Dual roles of a novel oncolytic viral vector-based SARS-CoV-2 vaccine: preventing COVID-19 and treating tumor progression

The ongoing coronavirus disease 2019 (COVID-19) pandemic is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cancer patients are usually immunocompromised and thus are particularly susceptible to SARS-CoV-2 infection resulting in COVID-19. Although many vaccines against COVID-19 are being preclinically or clinically tested or approved, none have yet been specifically developed for cancer patients or reported as having potential dual functions to prevent COVID-19 and treat cancer. Here, we confirmed that COVID-19 patients with cancer have low levels of antibodies against the spike (S) protein, a viral surface protein mediating the entry of SARS-CoV-2 into host cells, compared with COVID-19 patients without cancer. We developed an oncolytic herpes simplex virus-1 vector-based vaccine named oncolytic virus (OV)-spike. OV-spike induced abundant anti-S protein neutralization antibodies in both tumor-free and tumor-bearing mice, which inhibit infection of VSV-SARS-CoV-2 and wild-type (WT) live SARS-CoV-2 as well as the B.1.1.7 variant in vitro. In the tumor-bearing mice, OV-spike also inhibited tumor growth, leading to better survival in multiple preclinical tumor models than the untreated control. Furthermore, OV-spike induced anti-tumor immune response and SARS-CoV-2-specific T cell response without causing serious adverse events. Thus, OV-spike is a promising vaccine candidate for both preventing COVID-19 and enhancing the anti-tumor response.

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AOA-2 Derivatives as Outer Membrane Protein A Inhibitors for Treatment of Gram-Negative Bacilli Infections

Frontiers in Microbiology ◽

10.3389/fmicb.2021.634323 ◽

2021 ◽

Vol 12 ◽

Author(s):

Rafael Ayerbe-Algaba ◽

Nuria Bayó ◽

Ester Verdú ◽

Raquel Parra-Millán ◽

Jesús Seco ◽

...

Keyword(s):

Protein A ◽

A549 Cells ◽

Lung Epithelial Cells ◽

Host Cells ◽

Gram Negative ◽

E Coli ◽

Cyclic Hexapeptide ◽

Diphenyltetrazolium Bromide ◽

Peptide Derivatives

Previously, we identified that a cyclic hexapeptide AOA-2 inhibited the interaction of Gram-negative bacilli (GNB) like Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli to host cells thereby preventing the development of infection in vitro and in a murine sepsis peritoneal model. In this work, we aimed to evaluate in vitro a library of AOA-2 derivatives in order to improve the effect of AOA-2 against GNB infections. Ten AOA-2 derivatives were synthetized for the in vitro assays. Their toxicities to human lung epithelial cells (A549 cells) for 24 h were evaluated by determining the A549 cells viability using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The effect of these peptide derivatives and AOA-2 at 250, 125, 62.5, and 31.25 μg/mL on the attachment of A. baumannii ATCC 17978, P. aeruginosa PAO1 and E. coli ATCC 25922 strains to A549 cells was characterized by adherence and viability assays. None of the 10 derivatives showed toxicity to A549 cells. RW01 and RW06 have reduced more the adherence of ATCC 17978, PAO1 and ATCC 2599 strains to A549 cells when compared with the original compound AOA-2. Moreover, both peptides have increased slightly the viability of infected A549 cells by PAO1 and ATCC 25922 than those observed with AOA-2. Finally, RW01 and RW06 have potentiated the activity of colistin against ATCC 17978 strain in the same level with AOA-2. The optimization program of AOA-2 has generated two derivatives (RW01 and RW06) with best effect against interaction of GNB with host cells, specifically against P. aeruginosa and E. coli.

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Programmed Cell Death-1: Programmed Cell Death-Ligand 1 Interaction Protects Human Cardiomyocytes Against T-Cell Mediated Inflammation and Apoptosis Response In Vitro

International Journal of Molecular Sciences ◽

10.3390/ijms21072399 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2399

Author(s):

Woan Ting Tay ◽

Yi-Hsien Fang ◽

Suet Theng Beh ◽

Yen-Wen Liu ◽

Ling-Wei Hsu ◽

...

Keyword(s):

Gene Expression ◽

Cell Death ◽

T Cell ◽

T Lymphocytes ◽

Programmed Cell Death ◽

T Cell Response ◽

Tumor Bearing ◽

Cd8 T Lymphocytes ◽

Programmed Cell Death 1

Aim: Immunological checkpoint therapy is considered a powerful method for cancer therapy and acts by re-activating autologous T cells to kill the cancer cell. Myocarditis cases have been reported in cancer patients after immunological therapy; for example, nivolumab treatment is a monoclonal antibody that blocks programmed cell death-1/programmed cell death ligand-1 ligand interaction. This project provided insight into the inflammatory response as a benchmark to investigate the potential cardiotoxic effect of T cell response to the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis in regulating cardiomyocyte injury in vitro. Methods and Results: We investigated cardiomyopathy resulted from the PD-1/PD-L1 axis blockade using the anti-PD-1 antibody in Rockefeller University embryonic stem cells-derived cardiomyocytes (RUES2-CMs) and a melanoma tumor-bearing murine model. We found that nivolumab alone did not induce inflammatory-related proteins, including PD-L1 expression, and did not induce apoptosis, which was contrary to doxorubicin, a cardiotoxic chemotherapy drug. However, nivolumab was able to exacerbate the immune response by increasing cytokine and inflammatory gene expression in RUES2-CMs when co-cultured with CD4+ T lymphocytes and induced apoptosis. This effect was not observed when RUES2-CMs were co-cultured with CD8+ T lymphocytes. The in vivo model showed that the heart function of tumor-bearing mice was decreased after treatment with anti-PD-1 antibody and demonstrated a dilated left ventricle histological examination. The dilated left ventricle was associated with an infiltration of CD4+ and CD8+ T lymphocytes into the myocardium. PD-L1 and inflammatory-associated gene expression were significantly increased in anti-PD-1-treated tumor-bearing mice. Cleaved caspase-3 and mouse plasma cardiac troponin I expressions were increased significantly. Conclusion: PD-L1 expression on cardiomyocytes suppressed T-cell function. Blockade of PD-1 by nivolumab enhanced cardiomyocyte inflammation and apoptosis through the enhancement of T-cell response towards cardiomyocytes.

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Bacterial Immunoglobulin Superantigen Proteins A and L Activate Human Heart Mast Cells by Interacting with Immunoglobulin E

Infection and Immunity ◽

10.1128/iai.68.10.5517-5524.2000 ◽

2000 ◽

Vol 68 (10) ◽

pp. 5517-5524 ◽

Cited By ~ 59

Author(s):

Arturo Genovese ◽

Jean-Pierre Bouvet ◽

Giovanni Florio ◽

Bärbel Lamparter-Schummert ◽

Lars Björck ◽

...

Keyword(s):

Mast Cells ◽

Human Heart ◽

Immunoglobulin E ◽

Protein A ◽

Surface Protein ◽

Heart Tissue ◽

Protein L ◽

Cysteinyl Leukotriene ◽

Proinflammatory Mediators

ABSTRACT Human heart mast cells (HHMC) have been identified in heart tissue, perivascularly, and in the intima of coronary arteries. In vitro activation of isolated HHMC induces the release of vasoactive and proinflammatory mediators (histamine, tryptase, and cysteinyl leukotriene C4 [LTC4]). We investigated the effects of several bacterial proteins on HHMC activation in vitro. HHMC released histamine, tryptase, and LTC4 in response toStaphylococcus aureus Cowan 1 and the immunoglobulin (Ig)-binding protein A, but not to S. aureus Wood 46, which does not synthesize protein A. The effect of protein A was inhibited by preincubation with monoclonal IgM VH3+. Some strains of Peptostreptococcus magnus express an Ig light chain-binding surface protein called protein L. Such bacteria and soluble protein L stimulated the release of preformed and newly synthesized mediators from HHMC. Preincubation of HHMC with either protein A or protein L resulted in complete cross-desensitization to a subsequent challenge with the heterologous stimulus or anti-IgE. Monoclonal IgE (κ chains) blocked protein L-induced release, whereas IgE (λ chains) had no effect. Streptococcal protein G, formyl-containing tripeptide, and pepstatin A did not activate HHMC. Bacterial products protein A and protein L and intact bacteria (S. aureus and P. magnus) activate HHMC by acting as Ig superantigens.

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Formation, characterization and detection of a ternary complex between S protein, thrombin and antithrombin III in serum

Biochemical Journal ◽

10.1042/bj2430105 ◽

1987 ◽

Vol 243 (1) ◽

pp. 105-111 ◽

Cited By ~ 33

Author(s):

K T Preissner ◽

L Zwicker ◽

G Müller-Berghaus

Keyword(s):

Antithrombin Iii ◽

Protein A ◽

Time Intervals ◽

S Protein ◽

Protein Complex Formation ◽

Gradient Gel Electrophoresis ◽

Radiometric Assay ◽

Plasma Glycoprotein ◽

Protein Serum

S protein, a plasma glycoprotein with Mr 78,000, has been shown to interfere with the heparin-catalysed inhibition of thrombin by antithrombin III. This interaction was further evaluated in the present study. Native human blood was replaced by either radiolabelled antithrombin III or radiolabelled prothrombin in the reaction mixture, which was incubated at 37 degrees C. At various time intervals the serum formed from the incubated blood was withdrawn and analysed by crossed immunoelectrophoresis against anti-(S protein) serum in the second dimension. Increasing quantities of radioactivity originating both from antithrombin III and from thrombin were precipitated in a cathodal shoulder to the S protein peak. This observation indicated the formation of a ternary S protein-thrombin-antithrombin III (STAT) complex in serum. This complex could also be observed by the same technique after incubation of purified thrombin in the presence of antithrombin III and S protein. Complex-formation was independent of the presence of heparin and did not require Ca2+ ions. Owing to the association of S protein with the thrombin-antithrombin III (TAT) complex, the STAT complex assembled in vitro exhibited a higher Mr than the TAT complex as judged by polyacrylamide-gradient-gel electrophoresis in the absence of SDS. Both the serum-originated STAT complex and the STAT complex assembled from purified components sedimented faster than the single components and showed comparable apparent sedimentation coefficients in the range 11-14 S, corresponding to a mean Mr of 350,000. The STAT complex could be detected in serum at a dilution of 1:3200 by a sensitive immuno-radiometric assay employing affinity-purified IgG against S protein. These results indicate that S protein, in addition to its role as a heparin-neutralizing factor, becomes incorporated into the nascent TAT complex or can bind to preformed TAT complex during the clotting process.

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Rikkunshito Ameliorates Cancer Cachexia Partly through Elevation of Glucarate in Plasma

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2015/871832 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 6

Author(s):

Katsuya Ohbuchi ◽

Shin Nishiumi ◽

Naoki Fujitsuka ◽

Tomohisa Hattori ◽

Masahiro Yamamoto ◽

...

Keyword(s):

Weight Loss ◽

Herbal Medicine ◽

Rat Model ◽

Cancer Cachexia ◽

Host Cells ◽

Metabolome Analysis ◽

Traditional Herbal Medicine ◽

Delayed Onset ◽

Tumor Bearing

Cancer cachexia, which is characterized by decreased food intake, weight loss and systemic inflammation, increases patient’s morbidity and mortality. We previously showed that rikkunshito (RKT), a Japanese traditional herbal medicine (Kampo), ameliorated the symptoms of cancer cachexia through ghrelin signaling-dependent and independent pathways. To investigate other mechanisms of RKT action in cancer cachexia, we performed metabolome analysis of plasma in a rat model bearing the Yoshida AH-130 hepatoma. A total of 110 metabolites were detected in plasma and RKT treatment significantly altered levels of 23 of those metabolites in cachexia model rats. Among them, glucarate, which is known to have anticarcinogenic activity through detoxification of carcinogens via inhibition ofβ-glucuronidase, was increased in plasma following administration of RKT. In our AH-130 ascites-induced cachexia rat model, administration of glucarate delayed onset of weight loss, improved muscle atrophy, and reduced ascites content. Additionally, glucarate reduced levels of plasma interferon-γ(IFN-γ) in tumor-bearing rats and was also found to suppress LPS-induced IFN-γexpression in splenocytesin vitro. These results suggest that glucarate has anti-inflammatory activity via a direct effect on immune host cells and suggest that RKT may also ameliorate inflammation partly through the elevation of glucarate in plasma.

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Expression of Truncated Internalin A Is Involved in Impaired Internalization of Some Listeria monocytogenes Isolates Carried Asymptomatically by Humans

Infection and Immunity ◽

10.1128/iai.71.3.1217-1224.2003 ◽

2003 ◽

Vol 71 (3) ◽

pp. 1217-1224 ◽

Cited By ~ 65

Author(s):

Maïwenn Olier ◽

Fabrice Pierre ◽

Sandrine Rousseaux ◽

Jean-Paul Lemaître ◽

André Rousset ◽

...

Keyword(s):

Listeria Monocytogenes ◽

Surface Protein ◽

Human Infection ◽

Host Cells ◽

Genetic Lineage ◽

Chick Embryos ◽

Asymptomatic Carriage ◽

High Degree ◽

Internalin A

ABSTRACT Fourteen human carriage Listeria monocytogenes isolates were compared to sporadic and epidemic-associated human strains in order to ascertain the pathogenic behavior of these unrecognized asymptomatic strains. Experimental infection of 14-day-old chick embryos revealed that the majority of the carriage strains were attenuated for virulence. Of the 10 attenuated carriage strains, 5 were affected in their invasion capacities in vitro. Western blot analysis with antibody directed against InlA, the surface protein implicated in the internalization in host cells, allowed correlation between the ability of the carriage strains to enter Caco-2 cells and InlA expression. Indeed, these five carriage strains produced truncated forms of InlA. Four of the five truncated forms of InlA had an apparent molecular mass of 47 kDa. In order to assess the existence of a genetic lineage, partial sequences of inlA gene of these four strains were compared and revealed that they had a high degree of sequence conservation at the gene (99.86%) and amino acid (100%) levels. Comparison of their nucleotide sequences with that of the corresponding segment of inlA from EGD-e and Scott A strains, taken as epidemic references, showed more divergence. Taken together, these observations suggest the presence of specific traits that characterize L. monocytogenes strains isolated during asymptomatic carriage. Some of these traits could provide some explanations about the determinants that make them unable to cause systemic human infection.

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Reduced Virulence of HWP1-Deficient Mutants of Candida albicans and Their Interactions with Host Cells

Infection and Immunity ◽

10.1128/iai.68.4.1997-2002.2000 ◽

2000 ◽

Vol 68 (4) ◽

pp. 1997-2002 ◽

Cited By ~ 84

Author(s):

Noboru Tsuchimori ◽

Laura L. Sharkey ◽

William A. Fonzi ◽

Samuel W. French ◽

John E. Edwards ◽

...

Keyword(s):

Candida Albicans ◽

Cell Injury ◽

Gene Dosage ◽

Surface Protein ◽

Host Cells ◽

Null Mutant ◽

Gene Dosage Effect ◽

Hyphal Development

ABSTRACT The Candida albicans gene HWP1 encodes a surface protein that is required for normal hyphal development in vitro. We used mutants lacking one or both alleles of HWP1to investigate the role of this gene in virulence. Mice infected intravenously with the homozygous hwp1 null mutant, CAL3, survived a median of >14 days, whereas mice infected with a control strain containing two functional alleles of HWP1 survived only 3.5 days. After 1 day of infection, all strains produced similar levels of infection in the kidneys, spleen, and blood. However, after 2 and 3 days, there was a significant decrease in the number of organisms in the kidneys of the mice infected with CAL3. This finding suggests that the hwp1 homozygous null mutant is normal in its ability to initiate infection but deficient in its capacity to maintain infection. CAL3 also germinated minimally in the kidneys. The ability of the heterozygous null mutant to germinate and cause mortality in mice was intermediate to CAL3, suggesting a gene dosage effect. To investigate potential mechanisms for the diminished virulence of CAL3, we examined its interactions with endothelial cells and neutrophils in vitro. CAL3 caused less endothelial cell injury than the heterozygoushwp1 mutant. We conclude that the HWP1 gene product is important for both in vivo hyphal development and pathogenicity of C. albicans. Also, the ability to form filaments may be critical for candidal virulence by enabling the fungus to induce cellular injury and maintain a deep-seated infection.

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Borrelia burgdorferi Escape Mutants That Survive in the Presence of Antiserum to the OspA Vaccine Are Killed When Complement Is Also Present

Infection and Immunity ◽

10.1128/iai.66.6.2540-2546.1998 ◽

1998 ◽

Vol 66 (6) ◽

pp. 2540-2546 ◽

Cited By ~ 7

Author(s):

Mónica Solé ◽

Carlos Bantar ◽

Karl Indest ◽

Yan Gu ◽

Ramesh Ramamoorthy ◽

...

Keyword(s):

Borrelia Burgdorferi ◽

Protein A ◽

Surface Protein ◽

Sensu Stricto ◽

Antibody Concentration ◽

Initial Attempt ◽

Outer Surface Protein A ◽

Escape Mutants ◽

Low Passage

ABSTRACT As an initial attempt to investigate the possible role of outer surface protein A (OspA) escape mutants of Borrelia burgdorferi in decreasing the efficacy of the OspA vaccine, mutants of the HB19 strain of B. burgdorferi sensu stricto were selected in vitro from an uncloned, low-passage-number isolate. The antiserum used for selection was obtained from rhesus monkeys that had been given a vaccine of the same formulation and dose, and by the same route of administration, as that given to humans in several trials. All of the mutants selected in liquid medium and subsequently cloned twice in solid medium expressed a single abundant protein of 28 to 34 kDa instead of both OspA and OspB. Depending on the mutant, this protein reacted strongly, weakly, or not detectably with the anti-OspA antibody used for selection. Analysis of the ospAB locus of each of four representatives from these three groups of mutants by PCR with oligonucleotide primers that hybridize to flanking regions of theospAB operon, and of the corresponding phenotype with monoclonal antibodies that bind to the amino or carboxyl terminus of the OspA or OspB polypeptide, indicated that in all cases a deletion within the operon had occurred. Spirochetes from the four mutant strains chosen for further analysis could be killed in antibody-dependent, complement-mediated killing assays with the selecting anti-OspA antibody, despite their resistance to killing with this antibody in the absence of complement. Complement-mediated killing occurred at an antibody concentration higher than that required to kill wild-type spirochetes. If anti-OspA antibody acts only within the tick, where complement is probably ineffective due to tick-derived decomplementing factors, then OspA escape mutants, if infectious, could seriously diminish the efficacy of OspA vaccines. On the other hand, if the killing of B. burgdorferi with anti-OspA antibody also takes place within the human host, then our results indicate that chimeric/deletion escape mutants will be killed as well.

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Antimicrobial activity of Tachyplesin 1 againstBurkholderia pseudomallei: an in vitro and in silico approach

PeerJ ◽

10.7717/peerj.2468 ◽

2016 ◽

Vol 4 ◽

pp. e2468 ◽

Cited By ~ 1

Author(s):

Lyn-Fay Lee ◽

Vanitha Mariappan ◽

Kumutha Malar Vellasamy ◽

Vannajan Sanghiran Lee ◽

Jamuna Vadivelu

Keyword(s):

In Silico ◽

Antimicrobial Agents ◽

Protein A ◽

Surface Protein ◽

In Vitro Study ◽

Planktonic Cell ◽

Mammalian Cell Lines ◽

Electrostatic Contribution ◽

Conventional Antibiotics

Burkholderia pseudomallei, the causative agent of melioidosis, is intrinsically resistant to many conventional antibiotics. Therefore, alternative antimicrobial agents such as antimicrobial peptides (AMPs) are extensively studied to combat this issue. Our study aims to identify and understand the mode of action of the potential AMP(s) that are effective againstB. pseudomalleiin both planktonic and biofilm state as well as to predict the possible binding targets on using in vitro and in silico approaches. In the in vitro study, 11 AMPs were tested against 100B. pseudomalleiisolates for planktonic cell susceptibility, where LL-37, and PG1, demonstrated 100.0% susceptibility and TP1 demonstrated 83% susceptibility. Since theB. pseudomalleiactivity was reported on LL-37 and PG1, TP1 was selected for further investigation. TP1 inhibitedB. pseudomalleicells at 61.69 μM, and membrane blebbing was observed using scanning electron microscopy. Moreover, TP1 inhibitedB. pseudomalleicell growth, reaching bactericidal endpoint within 2 h post exposure as compared to ceftazidime (CAZ) (8 h). Furthermore, TP1 was shown to suppress the growth ofB. pseudomalleicells in biofilm state at concentrations above 221 μM. However, TP1 was cytotoxic to the mammalian cell lines tested. In the in silico study, molecular docking revealed that TP1 demonstrated a strong interaction to the common peptide or inhibitor binding targets for lipopolysaccharide ofEscherichia coli, as well as autolysin, pneumolysin, and pneumococcal surface protein A (PspA) ofStreptococcus pneumoniae. Homology modelledB. pseudomalleiPspA protein (YDP) also showed a favourable binding with a strong electrostatic contribution and nine hydrogen bonds. In conclusion, TP1 demonstrated a good potential as an anti-B. pseudomalleiagent.

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Co-Administration of Anticancer Candidate MK-2206 Enhances the Efficacy of BCG Vaccine Against Mycobacterium tuberculosis in Mice and Guinea Pigs

Frontiers in Immunology ◽

10.3389/fimmu.2021.645962 ◽

2021 ◽

Vol 12 ◽

Author(s):

Rania Bouzeyen ◽

Saurabh Chugh ◽

Tannu Priya Gosain ◽

Mohamed-Ridha Barbouche ◽

Meriam Haoues ◽

...

Keyword(s):

T Cells ◽

Guinea Pigs ◽

Protective Efficacy ◽

T Cell Response ◽

Host Cells ◽

Mice Model ◽

Akt Inhibitor ◽

Induction Of Apoptosis ◽

Induced Immunity

The failure of M. bovis BCG to induce long-term protection has been endowed to its inability to escape the phagolysosome, leading to mild activation of CD8+ mediated T cell response. Induction of apoptosis in host cells plays an important role in potentiating dendritic cells-mediated priming of CD8+ T cells, a process defined as “cross-priming.” Moreover, IL-10 secretion by infected cells has been reported to hamper BCG-induced immunity against Tuberculosis (TB). Previously, we have reported that apoptosis of BCG-infected macrophages and inhibition of IL-10 secretion is FOXO3 dependent, a transcription factor negatively regulated by the pro-survival activated threonine kinase, Akt. We speculate that FOXO3-mediated induction of apoptosis and abrogation of IL-10 secretion along with M. bovis BCG immunization might enhance the protection imparted by BCG. Here, we have assessed whether co-administration of a known anti-cancer Akt inhibitor, MK-2206, enhances the protective efficacy of M. bovis BCG in mice model of infection. We observed that in vitro MK-2206 treatment resulted in FOXO3 activation, enhanced BCG-induced apoptosis of macrophages and inhibition of IL-10 secretion. Co-administration of M. bovis BCG along with MK-2206 also increased apoptosis of antigen-presenting cells in draining lymph nodes of immunized mice. Further, MK-2206 administration improved BCG-induced CD4+ and CD8+ effector T cells responses and its ability to induce both effector and central memory T cells. Finally, we show that co-administration of MK-2206 enhanced the protection imparted by M. bovis BCG against Mtb in aerosol infected mice and guinea pigs. Taken together, we provide evidence that MK-2206-mediated activation of FOXO3 potentiates BCG-induced immunity and imparts protection against Mtb through enhanced innate immune response.

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