Virologies
Abstract
Respiratory syncytial virus (RSV) infection causes significant morbidity and mortality in infants, immunocompromised, and older individuals. There is an urgent need for effective antivirals and vaccines for high risk individuals. We used two complementary in vivo models to analyze RSV-associated human lung pathology and human immune correlates of protection. RSV infection resulted in widespread human lung epithelial damage, a pro-inflammatory innate immune response, and elicited a natural adaptive human immune response that conferred protective immunity. We demonstrated a key role for human T cells in controlling RSV infection. Specifically, primed human CD8+ T cells or CD4+ T cells effectively and independently control RSV replication in human lung tissue in the absence of an RSV-specific antibody response. These preclinical data support the development of RSV vaccines which also elicit effective T cell responses to improve RSV vaccine efficacy.
Authors
Chandrav De, Raymond J. Pickles, Wenbo Yao, Baolin Liao, Allison E. Boone, Mingyu Choi, Diana M. Battaglia, Frederic B. Askin, Jason K. Whitmire, Guido Silvestri, J. Victor Garcia, Angela Wahl
Abstract
Hepatitis delta virus (HDV), a satellite virus of HBV, is regarded as the most severe type of hepatitis virus because of the substantial morbidity and mortality. The IFN system is the first line of defense against viral infections and an essential element of antiviral immunity; however, the role of the hepatic IFN system in controlling HBV-HDV infection remains poorly understood. Herein, we showed that HDV infection of human hepatocytes induced a potent and persistent activation of the IFN system whereas HBV was inert in triggering hepatic antiviral response. Moreover, we demonstrated that HDV-induced constitutive activation of the hepatic IFN system resulted in a potent suppression of HBV while modestly inhibiting HDV. Thus, these pathogens are equipped with distinctive immunogenicity and varying sensitivity to the antiviral effectors of IFN, leading to the establishment of a paradoxical mode of viral interference wherein HDV, the superinfectant, outcompetes HBV, the primary pathogen. Furthermore, our study revealed that HDV-induced constitutive IFN system activation led to a state of IFN refractoriness, rendering therapeutic IFNs ineffective. The present study provides potentially novel insights into the role of the hepatic IFN system in regulating HBV-HDV infection dynamics and its therapeutic implications through elucidating the molecular basis underlying the inefficacy of IFN-based antiviral strategies against HBV-HDV infection.
Authors
Takeshi Chida, Yuji Ishida, Sho Morioka, Go Sugahara, Christine Han, Bill Lam, Chihiro Yamasaki, Remi Sugahara, Meng Li, Yasuhito Tanaka, T. Jake Liang, Chise Tateno, Takeshi Saito
Abstract
Human T lymphotropic virus type 1–assoicated (HTLV-1–associated) myelopathy/tropical spastic paraparesis (HAM/TSP) is a neuroinflammatory disease caused by the persistent proliferation of HTLV-1–infected T cells. Here, we performed a T cell receptor (TCR) repertoire analysis focused on HTLV-1–infected cells to identify and track the infected T cell clones that are preserved in patients with HAM/TSP and migrate to the CNS. TCRβ repertoire analysis revealed higher clonal expansion in HTLV-1–infected cells compared with noninfected cells from patients with HAM/TSP and asymptomatic carriers (ACs). TCR clonality in HTLV-1–infected cells was similar in patients with HAM/TSP and ACs. Longitudinal analysis showed that the TCR repertoire signature in HTLV-1–infected cells remained stable, and highly expanded infected clones were preserved within each patient with HAM/TSP over years. Expanded HTLV-1–infected clones revealed different distributions between cerebrospinal fluid (CSF) and peripheral blood and were enriched in the CSF of patients with HAM/TSP. Cluster analysis showed similarity in TCRβ sequences in HTLV-1–infected cells, suggesting that they proliferate after common antigen stimulation. Our results indicate that exploring TCR repertoires of HTLV-1–infected cells can elucidate individual clonal dynamics and identify potential pathogenic clones expanded in the CNS.
Authors
Satoshi Nozuma, Eiji Matsuura, Masakazu Tanaka, Daisuke Kodama, Toshio Matsuzaki, Akiko Yoshimura, Yusuke Sakiyama, Shingo Nakahata, Kazuhiro Morishita, Yoshimi Enose-Akahata, Steven Jacoboson, Ryuji Kubota, Hiroshi Takashima
Abstract
Rhesus cytomegalovirus (RhCMV)-based vaccine vectors induce immune responses that protect ~60% of rhesus macaques (RMs) from SIVmac239 challenge. This efficacy depends on induction of effector memory (EM)-biased CD8+ T cells recognizing SIV peptides presented by major histocompatibility complex (MHC)-E instead of MHC-Ia. The phenotype, durability, and efficacy of RhCMV/SIV-elicited cellular immune responses were maintained when vector spread was severely reduced by deleting the anti-host intrinsic immunity factor pp71. Here, we examined the impact of an even more stringent attenuation strategy on vector-induced immune protection against SIV. Fusion of the FK506-binding protein (FKBP) degradation domain to Rh108, the orthologue of the essential human CMV (HCMV) late gene transcription factor UL79, generated RhCMV/SIV vectors that conditionally replicate only when the FK506-analog Shield-1 is present. Despite lacking in vivo dissemination and reduced innate and B cell responses to vaccination, Rh108-deficient 68-1 RhCMV/SIV vectors elicited high frequency, durable, EM-biased, SIV-specific T cell responses in RhCMV-seropositive RM at doses of ≥106 PFU. Strikingly, elicited CD8+ T cells exclusively targeted MHC-Ia-restricted epitopes and failed to protect against SIVmac239 challenge. Thus, Rh108-dependent late gene expression is required for both induction of MHC-E-restricted T cells and protection against SIV.
Authors
Scott G. Hansen, Jennie L. Womack, Wilma Perez, Kimberli A. Schmidt, Emily Marshall, Ravi F. Iyer, Hillary Cleveland-Rubeor, Claire E. Otero, Husam Taher, Nathan H. Vande Burgt, Richard Barfield, Kurt T. Randall, David Morrow, Colette M. Hughes, Andrea N. Selseth, Roxanne M. Gilbride, Julia C. Ford, Patrizia Caposio, Alice Tarantal, Cliburn Chan, Daniel Malouli, Peter A. Barry, Sallie R. Permar, Louis J. Picker, Klaus Frueh
Abstract
Type 1 diabetes (T1D) is an autoimmune disease resulting in pancreatic β-cell destruction. Coxsackievirus B3 (CVB3) infection and melanoma differentiation-associated protein 5 (MDA5)-dependent antiviral responses are linked with T1D development. Mutations within IFIH1, encoding for MDA5, are correlated with T1D susceptibility, but how these mutations contribute to T1D remains unclear. Utilizing non-obese diabetic (NOD) mice lacking Ifih1 expression (KO) or containing an in-frame deletion within the ATPase site of the helicase 1 domain of MDA5 (ΔHel1), we tested the hypothesis that partial or complete loss-of-function mutations in MDA5 would delay T1D by impairing proinflammatory pancreatic macrophage and T cell responses. Spontaneous T1D developed in female NOD and KO mice similarly, but was significantly delayed in ΔHel1 mice that may be partly due to a concomitant increase in myeloid-derived suppressor cells. Interestingly, KO male mice had increased spontaneous T1D compared to NOD mice. While NOD and KO mice developed CVB3-accelerated T1D, ΔHel1 mice were protected partly due to decreased type I interferons, pancreatic-infiltrating TNF+ macrophages, IFN-γ+ CD4+ T cells, and perforin+ CD8+ T cells. Furthermore, ΔHel1 MDA5 protein had reduced ATP hydrolysis compared to wild-type MDA5. Our results suggest dampened MDA5 function delays T1D, yet loss of MDA5 promotes T1D.
Authors
Samuel I. Blum, Jared P. Taylor, Jessie M. Barra, Ashley R. Burg, Qiao Shang, Shihong Qiu, Oren Shechter, Aleah R. Hayes, Todd J. Green, Aron M. Geurts, Yi-Guang Chen, Hubert M. Tse
Abstract
In spite of the rollout of oral pre-exposure prophylaxis (PrEP), the rate of new HIV infections remains a major health crisis. In the United States, new infections occur predominantly in men having sex with men (MSM) in rural settings where access to PrEP can be limited. As an alternative congruent with MSM sexual behavior, we have optimized and tested tenofovir (TFV) and analog-based iso-osmolar and hypo-osmolar (HOsm) rectal douches for efficacy against rectal simian/human immunodeficiency virus (SHIV) infection of macaques. Single TFV HOsm high-dose douches achieved peak plasma TFV levels similar to daily oral PrEP, while other formulations yielded lower concentrations. Rectal tissue TFV-diphosphate (TFV-DP) concentrations at the portal of virus entry, however, were markedly higher after HOsm douching than daily oral PrEP. Repeated douches led to significantly higher plasma TFV and higher TFV-DP concentrations in rectal tissue at 24 hours compared with single douches, without detectable mucosal or systemic toxicity. Using stringent repeated intrarectal SHIV exposures, single HOsm high-dose douches delivered greater protection from virus acquisition for more than 24 hours compared with oral PrEP. Our results demonstrate a rapid delivery of protective TFV doses to the rectal portal of virus entry as a potential low-cost and safe PrEP alternative.
Authors
Peng Xiao, Sanjeev Gumber, Mark A. Marzinke, Thuy Hoang, Rohan Myers, Abhijit A. Date, Justin Hanes, Laura M. Ensign, Lin Wang, Lisa C. Rohan, Richard Cone, Edward J. Fuchs, Craig W. Hendrix, Francois Villinger
Abstract
Subtype B HIV-1 reservoirs have been intensively investigated, but reservoirs in other subtypes and how they respond to antiretroviral therapy (ART) is substantially less established. To characterize subtype C HIV-1 reservoirs, we implemented postmortem frozen, as well as formalin fixed paraffin embedded (FFPE) tissue sampling of central nervous system (CNS) and peripheral tissues. HIV-1 LTR, gag, envelope (env) DNA and RNA was quantified using genomic DNA and RNA extracted from frozen tissues. RNAscope was used to localize subtype C HIV-1 DNA and RNA in FFPE tissue. Despite uniform viral load suppression in our cohort, PCR results showed that subtype C HIV-1 proviral copies vary both in magnitude and tissue distribution, with detection primarily in secondary lymphoid tissues. Interestingly, the appendix harbored proviruses in all subjects. Unlike subtype B, subtype C provirus was rarely detectable in the CNS, and there was no detectable HIV-1 RNA. HIV-1 RNA was detected in peripheral lymphoid tissues of 6 out of 8 ART-suppressed cases. In addition to active HIV-1 expression in lymphoid tissues, RNAscope revealed HIV RNA detection in CD4-expressing cells in the appendix, suggesting that this tissue was a previously unreported potential treatment-resistant reservoir for subtype C HIV-1.
Authors
Zhou Liu, Peter Julius, Guobin Kang, John T. West, Charles Wood
Abstract
Diabetes mellitus (DM) is highly comorbid with severe dengue diseases; however, the underlying mechanisms are unclear. DM patients display a 1.61-fold increased risk of developing dengue hemorrhagic fever. In search of host factors involved in DENV infection, this study utilizes high glucose (HG) treatment and shows that HG increases viral protein expression and virion release but has no effects on the early stages of viral infection. Following HG stimulation, DEN-Luc-transfected assay and cellular replicon-based assay display increased viral translation, while using the glucose uptake inhibitor phloretin blocks this effect. HG treatment increases the translational factor poly(A)-binding protein (PABP) in a glucose transporter-associated PI3K/AKT-regulated manner. Silencing PABP significantly decreases HG-prompted virion production. HG enhances the formation of the PABP-eIF4G complex, which is regulated by protein-disulfide isomerase. Hyperglycemia increases PABP expression, mortality, viral protein expression, and viral loads in streptozotocin-induced DM mice. Overall, hyperglycemic stress facilitates DENV infection by strengthening PABP-mediated viral translation.
Authors
Ting-Jing Shen, Chia-Ling Chen, Tsung-Ting Tsai, Ming-Kai Jhan, Chyi-Huey Bai, Yu-Chun Yen, Ching-Wen Tsai, Cheng-Yi Lee, Po-Chun Tseng, Chia-Yi Yu, Chiou-Feng Lin
Abstract
Celiac disease is an immune-mediated intestinal disorder that results from loss of oral tolerance (LOT) to dietary gluten. Reovirus elicits inflammatory Th1 cells and suppresses Treg responses to dietary antigen in a strain-dependent manner. Strain type 1 Lang (T1L) breaks oral tolerance, while strain type 3 Dearing reassortant virus (T3D-RV) does not. We discovered that intestinal infection by T1L in mice leads to the recruitment and activation of NK cells in mesenteric lymph nodes (MLNs) in a type I IFN–dependent manner. Once activated following infection, NK cells produce type II IFN and contribute to IFN-stimulated gene expression in the MLNs, which in turn induces inflammatory DC and T cell responses. Immune depletion of NK cells impairs T1L-induced LOT to newly introduced food antigen. These studies indicate that NK cells modulate the response to dietary antigen in the presence of a viral infection.
Authors
Pamela H. Brigleb, Elaine Kouame, Kay L. Fiske, Gwen M. Taylor, Kelly Urbanek, Luzmariel Medina Sanchez, Reinhard Hinterleitner, Bana Jabri, Terence S. Dermody
Abstract
Long COVID, a type of Post-Acute Sequelae of SARS-CoV-2 (PASC), has been associated with sustained elevated levels of immune activation and inflammation. However, the mechanisms that drive this inflammation remain unknown. Inflammation during acute Coronavirus Disease 2019 could be exacerbated by microbial translocation (from gut and/or lung) to blood. Whether microbial translocation contributes to inflammation during PASC is unknown. We did not observe a significant elevation in plasma markers of bacterial translocation during PASC. However, we observed higher levels of fungal translocation – measured as β-glucan, a fungal cell wall polysaccharide – in the plasma of individuals experiencing PASC compared to those without PASC or SARS-CoV-2 negative controls. The higher β-glucan correlated with higher inflammation and elevated levels of host metabolites involved in activating N-Methyl-D-aspartate receptors (such as metabolites within the tryptophan catabolism pathway) with established neuro-toxic properties. Mechanistically, β-glucan can directly induce inflammation by binding to myeloid cells (via Dectin-1) and activating Syk/NF-κB signaling. Using a Dectin-1/NF-κB reporter model, we found that plasma from individuals experiencing PASC induced higher NF-κB signaling compared to plasma from negative controls. This higher NF-κB signaling was abrogated by Piceatannol (Syk inhibitor). These data suggest a potential targetable mechanism linking fungal translocation and inflammation during PASC.
Authors
Leila B. Giron, Michael J. Peluso, Jianyi Ding, Grace Kenny, Netanel F. Zilberstein, Jane Koshy, Kai Ying Hong, Heather Rasmussen, Gregory E. Miller, Faraz Bishehsari, Robert A. Balk, James N. Moy, Rebecca Hoh, Scott Lu, Aaron R. Goldman, Hsin-Yao Tang, Brandon C. Yee, Ahmed Chenna, John W. Winslow, Christos J. Petropoulos, J. Daniel Kelly, Haimanot Wasse, Jeffrey N. Martin, Qin Liu, Ali Keshavarzian, Alan Landay, Steven G. Deeks, Timothy J. Henrich, Mohamed Abdel-Mohsen
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