression of adaptive immune response

2021 ◽  
Author(s):  
Armi Chaudhari ◽  
Dr. Indira Singh ◽  
Dr. Madhvi Joshi ◽  
Dr. AMRUTLAL PATEL ◽  
Proff. Chaitanya Joshi
Keyword(s):  
Amino Acids ◽  
Immune Response ◽  
Adaptive Immune Response ◽  
Host Immune Response ◽  
Structural Instability ◽  
Salt Bridges ◽  
Wild Type ◽  
Mhc I ◽  
Second Wave ◽  
Short Timeframe

In India, the breakthrough infections during second wave of COVID-19 pandemic was due to SARS-COV-2 delta variant (B.1.617.2). It was reported that majority of the infections were caused by the delta variant and only 9.8% percent cases required hospitalization whereas, only 0.4% fatality was observed. Sudden dropdown in COVID-19 infections was observed within a short timeframe, suggesting better host adaptation with evolved delta variant. Down regulation of host immune response against SARS-CoV-2 by ORF8 induced MHC-I degradation has been reported earlier. The Delta variant carried mutations (deletion) at Asp119 and Phe120 amino acids which are critical for ORF8 dimerization. The deletions of amino acids Asp119 and Phe120 in ORF8 of delta variant results in structural instability of ORF8 dimer caused by disruption of hydrogen bonding and salt bridges as revealed by structural analysis and MD simulation studies of ORF8 dimer. Further, flexible docking of wild type and mutant ORF8 dimer revealed reduced interaction of mutant ORF8 dimer with MHC-I as compared to wild type ORF8 dimer with MHC-1, thus implicating its possible role in MHC-I expression and host immune response against SARS-CoV-2. We thus propose that mutant ORF8 may not hindering the MHC-I expression thereby resulting in better immune response against SARS-CoV-2 delta variant, which partly explains the sudden drop of SARS-CoV-2 infection rate in the second wave of SARS-CoV-2 predominated by delta variant in India

scholarly journals Cytotoxic CD8+T lymphocytes expressing ALS-causing SOD1 mutant selectively trigger death of spinal motoneurons

2019 ◽  
Vol 116 (6) ◽  
pp. 2312-2317 ◽  
Author(s):  
Emmanuelle Coque ◽  
Céline Salsac ◽  
Gabriel Espinosa-Carrasco ◽  
Béla Varga ◽  
Nicolas Degauque ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Interaction Strength ◽  
Adaptive Immune Response ◽  
Clonal Diversity ◽  
Mhc I ◽  
Mutant Sod1 ◽  
Cytotoxicity Activity

Adaptive immune response is part of the dynamic changes that accompany motoneuron loss in amyotrophic lateral sclerosis (ALS). CD4+T cells that regulate a protective immunity during the neurodegenerative process have received the most attention. CD8+T cells are also observed in the spinal cord of patients and ALS mice although their contribution to the disease still remains elusive. Here, we found that activated CD8+T lymphocytes infiltrate the central nervous system (CNS) of a mouse model of ALS at the symptomatic stage. Selective ablation of CD8+T cells in mice expressing the ALS-associated superoxide dismutase-1 (SOD1)G93Amutant decreased spinal motoneuron loss. Using motoneuron-CD8+T cell coculture systems, we found that mutant SOD1-expressing CD8+T lymphocytes selectively kill motoneurons. This cytotoxicity activity requires the recognition of the peptide-MHC-I complex (where MHC-I represents major histocompatibility complex class I). Measurement of interaction strength by atomic force microscopy-based single-cell force spectroscopy demonstrated a specific MHC-I-dependent interaction between motoneuron andSOD1G93ACD8+T cells. Activated mutant SOD1 CD8+T cells produce interferon-γ, which elicits the expression of the MHC-I complex in motoneurons and exerts their cytotoxic function through Fas and granzyme pathways. In addition, analysis of the clonal diversity of CD8+T cells in the periphery and CNS of ALS mice identified an antigen-restricted repertoire of their T cell receptor in the CNS. Our results suggest that self-directed immune response takes place during the course of the disease, contributing to the selective elimination of a subset of motoneurons in ALS.

scholarly journals Adaptive Immune Response to Shigella flexneri 2acydC in Immunocompetent Mice and Mice Lacking Immunoglobulin A

1999 ◽  
Vol 67 (4) ◽  
pp. 2001-2004 ◽  
Author(s):  
Sing Sing Way ◽  
Alain C. Borczuk ◽  
Marcia B. Goldberg
Keyword(s):  
Immune Response ◽  
Adaptive Immunity ◽  
Shigella Flexneri ◽  
Immunoglobulin A ◽  
Adaptive Immune Response ◽  
Model System ◽  
Wild Type ◽  
Adaptive Immune ◽  
Immunocompetent Mice

ABSTRACT Shigella flexneri cydC, which is deficient in cytochrome bd, was rapidly cleared from the lungs of intranasally inoculated mice and was Sereny negative, yet it induced 93% protection against challenge with wild-type S. flexneri. Mice that lack immunoglobulin A (IgA) were fully protected, suggesting that IgA may not be required for adaptive immunity in this model system.

scholarly journals The Polysaccharide Capsule of Campylobacter jejuni Modulates the Host Immune Response

2012 ◽  
Vol 81 (3) ◽  
pp. 665-672 ◽  
Author(s):  
Alexander C. Maue ◽  
Krystle L. Mohawk ◽  
David K. Giles ◽  
Frédéric Poly ◽  
Cheryl P. Ewing ◽  
...  
Keyword(s):  
Immune Response ◽  
Campylobacter Jejuni ◽  
Diarrheal Disease ◽  
Host Immune Response ◽  
Interleukin 17 ◽  
Wild Type ◽  
Content Type ◽  
Polysaccharide Capsule ◽  
Colonization Model

ABSTRACTCampylobacter jejuniis a major cause of bacterial diarrheal disease worldwide. The organism is characterized by a diversity of polysaccharide structures, including a polysaccharide capsule. MostC. jejunicapsules are known to be decorated nonstoichiometrically with methyl phosphoramidate (MeOPN). The capsule ofC. jejuni81-176 has been shown to be required for serum resistance, but here we show that an encapsulated mutant lacking the MeOPN modification, anmpnCmutant, was equally as sensitive to serum killing as the nonencapsulated mutant. A nonencapsulated mutant, akpsMmutant, exhibited significantly reduced colonization compared to that of wild-type 81-176 in a mouse intestinal colonization model, and thempnCmutant showed an intermediate level of colonization. Both mutants were associated with higher levels of interleukin 17 (IL-17) expression from lamina propria CD4+cells than from cells from animals infected with 81-176. In addition, reduced levels of Toll-like receptor 4 (TLR4) and TLR2 activation were observed followingin vitrostimulation of human reporter cell lines with thekpsMandmpnCmutants compared to those with wild-type 81-176. The data suggest that the capsule polysaccharide ofC. jejuniand the MeOPN modification modulate the host immune response.

scholarly journals Activation of NKT Cells Protects Mice from Tuberculosis

2002 ◽  
Vol 70 (11) ◽  
pp. 6302-6309 ◽  
Author(s):  
Alissa Chackerian ◽  
Jen Alt ◽  
Vaji Perera ◽  
Samuel M. Behar
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Tissue Injury ◽  
Adaptive Immune Response ◽  
Nkt Cells ◽  
Cell Immune Response ◽  
Class I Mhc ◽  
Mhc I ◽  
Mhc Ii

ABSTRACT The T-cell immune response to Mycobacterium tuberculosis is critical in preventing clinical disease. While it is generally accepted that both major histocompatibility complex class I (MHC-I)-restricted CD8+ and MHC-II-restricted CD4+ T cells are important for the immune response to M. tuberculosis, the role of non-MHC-restricted T cells is still not clearly delineated. We have previously reported that CD1d−/− mice do not differ from CD1d+/+ mice in their survival following infection with M. tuberculosis. We now show that, although CD1d-restricted NKT cells are not required for optimum immunity to M. tuberculosis, specific activation of NKT cells by the CD1d ligand α-galactosylceramide protects susceptible mice from tuberculosis. Treatment with α-galactosylceramide reduced the bacterial burden in the lungs, diminished tissue injury, and prolonged survival of mice following inoculation with virulent M. tuberculosis. The capacity of activated NKT cells to stimulate innate immunity and modulate the adaptive immune response to promote a potent antimicrobial immune response suggests that α-galactosylceramide administration could have a role in new strategies for the therapy of infectious diseases.

scholarly journals Role of Eosinophils and Neutrophils in Innate and Adaptive Protective Immunity to Larval Strongyloides stercoralis in Mice

2006 ◽  
Vol 74 (10) ◽  
pp. 5730-5738 ◽  
Author(s):  
Ann Marie Galioto ◽  
Jessica A. Hess ◽  
Thomas J. Nolan ◽  
Gerhard A. Schad ◽  
James J. Lee ◽  
...  
Keyword(s):  
Immune Response ◽  
Protective Immunity ◽  
Experimental Approach ◽  
Adaptive Immune Response ◽  
Strongyloides Stercoralis ◽  
Cell Populations ◽  
Wild Type ◽  
Diffusion Chambers ◽  
Adaptive Immune

ABSTRACT The goal of this study was to determine the roles of eosinophils and neutrophils in innate and adaptive protective immunity to larval Strongyloides stercoralis in mice. The experimental approach used was to treat mice with an anti-CCR3 monoclonal antibody to eliminate eosinophils or to use CXCR2−/− mice, which have a severe neutrophil recruitment defect, and then determine the effect of the reduction or elimination of the particular cell type on larval killing. It was determined that eosinophils killed the S. stercoralis larvae in naïve mice, whereas these cells were not required for the accelerated killing of larvae in immunized mice. Experiments using CXCR2−/− mice demonstrated that the reduction in recruitment of neutrophils resulted in significantly reduced innate and adaptive protective immunity. Protective antibody developed in the immunized CXCR2−/− mice, thereby demonstrating that neutrophils were not required for the induction of the adaptive protective immune response. Moreover, transfer of neutrophil-enriched cell populations recovered from either wild-type or CXCR2−/− mice into diffusion chambers containing larvae demonstrated that larval killing occurred with both cell populations when the diffusion chambers were implanted in immunized wild-type mice. Thus, the defect in the CXCR2−/− mice was a defect in the recruitment of the neutrophils and not a defect in the ability of these cells to kill larvae. This study therefore demonstrated that both eosinophils and neutrophils are required in the protective innate immune response, whereas only neutrophils are necessary for the protective adaptive immune response to larval S. stercoralis in mice.

scholarly journals Uropathogenic Escherichia coli Suppresses the Host Inflammatory Response via Pathogenicity Island Genes sisA and sisB

2009 ◽  
Vol 77 (12) ◽  
pp. 5322-5333 ◽  
Author(s):  
Amanda L. Lloyd ◽  
Sara N. Smith ◽  
Kathryn A. Eaton ◽  
Harry L. T. Mobley
Keyword(s):  
Escherichia Coli ◽  
Immune Response ◽  
Urinary Tract ◽  
Inflammatory Response ◽  
Shigella Flexneri ◽  
Pathogenicity Island ◽  
Host Immune Response ◽  
Wild Type ◽  
Host Inflammatory Response

ABSTRACT Extraintestinal pathogenic Escherichia coli can successfully colonize the urinary tract of the immunocompetent host. In part, this is accomplished by dampening the host immune response. Indeed, the sisA and sisB genes (shiA-like inflammation suppressor genes A and B) of uropathogenic E. coli strain CFT073, homologs of the Shigella flexneri SHI-2 pathogenicity island gene shiA, suppress the host inflammatory response. A double deletion mutant (ΔsisA ΔsisB) resulted in a hyperinflammatory phenotype in an experimental model of ascending urinary tract infection. The ΔsisA ΔsisB mutant not only caused significantly more inflammatory foci in the kidneys of CBA/J mice (P = 0.0399), but these lesions were also histologically more severe (P = 0.0477) than lesions observed in mice infected with wild-type CFT073. This hyperinflammatory phenotype could be suppressed to wild-type levels by in vivo complementation of the ΔsisA ΔsisB mutant with either the sisA or sisB gene in trans. The ΔsisA ΔsisB mutant was outcompeted by wild-type CFT073 during cochallenge infection in the bladder (P = 0.0295) at 48 h postinoculation (hpi). However, during cochallenge infections, we reasoned that wild-type CFT073 could partially complement the ΔsisA ΔsisB mutant. Consistent with this, the most significant colonization defect of the ΔsisA ΔsisB mutant in vivo was observed during independent challenge relative to wild-type CFT073, with attenuation of the mutant observed in the bladder (P < 0.0001) and kidneys (P = 0.0003) at 6 hpi. By 24 and 48 hpi, the ΔsisA ΔsisB mutant was no longer significantly attenuated in the bladder or kidneys, suggesting that the sisA and sisB genes may be important for suppressing the host immune response during the initial stages of infection.

scholarly journals Hide and Seek: The Interplay Between Zika Virus and the Host Immune Response

2021 ◽  
Vol 12 ◽  
Author(s):  
Lim Jack Lee ◽  
Thamil Vaani Komarasamy ◽  
Nur Amelia Azreen Adnan ◽  
William James ◽  
Vinod RMT Balasubramaniam
Keyword(s):  
Immune Response ◽  
Zika Virus ◽  
Large Scale ◽  
Vaccine Development ◽  
Sexual Transmission ◽  
Adaptive Immune Response ◽  
Host Immune Response ◽  
Interferon Response ◽  
Current Status ◽  
Successful Infection

Zika virus (ZIKV) received worldwide attention over the past decade when outbreaks of the disease were found to be associated with severe neurological syndromes and congenital abnormalities. Unlike most other flaviviruses, ZIKV can spread through sexual and transplacental transmission, adding to the complexity of Zika pathogenesis and clinical outcomes. In addition, the spread of ZIKV in flavivirus-endemic regions, and the high degree of structural and sequence homology between Zika and its close cousin Dengue have raised questions on the interplay between ZIKV and the pre-existing immunity to other flaviviruses and the potential immunopathogenesis. The Zika epidemic peaked in 2016 and has affected over 80 countries worldwide. The re-emergence of large-scale outbreaks in the future is certainly a possibility. To date, there has been no approved antiviral or vaccine against the ZIKV. Therefore, continuing Zika research and developing an effective antiviral and vaccine is essential to prepare the world for a future Zika epidemic. For this purpose, an in-depth understanding of ZIKV interaction with many different pathways in the human host and how it exploits the host immune response is required. For successful infection, the virus has developed elaborate mechanisms to escape the host response, including blocking host interferon response and shutdown of certain host cell translation. This review provides a summary on the key host factors that facilitate ZIKV entry and replication and the mechanisms by which ZIKV antagonizes antiviral innate immune response and involvement of adaptive immune response leading to immunopathology. We also discuss how ZIKV modulates the host immune response during sexual transmission and pregnancy to induce infection, how the cross-reactive immunity from other flaviviruses impacts ZIKV infection, and provide an update on the current status of ZIKV vaccine development.

scholarly journals Myeloperoxidase Attenuates Pathogen Clearance during Plasmodium yoelii Nonlethal Infection

2016 ◽  
Vol 85 (1) ◽  
Author(s):  
Wiebke Theeß ◽  
Julie Sellau ◽  
Christiane Steeg ◽  
Anna Klinke ◽  
Stephan Baldus ◽  
...  
Keyword(s):  
Immune Response ◽  
Inflammatory Diseases ◽  
Adaptive Immune Response ◽  
Parasite Clearance ◽  
Plasmodium Yoelii ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Adaptive Immune ◽  
Deficient Mice

ABSTRACT Myeloperoxidase (MPO), a leukocyte-derived enzyme mainly secreted by activated neutrophils, is known to be involved in the immune response during bacterial and fungal infection and inflammatory diseases. Nevertheless, the role of MPO in a parasitic disease like malaria is unknown. We hypothesized that MPO contributes to parasite clearance. To address this hypothesis, we used Plasmodium yoelii nonlethal infection in wild-type and MPO-deficient mice as a murine malaria model. We detected high MPO plasma levels in wild-type mice with Plasmodium yoelii infection. Unexpectedly, infected MPO-deficient mice did not show increased parasite loads but were able to clear the infection more rapidly than wild-type mice. Additionally, the presence of neutrophils at the onset of infection seemed not to be essential for the control of the parasitemia. The effect of decreased parasite levels in MPO-deficient mice was absent from animals lacking mature T and B cells, indicating that this effect is most likely dependent on adaptive immune response mechanisms. Indeed, we observed increased gamma interferon and tumor necrosis factor alpha production by T cells in infected MPO-deficient mice. Together, these results suggest that MPO modulates the adaptive immune response during malaria infection, leading to an attenuated parasite clearance.

scholarly journals Congenital Asplenia Interrupts Immune Homeostasis and Leads to Excessive Systemic Inflammation in Zebrafish

2021 ◽  
Vol 11 ◽  
Author(s):  
Lang Xie ◽  
Zheyu Chen ◽  
Hui Guo ◽  
Yixi Tao ◽  
Xiaomin Miao ◽  
...  
Keyword(s):  
Immune Response ◽  
Inflammatory Cytokines ◽  
Adaptive Immune Response ◽  
Immune Homeostasis ◽  
Biological Processes ◽  
Wild Type ◽  
Adaptive Immune ◽  
Immune Related Genes ◽  
Insight Into ◽  
Pro Inflammatory Cytokines

Splenectomy or congenital asplenia in humans increases susceptibility to infections. We have previously reported that congenital asplenia in zebrafish reduces resistance to Aeromonas hydrophila infection. However, the molecular mechanism of systemic immune response in congenitally asplenic individuals is largely unexplored. In this study, we found that pro-inflammatory cytokines were more highly induced in congenitally asplenic zebrafish than wild-type after pathogenic A. hydrophila infection and lipopolysaccharide exposure. In addition, a higher aggregation of apoptotic cells was observed in congenitally asplenic zebrafish than that in wild-type. Next, we examined the transcriptome profiles of whole kidneys from wild-type and congenitally asplenic zebrafish to investigate the effects of congenital asplenia on innate and adaptive immune responses induced by the inactivated A. hydrophila. Congenital asplenia inactivated the splenic anti-inflammatory reflex, disrupted immune homeostasis, and induced excessive inflammation as evidenced by the highly induced stress response–related biological processes, inflammatory and apoptosis-associated pathways, and pro-inflammatory cytokines/chemokines in congenitally asplenic zebrafish compared with wild-type after vaccination. In addition, complement component genes (c3a.1, c3a.6, c4, c6, and c9) and several important immune-related genes (tabp.1, tap1, hamp, prg4b, nfil3, defbl1, psmb9a, tfr1a, and sae1) were downregulated in congenitally asplenic zebrafish. Furthermore, congenital asplenia impaired adaptive immunity as demonstrated by downregulation of biological processes and signaling pathways involved in adaptive immune response after vaccination in congenitally asplenic zebrafish. The expression of MHCII/IgM was also significantly reduced in the congenitally asplenic zebrafish when compared with wild-type. Together, our study provides an in-depth understanding of spleen function in controlling immune homeostasis and may offer insight into the pathological response in splenectomized or congenitally asplenic patients after infections.

scholarly journals De novo histidine biosynthesis protects Mycobacterium tuberculosis from host IFN-γ mediated histidine starvation

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Abhisek Dwivedy ◽  
Anam Ashraf ◽  
Bhavya Jha ◽  
Deepak Kumar ◽  
Nisheeth Agarwal ◽  
...  
Keyword(s):  
Amino Acids ◽  
Immune Response ◽  
Mycobacterium Tuberculosis ◽  
De Novo ◽  
Host Cells ◽  
Wild Type ◽  
Histidine Biosynthesis ◽  
Pertinent Question ◽  
Ifn Γ

AbstractIntracellular pathogens including Mycobacterium tuberculosis (Mtb) have evolved with strategies to uptake amino acids from host cells to fulfil their metabolic requirements. However, Mtb also possesses de novo biosynthesis pathways for all the amino acids. This raises a pertinent question- how does Mtb meet its histidine requirements within an in vivo infection setting? Here, we present a mechanism in which the host, by up-regulating its histidine catabolizing enzymes through interferon gamma (IFN-γ) mediated signalling, exerts an immune response directed at starving the bacillus of intracellular free histidine. However, the wild-type Mtb evades this host immune response by biosynthesizing histidine de novo, whereas a histidine auxotroph fails to multiply. Notably, in an IFN-γ−/− mouse model, the auxotroph exhibits a similar extent of virulence as that of the wild-type. The results augment the current understanding of host-Mtb interactions and highlight the essentiality of Mtb histidine biosynthesis for its pathogenesis.

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