Anandi Krishnan, Postdoctoral Research Mentor
SARS-CoV-2 Vaccine Development: An Overview and Perspectives.
ACS pharmacology & translational science
2020; 3 (5): 844–58
Coronavirus disease 2019, abbreviated as COVID-19, is caused by a new strain of coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It started in late December 2019 in Wuhan, China, and by mid-March 2020, the disease had spread globally. As of July 17, 2020, this pandemic virus has infected 13.9 million people and claimed the life of approximately 593 000 people globally, and the numbers continue to climb. An unprecedented effort is underway to develop therapeutic and prophylactic strategies against this disease. Various drugs and vaccines are undergoing rapid development, and some of these are already in phase III clinical trials. Although Russia was the first to release a vaccine by skipping phase III clinical trials, there is no evidence of large-scale clinical trials, and the safety and efficacy of the vaccine are still a concern. Nevertheless, critical lessons can be learned and data garnered for developing promising vaccines against this rapidly emerging virus or other similar pathogens in the future. In this overview, we cover the available information on the various vaccine development initiatives by different companies, the potential strategies adopted for vaccine design, and the challenges and clinical impact expected from these vaccines. We also briefly discuss the possible role of these vaccines and the specific concerns for their use in patients with pre-existing disease conditions such as cardiovascular, lung, kidney, and liver diseases, cancer patients who are receiving immunosuppressive medications, including anticancer chemotherapies, and many other sensitive populations, such as children and the elderly.
View details for DOI 10.1021/acsptsci.0c00109
View details for PubMedID 33062951
Ultrasound-Mediated Long-Circulating Nanopolymer Delivery of Therapeutic siRNA and Antisense MicroRNAs Leads to Enhanced Paclitaxel Sensitivity in Epithelial Ovarian Cancer Chemotherapy
ACS BIOMATERIALS SCIENCE & ENGINEERING
2020; 6 (7): 4036–50
Epithelial ovarian cancer (EOC) is one of the leading malignant tumors that seriously threaten women's health. The development of new drugs or increasing the sensitivities of current chemotherapy drugs is critically needed. The purpose of this study was to assess the synergistic effects of two silencing RNAs [salt-inducible kinase 2 (SIK2) siRNA and antisense-microRNA21 (anti-miR21)] encapsulated in long-circulating folate-lipid-poly(lactic-co-glycolic acid) (PLGA) hybrid nanopolymers (FaLPHNPs) administered using an ultrasound- and microbubble (US-MB)-mediated approach to sensitize human EOC xenografts to paclitaxel (PTX). In the in vitro assays, this lipid-PLGA hybrid nanopolymer exhibited an extended circulation profile (t1/2: ∼8.5 h); US-MB-mediated complementary delivery of FaLPHNPs resulted in a significant reduction in EOC cell (OVCR3, A2780, and SKOV3) proliferation. In vivo, there was a 2.5-fold increase (p < 0.05) in RNA delivery in EOC xenografts, which resulted in a notable inhibition of tumor growth compared with that in the non-ultrasound-mediated and PTX alone-treated controls. We validated the therapeutic roles of SIK2, the target gene in treating advanced ovarian cancer, and anti-miR21 by evaluating the significant inhibition of tumor growth upon SIK2 silencing and inhibition of endogenous miR21 function. In summary, the results of this study revealed that US-MB-mediated codelivery of SIK2 siRNA, and anti-miR21 encapsulated in a folate-lipid-PLGA hybrid polymer nanoparticle could significantly improve the sensitivity of EOC tumors to PTX and is a highly effective approach for treating EOC in complementary experiments. Further research of this strategy could lead to better treatment results for patients with EOC.
View details for DOI 10.1021/acsbiomaterials.0c00330
View details for Web of Science ID 000551355300030
View details for PubMedID 33463352
Oncostatin M Is a Prognostic Biomarker and Inflammatory Mediator for Sepsis
JOURNAL OF INFECTIOUS DISEASES
2020; 221 (12): 1989–98
Oncostatin M (OSM) is a pleiotropic cytokine of the interleukin-6 family. The role of OSM in sepsis remains unknown.Serum OSM level was determined and analyzed in septic patients on the day of intensive care unit (ICU) admission. Furthermore, the effects of OSM on polymicrobial sepsis induced by cecal ligation and puncture (CLP) were assessed.On the day of ICU admission, septic patients had significantly higher serum OSM levels when compared with ICU patient controls and healthy volunteers, which were related to the severity of sepsis, including parameters such as the sequential (sepsis-related) organ failure assessment score, procalcitonin level, and white blood cell number. A high serum OSM level on ICU admission was associated with 28-day mortality in septic patients. In CLP-induced polymicrobial sepsis, anti-OSM antibody decreased tissue inflammation and injury, and thus improved survival, while local and systemic bacterial dissemination was almost constant. Complementarily, supplementation with recombinant OSM protein in septic mice increased tissue injury, amplified inflammation, and worsened mortality after CLP, while it did not affect bacterial dissemination in septic mice.Sepsis results in an increased production of OSM, which might be a potential prognostic biomarker and therapeutic target for sepsis.
View details for DOI 10.1093/infdis/jiaa009
View details for Web of Science ID 000544189300011
View details for PubMedID 31930328
Interleukin-17D Aggravates Sepsis by Inhibiting Macrophage Phagocytosis
CRITICAL CARE MEDICINE
2020; 48 (1): E58–E65
Interleukin-17D has been shown to participate in the control of viral infections and cancer. Here we hypothesized that interleukin-17D may play a potential role in sepsis.Prospective randomized animal investigation and in vitro human blood studies.Research laboratory from a university hospital.Female C57BL/6J mice, sepsis patients by Sepsis-3 definitions, ICU patient controls, and healthy individuals.Serum concentrations of interleukin-17D were measured and analyzed in human sepsis patients, patient controls, and healthy individuals. The contribution of interleukin-17D to sepsis-related survival, bacterial burden, and organ injury was assessed in a murine model of cecal ligation and puncture-induced polymicrobial sepsis by the use of anti-interleukin-17D antibody and recombinant interleukin-17D protein. The effects of interleukin-17D on bacterial phagocytosis by macrophages were also investigated using in vitro cell models.On the day of ICU admission (day 0), septic patients had significantly higher serum concentrations of interleukin-17D than patient controls and healthy individuals. Serum interleukin-17D levels remained significantly elevated in septic patients from ICU admission to day 3 and correlated with Sequential (Sepsis-related) Organ Failure Assessment scores and documented bacteremia on day 0. Furthermore, nonsurvivors of septic patients displayed significantly higher interleukin-17D levels compared with survivors of septic patients on days 0 and 1 of ICU admission. In animal models of sepsis, treatment with anti-interleukin-17D antibody protected mice from cecal ligation and puncture-induced severe sepsis, which was associated with improved bacterial clearance and organ injury. Conversely, administration of recombinant interleukin-17D protein aggravated cecal ligation and puncture-induced nonsevere sepsis. Furthermore, we found that interleukin-17D impaired bacterial phagocytosis by macrophages. Phagocytosis inhibition by interleukin-17D involved its ability to down-regulate the activation of nuclear factor-κB signaling pathway in macrophages upon bacterial infection.This study indicates a previously undescribed role of interleukin-17D in sepsis and identifies a new target for antisepsis treatment.
View details for DOI 10.1097/CCM.0000000000004070
View details for Web of Science ID 000502770900016
View details for PubMedID 31634237
Assessment of Apoptosis Inhibitor of Macrophage/CD5L as a Biomarker to Predict Mortality in the Critically Ill With Sepsis
2019; 156 (4): 696–705
To determine the utility of apoptosis inhibitor of macrophage (AIM)/CD5L as a potentially novel biomarker of morbidity and mortality in patients with sepsis who are critically ill.There were 150 adult patients with sepsis studied. Serum AIM levels on day of ICU admission were determined and compared with survival status and organ dysfunction. For validation, 60 adult patients with sepsis from another medical center were studied. Furthermore, the role of AIM as an outcome predictor in 51 pediatric patients with sepsis was investigated.In the derivation cohort of adult patients, patients with sepsis had markedly increased admission levels of serum AIM compared with ICU control subjects and healthy control subjects. Higher serum AIM levels at admission were significantly associated with higher Sequential (sepsis-related) Organ Failure Assessment (SOFA) scores. On day of ICU admission, the area under the receiver operating characteristic curve (AUC) for AIM level association with 28-day mortality was 0.86, higher than the AUC for SOFA (0.77), procalcitonin (0.73), lactate (0.67), IL-27 (0.65), and C-reactive protein (0.55). Patients with sepsis with higher admission levels of AIM (> 543.66 ng/mL) had significantly increased 28-day mortality compared with those with lower AIM levels (≤ 543.66 ng/mL). The association between admission levels of AIM and 28-day mortality was confirmed in the validation cohort of adult patients. In another cohort of pediatric patients with sepsis, the AUC for AIM level association with 28-day mortality was 0.82.Circulating AIM levels at admission were markedly increased in patients with sepsis, which can serve as a novel prognostic biomarker for predicting mortality.
View details for DOI 10.1016/j.chest.2019.04.134
View details for Web of Science ID 000489035200015
View details for PubMedID 31154043
Interleukin-26 is overexpressed in human sepsis and contributes to inflammation, organ injury, and mortality in murine sepsis
2019; 23 (1): 290
Sepsis is a serious syndrome that is caused by an unbalanced host inflammatory response to an infection. The cytokine network plays a pivotal role in the orchestration of inflammatory response during sepsis. IL-26 is an emerging proinflammatory member of the IL-10 cytokine family with multifaceted actions in inflammatory disorders. However, its role in the pathogenesis of sepsis remains unknown.Serum IL-26 level was measured and analyzed in 52 septic patients sampled on the day of intensive care unit (ICU) admission, 18 non-septic ICU patient controls, and 30 healthy volunteers. In addition, the effects of recombinant human IL-26 on host inflammatory response in cecal ligation and puncture (CLP)-induced polymicrobial sepsis were determined.On the day of ICU admission, the patients with sepsis showed a significant increase in serum IL-26 levels compared with ICU patient controls and healthy volunteers, and the serum IL-26 levels were related to the severity of sepsis. Nonsurvivors of septic patients displayed significantly higher serum IL-26 levels compared with survivors. A high serum IL-26 level on ICU admission was associated with 28-day mortality, and IL-26 was found to be an independent predictor of 28-day mortality in septic patients by logistic regression analysis. Furthermore, administration of recombinant human IL-26 increased lethality in CLP-induced polymicrobial sepsis. Despite a lower bacterial load, septic mice treated with recombinant IL-26 had higher concentrations of IL-1β, IL-4, IL-6, IL-10, IL-17A, TNF-α, CXCL1, and CCL2 in peritoneal lavage fluid and blood and demonstrated more severe multiple organ injury (including lung, liver and kidney) as indicated by clinical chemistry and histopathology. Furthermore, septic mice treated with recombinant human IL-26 showed an increased neutrophil recruitment to the peritoneal cavity.Septic patients had elevated serum IL-26 levels, which may correlate with disease severity and mortality. In experimental sepsis, we demonstrated a previously unrecognized role of IL-26 in increasing lethality despite promoting antibacterial host responses.
View details for DOI 10.1186/s13054-019-2574-7
View details for Web of Science ID 000483515900001
View details for PubMedID 31464651
View details for PubMedCentralID PMC6716900
Interleukin 28 is a potential therapeutic target for sepsis
2019; 205: 29–34
Identification of new therapeutic targets for the treatment of sepsis is imperative. We report here that cytokine IL-28 (IFN-λ) levels were elevated in clinical and experimental sepsis. Neutralization of IL-28 protected mice from lethal sepsis induced by cecal ligation and puncture (CLP), which was associated with improved bacterial clearance and enhanced neutrophil infiltration. Conversely, administration of recombinant IL-28 aggravated mortality, facilitated bacterial dissimilation and limited neutrophil recruitment, in the model of sepsis induced by CLP. This study defines IL-28 as a detrimental mediator during sepsis and identifies a potential therapeutic target for the immune therapy in sepsis.
View details for DOI 10.1016/j.clim.2019.05.012
View details for Web of Science ID 000482172600006
View details for PubMedID 31121287
Photothermal therapy mediated by phase-transformation nanoparticles facilitates delivery of anti-PD1 antibody and synergizes with antitumor immunotherapy for melanoma
JOURNAL OF CONTROLLED RELEASE
2019; 306: 15–28
Melanoma remains one of the most challenging malignant tumor related deaths worldwide and alternative approaches to efficiently treat melanoma are eagerly needed. Anti-PD1 antibody (aPD1) immunotherapy is the most significant and impactful therapy for melanoma by immune checkpoint inhibition and T cell stimulation to mediate tumor killing. But the clinical remission rate of aPD1 immunotherapy is limited in melanoma. Here we show a potent combination of aPD1 and photothermal therapy (PTT) by effective delivery of a multifunctional phase-transformation nanocarrier to melanoma tumor. We successfully synthesized multifunctional nanoparticles (NPs) encapsulated with aPD1, iron oxide and perfluoropentane (PFP) in lactic-co-glycolic acid (PLGA) shell modified with poly ethylene glycol (PEG) and Gly-Arg-Gly-Asp-Ser (GRGDS) peptides (GOP@aPD1). In vitro, GOP@aPD1 NPs were characterized for particle size and drug-loading efficiency. The NPs were also tested for photothermal property, optical droplet vaporization (ODV) capacity and the ability of aPD1 release profile. In vivo, GOP@aPD1 NPs were systemically administered to melanoma-bearing mice demonstrated no toxicity and accumulation at tumor site. When mediated with PTT, this synergistic treatment achieved enhanced antitumor efficacy, due to combination of the effective aPD1 release and increased CD8+ T cell infiltration in tumor site. In conclusion, GOP@aPD1 NPs combined with PTT could potentiate the efficacy of aPD1 not only by tumor-targeted delivery of aPD1 but also by activating the immune system in the tumor microenvironment, which is a highly effective approach to treat melanoma.
View details for DOI 10.1016/j.jconrel.2019.05.036
View details for Web of Science ID 000474822700002
View details for PubMedID 31132380
Flagellin attenuates experimental sepsis in a macrophage-dependent manner
2019; 23: 106
Sepsis is the leading cause of death among critically ill patients, and no specific therapeutic agent is currently approved for the treatment of sepsis.We assessed the effects of flagellin administration on survival, bacterial burden, and tissue injury after sepsis. In addition, we examined the effects on phagocytosis and bacterial killing in monocytes/macrophages.Therapeutic administration of flagellin increased bacterial clearance, decreased organ inflammation and injury, and reduced immune cell apoptosis after experimental sepsis, in a Toll-like receptor 5 (TLR5)-dependent manner. Macrophages, but not neutrophils, mediated the beneficial effects of flagellin on experimental sepsis, and flagellin induced macrophage polarization into M1 in septic mice. Flagellin treatment could directly enhance phagocytosis and bacterial killing of macrophages, but not neutrophils. Subsequent studies demonstrated that flagellin could promote phagosome formation and increase reactive oxygen species (ROS) levels in macrophages. Finally, we found that the expression of TLR5 was significantly elevated on the surface of circulating monocytes, but not neutrophils, from patients with sepsis. Higher expression levels of TLR5 on monocytes were associated with increased mortality, documented bacteremia, and higher Sequential Organ Failure Assessment scores of the septic patients. Moreover, flagellin treatment rescued the impaired phagocytosis and bacterial killing ability of monocytes/macrophages from patients who died of sepsis.These novel findings not only established the potential value of application of flagellin as an immunoadjuvant in treating sepsis, but also provided new insights into targeted therapeutic strategy on the basis of monocyte TLR5 expression in septic patients.
View details for DOI 10.1186/s13054-019-2408-7
View details for Web of Science ID 000463795500003
View details for PubMedID 30944018
View details for PubMedCentralID PMC6446324
IR780-loaded folate-targeted nanoparticles for near-infrared fluorescence image-guided surgery and photothermal therapy in ovarian cancer
INTERNATIONAL JOURNAL OF NANOMEDICINE
2019; 14: 2757–72
Background and purpose: Surgery is regarded as the gold standard for patients with advanced ovarian cancer. However, complete surgical removal of tumors remains extremely challenging; fewer than 40% of patients are cured. Here, we developed a new modality of theranostics for ovarian cancer based on a near-infrared light-triggered nanoparticle. Methods: Nanoparticles loading IR780 iodide on base of folate modified liposomes were prepared and used for theranostics of ovarian cancer. Tumor targeting of FA-IR780-NP was evaluated in vitro and in an ovarian xenograft tumor model. A fluorescence stereomicroscope was applied to evaluate the tumor recognition of FA-IR780-NP during surgery. FA-IR780-NP mediated photothermal therapy effect was compared with other treatments in vivo. Results: FA-IR780-NP was demonstrated to specifically accumulate in tumors. IR780 iodide selectively accumulated in tumors; the enhanced permeability and retention effect of the nanoparticles and the active targeting of folate contributed to the excellent tumor targeting of FA-IR780-NP. With the aid of tumor targeting, FA-IR780-NP could be used as an indicator for the real-time delineation of tumor margins during surgery. Furthermore, photothermal therapy mediated by FA-IR780-NP effectively eradicated ovarian cancer tumors compared with other groups. Conclusion: In this study, we present a potential, effective approach for ovarian cancer treatment through near-infrared fluorescence image-guided resection and photothermal therapy to eliminate malignant tissue.
View details for DOI 10.2147/IJN.S203108
View details for Web of Science ID 000465567400003
View details for PubMedID 31118609
View details for PubMedCentralID PMC6503636