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Cell Reports. Medicine Jun 2024Descendants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant now account for almost all SARS-CoV-2 infections. The Omicron variant and...
Descendants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant now account for almost all SARS-CoV-2 infections. The Omicron variant and its sublineages have spike glycoproteins that are highly diverged from the pandemic founder and first-generation vaccine strain, resulting in significant evasion from monoclonal antibody therapeutics and vaccines. Understanding how commonly elicited antibodies can broaden to cross-neutralize escape variants is crucial. We isolate IGHV3-53, using "public" monoclonal antibodies (mAbs) from an individual 7 months post infection with the ancestral virus and identify antibodies that exhibit potent and broad cross-neutralization, extending to the BA.1, BA.2, and BA.4/BA.5 sublineages of Omicron. Deep mutational scanning reveals these mAbs' high resistance to viral escape. Structural analysis via cryoelectron microscopy of a representative broadly neutralizing antibody, CAB-A17, in complex with the Omicron BA.1 spike highlights the structural underpinnings of this broad neutralization. By reintroducing somatic hypermutations into a germline-reverted CAB-A17, we delineate the role of affinity maturation in the development of cross-neutralization by a public class of antibodies.
Topics: SARS-CoV-2; Humans; Antibodies, Viral; COVID-19; Spike Glycoprotein, Coronavirus; Antibodies, Neutralizing; Antibodies, Monoclonal; Cross Reactions; Cryoelectron Microscopy; Neutralization Tests
PubMed: 38761799
DOI: 10.1016/j.xcrm.2024.101577 -
Experimental and Clinical... Apr 2024BK virus is a major cause of chronic renal allograft failure.Transplant ureteral stent use has been reported as a risk factorfor BK virus infection. Recently, the use of... (Comparative Study)
Comparative Study
OBJECTIVES
BK virus is a major cause of chronic renal allograft failure.Transplant ureteral stent use has been reported as a risk factorfor BK virus infection. Recently, the use of a new type of ureteral stent (Magnetic Black Star) was reported in kidney transplant recipients. The aim ofthis preliminary report was to compare BK virus viremia and viruria occurrence depending on the type of double-J stent (standard versus Magnetic Black Star).
MATERIALS AND METHODS
We included all kidney transplants performed in our center from January to December 2022. Each case had double-J stent placement. Indwelling stents were either a 6- or 7-Fr standard double-J stent or a 6-Fr Magnetic Black Star double-J stent. The type of double-J stent was chosen according to the surgeon's preference. A standard BK virus screening protocol was followed during the study period, which consisted of routine polymerase chain reaction examination of plasma and urine samples during monthly follow-ups.
RESULTS
We assessed 120 patients without missing data: 92 patients received standard double-J stents and 28 patients received Magnetic Black Star stents. Patients were mostly male in the standard group (70.7%) versus the Magnetic Black Star group (42.9%) (P = .01). ABO- and HLA-incompatible transplant rates were similar in both groups. BK viremia occurrence and BK viruria occurrence were similar between groups at 1 month, 3 months, and 6 months.
CONCLUSIONS
This preliminary study showed no differences concerning BKvirus infection depending on the type of double-J stents used during kidney transplant.
Topics: Humans; Kidney Transplantation; BK Virus; Stents; Male; Viremia; Female; Middle Aged; Polyomavirus Infections; Risk Factors; Treatment Outcome; Adult; Tumor Virus Infections; Prosthesis Design; Time Factors; Preliminary Data; Retrospective Studies
PubMed: 38742316
DOI: 10.6002/ect.2024.0037 -
Signal Transduction and Targeted Therapy May 2024Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a 'highly transmissible respiratory pathogen, leading to severe multi-organ damage. However, knowledge...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a 'highly transmissible respiratory pathogen, leading to severe multi-organ damage. However, knowledge regarding SARS-CoV-2-induced cellular alterations is limited. In this study, we report that SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics and activates the EGFR-mediated cell survival signal cascade during the early stage of viral infection. SARS-CoV-2 causes an increase in mitochondrial transmembrane potential via the SARS-CoV-2 RNA-nucleocapsid cluster, thereby abnormally promoting mitochondrial elongation and the OXPHOS process, followed by enhancing ATP production. Furthermore, SARS-CoV-2 activates the EGFR signal cascade and subsequently induces mitochondrial EGFR trafficking, contributing to abnormal OXPHOS process and viral propagation. Approved EGFR inhibitors remarkably reduce SARS-CoV-2 propagation, among which vandetanib exhibits the highest antiviral efficacy. Treatment of SARS-CoV-2-infected cells with vandetanib decreases SARS-CoV-2-induced EGFR trafficking to the mitochondria and restores SARS-CoV-2-induced aberrant elevation in OXPHOS process and ATP generation, thereby resulting in the reduction of SARS-CoV-2 propagation. Furthermore, oral administration of vandetanib to SARS-CoV-2-infected hACE2 transgenic mice reduces SARS-CoV-2 propagation in lung tissue and mitigates SARS-CoV-2-induced lung inflammation. Vandetanib also exhibits potent antiviral activity against various SARS-CoV-2 variants of concern, including alpha, beta, delta and omicron, in in vitro cell culture experiments. Taken together, our findings provide novel insight into SARS-CoV-2-induced alterations in mitochondrial dynamics and EGFR trafficking during the early stage of viral infection and their roles in robust SARS-CoV-2 propagation, suggesting that EGFR is an attractive host target for combating COVID-19.
Topics: SARS-CoV-2; Mitochondria; Humans; Animals; Mice; COVID-19; ErbB Receptors; Virus Replication; Energy Metabolism; Vero Cells; Chlorocebus aethiops; Antiviral Agents; COVID-19 Drug Treatment; Membrane Potential, Mitochondrial; Oxidative Phosphorylation; Signal Transduction
PubMed: 38734691
DOI: 10.1038/s41392-024-01836-x -
American Journal of Transplantation :... May 2024The strategy for progressive multifocal leukoencephalopathy (PML) in solid organ transplant recipients primarily focuses on reducing immunosuppressive therapy. However,...
The strategy for progressive multifocal leukoencephalopathy (PML) in solid organ transplant recipients primarily focuses on reducing immunosuppressive therapy. However, this approach offers limited efficacy and carries a high risk of graft loss. Here, we present the case of a 64-year-old male kidney transplant recipient with a high degree of immunosuppression who developed PML in October 2022. Despite the standard reduction of immunosuppressive therapy, the patient's condition continued to deteriorate, as evidenced by worsening neurological symptoms and increasing JC virus (JCV) DNA levels in cerebrospinal fluid. This prompted the innovative use of BKPyV-virus-specific T cell (BKPyV-VST) therapy, given the genetic similarities between BK and JCVs. Infusion of third-party donor BKPyV-VST resulted in clinical stabilization, a significant reduction in JCV-DNA levels, and the emergence of a JCV-specific T cell response, as observed in enzyme-linked immunospot assays and TCRβ sequencing. This represents the first case report of successful third-party BKPyV-VST therapy in a kidney recipient presenting PML, without graft-versus-host disease or graft dysfunction.
PubMed: 38734417
DOI: 10.1016/j.ajt.2024.05.003 -
Clinical Transplantation and Research Jun 2024Polyomaviruses, particularly BK virus, are ubiquitous latent infections that may reactivate with immunosuppression during kidney transplantation, resulting in... (Review)
Review
Polyomaviruses, particularly BK virus, are ubiquitous latent infections that may reactivate with immunosuppression during kidney transplantation, resulting in polyomavirus nephropathy (PVN). The levels of viruria and viremia serve as tools for screening and making a presumptive diagnosis of PVN, respectively, while a definitive diagnosis requires a kidney biopsy. There are histologic classifications of PVN based on the extent of tubular cell viral infection, interstitial fibrosis, and interstitial inflammation. These classifications correlate to some degree with graft function and loss, aiding in determining treatment efficacy and prognostication. PVN has histologic overlap with acute cell-mediated rejection, making the differential diagnosis challenging, although there are suggestive features for these different causes of graft dysfunction. This article reviews the diagnosis, histologic findings, and classifications of PVN, and discusses how to differentiate viral nephropathy from acute rejection.
PubMed: 38725187
DOI: 10.4285/ctr.24.0006 -
PloS One 2024University spring break carries a two-pronged SARS-CoV-2 variant transmission risk. Circulating variants from universities can spread to spring break destinations, and...
BACKGROUND
University spring break carries a two-pronged SARS-CoV-2 variant transmission risk. Circulating variants from universities can spread to spring break destinations, and variants from spring break destinations can spread to universities and surrounding communities. Therefore, it is critical to implement SARS-CoV-2 variant surveillance and testing strategies to limit community spread before and after spring break to mitigate virus transmission and facilitate universities safely returning to in-person teaching.
METHODS
We examined the SARS-CoV-2 positivity rate and changes in variant lineages before and after the university spring break for two consecutive years. 155 samples were sequenced across four time periods: pre- and post-spring break 2021 and pre- and post-spring break 2022; following whole genome sequencing, samples were assigned clades. The clades were then paired with positivity and testing data from over 50,000 samples.
RESULTS
In 2021, the number of variants in the observed population increased from four to nine over spring break, with variants of concern being responsible for most of the cases; Alpha percent composition increased from 22.2% to 56.4%. In 2022, the number of clades in the population increased only from two to three, all of which were Omicron or a sub-lineage of Omicron. However, phylogenetic analysis showed the emergence of distantly related sub-lineages. 2022 saw a greater increase in positivity than 2021, which coincided with a milder mitigation strategy. Analysis of social media data provided insight into student travel destinations and how those travel events may have impacted spread.
CONCLUSIONS
We show the role that repetitive testing can play in transmission mitigation, reducing community spread, and maintaining in-person education. We identified that distantly related lineages were brought to the area after spring break travel regardless of the presence of a dominant variant of concern.
Topics: Humans; COVID-19; SARS-CoV-2; Travel; Universities; Whole Genome Sequencing; Phylogeny; Seasons
PubMed: 38722935
DOI: 10.1371/journal.pone.0301225 -
Clinical Transplantation May 2024Immunosuppression reduction for BK polyoma virus (BKV) must be balanced against risk of adverse alloimmune outcomes. We sought to characterize risk of alloimmune events...
BACKGROUND
Immunosuppression reduction for BK polyoma virus (BKV) must be balanced against risk of adverse alloimmune outcomes. We sought to characterize risk of alloimmune events after BKV within context of HLA-DR/DQ molecular mismatch (mMM) risk score.
METHODS
This single-center study evaluated 460 kidney transplant patients on tacrolimus-mycophenolate-prednisone from 2010-2021. BKV status was classified at 6-months post-transplant as "BKV" or "no BKV" in landmark analysis. Primary outcome was T-cell mediated rejection (TCMR). Secondary outcomes included all-cause graft failure (ACGF), death-censored graft failure (DCGF), de novo donor specific antibody (dnDSA), and antibody-mediated rejection (ABMR). Predictors of outcomes were assessed in Cox proportional hazards models including BKV status and alloimmune risk defined by recipient age and molecular mismatch (RAMM) groups.
RESULTS
At 6-months post-transplant, 72 patients had BKV and 388 had no BKV. TCMR occurred in 86 recipients, including 27.8% with BKV and 17% with no BKV (p = .05). TCMR risk was increased in recipients with BKV (HR 1.90, (95% CI 1.14, 3.17); p = .01) and high vs. low-risk RAMM group risk (HR 2.26 (95% CI 1.02, 4.98); p = .02) in multivariable analyses; but not HLA serological MM in sensitivity analysis. Recipients with BKV experienced increased dnDSA in univariable analysis, and there was no association with ABMR, DCGF, or ACGF.
CONCLUSIONS
Recipients with BKV had increased risk of TCMR independent of induction immunosuppression and conventional alloimmune risk measures. Recipients with high-risk RAMM experienced increased TCMR risk. Future studies on optimizing immunosuppression for BKV should explore nuanced risk stratification and may consider novel measures of alloimmune risk.
Topics: Humans; Kidney Transplantation; BK Virus; Female; Male; Polyomavirus Infections; Middle Aged; Graft Survival; Graft Rejection; Follow-Up Studies; Tumor Virus Infections; Viremia; Prognosis; Risk Factors; Kidney Function Tests; Glomerular Filtration Rate; Adult; Postoperative Complications; Immunosuppressive Agents; Retrospective Studies; Kidney Failure, Chronic; Kidney Diseases; Transplant Recipients
PubMed: 38722085
DOI: 10.1111/ctr.15329 -
BMC Infectious Diseases May 2024Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne viral disease caused by the SFTS virus (Dabie bandavirus), which has become a substantial...
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne viral disease caused by the SFTS virus (Dabie bandavirus), which has become a substantial risk to public health. No specific treatment is available now, that calls for an effective vaccine. Given this, we aimed to develop a multi-epitope DNA vaccine through the help of bioinformatics. The final DNA vaccine was inserted into a special plasmid vector pVAX1, consisting of CD8 T cell epitopes, CD4 T cell epitopes and B cell epitopes (six epitopes each) screened from four genome-encoded proteins--nuclear protein (NP), glycoprotein (GP), RNA-dependent RNA polymerase (RdRp), as well as nonstructural protein (NSs). To ascertain if the predicted structure would be stable and successful in preventing infection, an immunological simulation was run on it. In conclusion, we designed a multi-epitope DNA vaccine that is expected to be effective against Dabie bandavirus, but in vivo trials are needed to verify this claim.
Topics: Vaccines, DNA; Phlebovirus; Severe Fever with Thrombocytopenia Syndrome; Epitopes, T-Lymphocyte; Viral Vaccines; Humans; Computer-Aided Design; Epitopes, B-Lymphocyte; Animals; Computational Biology
PubMed: 38714948
DOI: 10.1186/s12879-024-09361-6 -
Microbiology Spectrum Jun 2024Transplant patients are at risk of infections due to long-term immunosuppression contributing to morbidity and mortality in this population. Post-transplant testing...
Transplant patients are at risk of infections due to long-term immunosuppression contributing to morbidity and mortality in this population. Post-transplant testing guidelines were established to monitor and guide therapeutic interventions in transplant recipients. We hypothesize that there are gaps in adherence to the recommended frequency of laboratory testing in post-transplant patients. We analyzed national reference laboratory data to compare viral post-transplant infection (PTI) testing frequency with their respective published guidelines to understand patient uptake and compliance. We evaluated the ordering patterns, positivity rates, and frequency of molecular infectious disease tests (MIDTs). We included 345 patients with International Classification of Diseases (ICD)-10 codes for transplant (Z940-Z942, Z944, Z9481, Z9483, Z9484) with at least two tests (within 7 days) in January 2019 and at least one test in December 2020 to find patients in the post-transplant period. We analyzed two cohorts: kidney transplant recipients (KTRs; 40%) and non-KTR (60%) then followed them longitudinally for the study period. In KTR cohort, high-to-low proportion of ordered MIDT was blood BK virus (bBKV) followed by cytomegalovirus (CMV); in non-KTR cohort, CMV was followed by Epstein-Barr virus (EBV). KTR cohort positivity was highest for urine BK virus (uBKV; 58%) followed by EBV (46%), bBKV (40%), and CMV (31%). Non-KTR cohort positivity was highest for uBKV (64%), EBV (51%), CMV (30%), bBKV (8%), and adenovirus (7%). All patients were tested at progressively longer intervals from the date of the first post-transplant ICD-10-coded test. More than 40% of the KTR cohort were tested less frequently for EBV and bBKV, and more than 20% of the non-KTR cohort were tested for EBV less frequently than published guidelines 4 months after transplant. Despite regular testing, the results of MIDT testing for KTR and non-KTR patients in the post-transplant period are not aligned with published guidelines.IMPORTANCEGuidance for post-transplant infectious disease testing is established, however, for certain infections it allows for clinician discretion. This leads to transplant center policies developing their own testing/surveillance strategies based on their specific transplant patient population (kidney, stem cell, etc.). The Organ Procurement and Transplant Network (OPTN) has developed a strategic plan to improve and standardize the transplant process in the US to improve outcomes of living donors and recipients. Publishing national reference lab data on the testing frequency and its alignment with the recommended guidelines for post-transplant infectious diseases can inform patient uptake and compliance for these strategic OPTN efforts.
Topics: Humans; Kidney Transplantation; Male; Middle Aged; Female; Transplant Recipients; Adult; Aged; BK Virus; Virus Diseases; Immunosuppression Therapy; Cytomegalovirus; Herpesvirus 4, Human; Retrospective Studies
PubMed: 38709030
DOI: 10.1128/spectrum.03575-23 -
Nature Communications May 2024Whole virus-based inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide have been critical to the COVID-19 pandemic response. Although these vaccines are...
Whole virus-based inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide have been critical to the COVID-19 pandemic response. Although these vaccines are protective against homologous coronavirus infection, the emergence of novel variants and the presence of large zoonotic reservoirs harboring novel heterologous coronaviruses provide significant opportunities for vaccine breakthrough, which raises the risk of adverse outcomes like vaccine-associated enhanced respiratory disease. Here, we use a female mouse model of coronavirus disease to evaluate inactivated vaccine performance against either homologous challenge with SARS-CoV-2 or heterologous challenge with a bat-derived coronavirus that represents a potential emerging disease threat. We show that inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide can cause enhanced respiratory disease during heterologous infection, while use of an alternative adjuvant does not drive disease and promotes heterologous viral clearance. In this work, we highlight the impact of adjuvant selection on inactivated vaccine safety and efficacy against heterologous coronavirus infection.
Topics: Animals; COVID-19 Vaccines; Female; COVID-19; Mice; Vaccines, Inactivated; SARS-CoV-2; Aluminum Hydroxide; Disease Models, Animal; Adjuvants, Immunologic; Adjuvants, Vaccine; Antibodies, Viral; Mice, Inbred BALB C; Humans; Severe acute respiratory syndrome-related coronavirus
PubMed: 38702297
DOI: 10.1038/s41467-024-47450-x