Infectious disease
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
Pseudomonas aeruginosa is one of the most common nosocomial infections worldwide, and frequently causes ventilator-associated acute pneumonia in immunocompromised patients. Abundant neutrophil extracellular traps (NETs) contribute to acute lung injury, thereby aggravating ventilator-induced lung damage. While pattern recognition receptors (PRRs) TLR4 and TLR5 are required for host defense against P. aeruginosa invasion, the PRR responsible for P. aeruginosa-induced NET formation, proinflammatory cytokine release, and acute lung injury remains unclear. We found that myeloid C-type lectin domain family 5 member A (CLEC5A) interacts with lipopolysaccharides of P. aeruginosa, and is responsible for P. aeruginosa-induced NET formation and lung inflammation. P. aeruginosa activates CLEC5A to induce caspase-1-dependent NET formation, but it neither causes gasdermin D (GSDMD) cleavage nor contributes to P. aeruginosa-induced neutrophil death. Blockade of CLEC5A attenuates P. aeruginosa-induced NETosis and lung injury, and simultaneous administration of anti-CLEC5A mAb with ciprofloxacin increases survival rate and decreases collagen deposition in the lungs of mice challenged with a lethal dose of P. aeruginosa. Thus, CLEC5A is a promising therapeutic target to reduce ventilator-associated lung injury and fibrosis in P. aeruginosa-induced pneumonia.
Authors
Pei-Shan Sung, Yu-Chun Peng, Shao-Ping Yang, Cheng-Hsun Chiu, Shie-Liang Hsieh
Abstract
BACKGROUND. Increased reinfection rates with SARS-CoV-2 have recently been reported, with some locations basing reinfection on a second positive PCR test at least 90 days after initial infection. In this study, we used the Johns Hopkins SARS-CoV-2 genomic surveillance data to evaluate the frequency of sequencing validated, confirmed and inferred reinfections between March 2020 and July 2022. METHODS. Patients who had two or more positive SARS-CoV-2 tests in our system with samples sequenced as a part of our surveillance efforts were identified as the cohort for our study. SARS-CoV-2 genomes of patients’ initial and later samples were compared. RESULTS. A total of 755 patients (920 samples) had a positive test at least 90 days after the initial test with a median time between tests of 377 days. Sequencing was attempted on 231 samples and was successful in 127. Successful sequencing spiked during the Omicron surge and showed higher median days from initial infection compared to failed sequences. A total of 122 (98%) patients showed evidence of reinfection, 45 of which had sequence validated reinfection and 77 had inferred reinfections (later sequence showed a clade that was not circulating when the patient was initially infected). Of 45 sequence validated reinfections, 43 (96%) were caused by the Omicron variant, 41 (91%) were symptomatic, 32 (71%) were vaccinated prior to the second infection, 6 (13%) were Immunosuppressed, and only 2 (4%) were hospitalized. CONCLUSIONS. Sequence validated reinfections increased with the Omicron variant but were generally associated with mild infections.
Authors
C. Paul Morris, Raghda E. Eldesouki, Amary Fall, David C. Gaston, Julie M. Norton, Nicholas D. Gallagher, Chun Huai Luo, Omar Abdullah, Eili Y. Klein, Heba H. Mostafa
Abstract
Pneumocystis is the most common fungal pulmonary infection in children under 5. In children with primary immunodeficiency, Pneumocystis often presents at 3-6 months that coincides with the nadir of maternal IgG and where IgM is the dominant immunoglobulin isotype. Since B cells are the dominant antigen-presenting cells for Pneumocystis, we hypothesized the presence of fungal specific IgMs in human and mice and that these IgM specificities would predict T cell antigens. We detected fungal specific IgMs in human and mouse serum and utilized immunoprecipitation to determine if any antigens were similar across donors. We then assessed T cell responses to these antigens. We found anti-Pneumocystis IgM in wild-type mice as well as Aicda-/- mice and in human cord blood. Immunoprecipitation of Pneumocystis murina with human cord blood identified shared antigens among these donors. Using class II MHC binding prediction, we designed peptides with these antigens and identified robust peptide specific lung T cell responses after P. murina infection. After mice were immunized with two of the antigens, adoptive transfer of vaccine elicited CD4+ T cells showed effector activity suggesting that these antigens contain protective Pneumocystis epitopes. These data support the notion that germline encoded IgM B-cell receptors are critical in antigen presentation and T cell priming in early Pneumocystis infection.
Authors
Kristin Noell, Guixiang Dai, Dora Pungan, Anna Ebacher, Janet E. McCombs, Samuel J. Landry, Jay K. Kolls
Abstract
Accumulation of activated natural killer (NK) cells in tissues during Ebola virus infection contributes to Ebola virus disease (EVD) pathogenesis. Yet, immunization with Ebola virus-like particles (VLPs) comprising glycoprotein (GP) and matrix protein VP40 provides rapid, NK cell-mediated protection against Ebola challenge. We used Ebola VLPs as the viral surrogates to elucidate the molecular mechanism by which Ebola virus triggers heightened NK cell activity. Incubation of human peripheral blood mononuclear cells (PBMCs) with Ebola VLPs or VP40 protein led to increased expression of IFN-γ, TNF-α, granzyme B, and perforin by CD3-CD56+ NK cells, along with concomitant increase in degranulation and cytotoxic activity of these cells. Optimal activation required accessory cells like CD14+ myeloid and CD14- cells and triggered increased secretion of numerous inflammatory cytokines. VP40-induced IFN-γ and TNF-α secretion by NK cells was dependent on IL-12 and IL-18 and suppressed by IL-10. In contrast, their increased degranulation was dependent on IL-12 with little influence of IL-18 or IL-10. These results demonstrate that Ebola VP40 stimulates NK cell functions in an IL-12 and IL-18 dependent manner that involves CD14+ and CD14- accessory cells. These novel findings may help in designing improved intervention strategies required to control viral transmission during Ebola outbreaks.
Authors
Hung Le, Paul Spearman, Stephen N. Waggoner, Karnail Singh
Abstract
Dysregulation in neutrophil extracellular trap (NET) formation and degradation may play a role in the pathogenesis and severity of COVID-19; however, its role in the pediatric manifestations of this disease including multisystem inflammatory syndrome in children (MIS-C) and chilblain-like lesions (CLL), otherwise known as “COVID toes”, remains unclear. Studying multinational cohorts, we found that, in CLL, NETs were significantly increased in serum and skin. There was geographic variability in the prevalence of increased NETs in MIS-C, in association with disease severity. MIS-C and CLL serum samples displayed decreased NET degradation ability, in association with C1q and G-actin or anti-NET antibodies, respectively, but not with genetic variants of DNases. In adult COVID-19, persistent elevations in NETs post-disease diagnosis were detected but did not occur in asymptomatic infection. COVID-19-affected adults displayed significant prevalence of impaired NET degradation, in association with anti-DNase1L3, G-actin, and specific disease manifestations, but not with genetic variants of DNases. NETs were detected in many organs of adult patients who died from COVID-19 complications. Infection with the Omicron variant was associated with decreased levels of NETs when compared to other SARS-CoV-2 strains. These data support a role for NETs in the pathogenesis and severity of COVID-19 in pediatric and adult patients.
Authors
Carmelo Carmona-Rivera, Yu Zhang, Kerry Dobbs, Tovah E. Markowitz, Clifton L. Dalgard, Andrew J. Oler, Dillon R. Claybaugh, Deborah Draper, Meng Truong, Ottavia M. Delmonte, Francesco Licciardi, Ugo Ramenghi, Nicoletta Crescenzio, Luisa Imberti, Alessandra Sottini, Virginia Quaresima, Chiara Fiorini, Valentina Discepolo, Andrea Lo Vecchio, Alfredo Guarino, Luca Pierri, Andrea Catzola, Andrea Biondi, Paolo Bonfanti, Maria Cecilia Poli Harlowe, Yazmin Espinosa, Camila A. Astudillo, Emma Rey-Jurado, Cecilia Vial, Javiera De la Cruz, Ricardo Gonzalez, Cecilia Pinera, Jacqueline W. Mays, Ashley Ng, Andrew Platt, Beth A. Drolet, John Moon, Edward W. Cowen, Heather Kenney, Sarah E. Weber, Riccardo Castagnoli, Mary K. Magliocco, Michael Austin Stack, Gina A. Montealegre Sanchez, Karyl Barron, Danielle L. Fink, Douglas B. Kuhns, Stephen M. Hewitt, Lisa M. Arkin, Daniel S. Chertow, Helen C. Su, Luigi D. Notarangelo, Mariana J. Kaplan
Abstract
The tight junction-associated protein Junctional Adhesion Molecule-A (JAM-A) is increased in sepsis although the significance of this is unknown. Here we show that septic JAM-A-/- mice have increased gut permeability. Paradoxically, septic JAM-A-/- mice have decreased bacteremia and systemic TNF and IL-1β. Survival is improved in JAM-A-/- mice. However intestine-specific JAM-A-/- deletion does not alter mortality suggesting the mortality benefit conferred in mice lacking JAM-A is independent of the intestine. Septic JAM-A-/- mice have increased splenic CD44hiCD4+ T cells with decreased frequency of TNF+CD4+ cells and elevated frequency of IL-2+CD4+ cells. Septic JAM-A-/- mice have increased B cells in mesenteric lymph nodes with elevated serum IgA and intraepithelial lymphocyte IgA production. JAM-A-/- x RAG -/- mice have improved survival compared to RAG-/- mice and identical mortality as WT mice. Gut neutrophil infiltration is increased in JAM-A-/- mice and neutrophil phagocytosis is increased. Septic JAM-A-/- mice depleted of neutrophils lose their survival advantage. Therefore increased bacterial clearance via neutrophils and an altered systemic inflammatory response with increased opsonizing IgA produced through the adaptive immune system results in improved survival in septic JAM-A-/- mice. JAM-A may be a therapeutic target in sepsis via immune mechanisms not related to its role in permeability.
Authors
Nathan J. Klingensmith, Katherine T Fay, David A. Swift, Julia M.R. Bazzano, John D. Lyons, Ching-wen Chen, Mei Meng, Kimberly M. Ramonell, Zhe Liang, Eileen M. Burd, Charles A. Parkos, Mandy L. Ford, Craig M. Coopersmith
Abstract
BACKGROUND Prolonged symptoms after SARS-CoV-2 infection are well documented. However, which factors influence development of long-term symptoms, how symptoms vary across ethnic groups, and whether long-term symptoms correlate with biomarkers are points that remain elusive.METHODS Adult SARS-CoV-2 reverse transcription PCR–positive (RT-PCR–positive) patients were recruited at Stanford from March 2020 to February 2021. Study participants were seen for in-person visits at diagnosis and every 1–3 months for up to 1 year after diagnosis; they completed symptom surveys and underwent blood draws and nasal swab collections at each visit.RESULTS Our cohort (n = 617) ranged from asymptomatic to critical COVID-19 infections. In total, 40% of participants reported at least 1 symptom associated with COVID-19 six months after diagnosis. Median time from diagnosis to first resolution of all symptoms was 44 days; median time from diagnosis to sustained symptom resolution with no recurring symptoms for 1 month or longer was 214 days. Anti-nucleocapsid IgG level in the first week after positive RT-PCR test and history of lung disease were associated with time to sustained symptom resolution. COVID-19 disease severity, ethnicity, age, sex, and remdesivir use did not affect time to sustained symptom resolution.CONCLUSION We found that all disease severities had a similar risk of developing post–COVID-19 syndrome in an ethnically diverse population. Comorbid lung disease and lower levels of initial IgG response to SARS-CoV-2 nucleocapsid antigen were associated with longer symptom duration.TRIAL REGISTRATION ClinicalTrials.gov, NCT04373148.FUNDING NIH UL1TR003142 CTSA grant, NIH U54CA260517 grant, NIEHS R21 ES03304901, Sean N Parker Center for Allergy and Asthma Research at Stanford University, Chan Zuckerberg Biohub, Chan Zuckerberg Initiative, Sunshine Foundation, Crown Foundation, and Parker Foundation.
Authors
Xiaolin Jia, Shu Cao, Alexandra S. Lee, Monali Manohar, Sayantani B. Sindher, Neera Ahuja, Maja Artandi, Catherine A. Blish, Andra L. Blomkalns, Iris Chang, William J. Collins, Manisha Desai, Hena Naz Din, Evan Do, Andrea Fernandes, Linda N. Geng, Yael Rosenberg-Hasson, Megan Ruth Mahoney, Abigail L. Glascock, Lienna Y. Chan, Sharon Y. Fong, CLIAHUB Consortium, Chan Zuckerberg Biohub, Maira Phelps, Olivia Raeber, Stanford COVID-19 Biobank Study Group, Natasha Purington, Katharina Röltgen, Angela J. Rogers, Theo Snow, Taia T. Wang, Daniel Solis, Laura Vaughan, Michelle Verghese, Holden Maecker, Richard Wittman, Rajan Puri, Amy Kistler, Samuel Yang, Scott D. Boyd, Benjamin A. Pinsky, Sharon Chinthrajah, Kari C. Nadeau
Abstract
Older people exhibit dysregulated innate immunity to respiratory viral infections, including influenza and SARS-CoV-2, to increase morbidity and mortality. Nanoparticles are a potential practical therapeutic that could reduce exaggerated innate immune responses within the lungs during viral infection. However, such therapeutics have not been examined for effectiveness during respiratory viral infection, particular in aged hosts. Here, we employed a lethal model of influenza viral infection in vulnerable aged mice to examine the ability of biodegradable, cargo-free nanoparticles, designated ONP-302, to resolve innate immune dysfunction and improve outcomes during infection. We administered ONP-302 via intravenous injection to aged mice at day 3 post-infection when the hyperinflammatory innate immune response is already established. During infection, we found that ONP-302 treatment reduced the numbers of inflammatory monocytes within the lungs and increased their number in both the liver and spleen, without impacting viral clearance. Importantly, cargo-free nanoparticles reduced lung damage, histological lung inflammation and improved gas exchange and, ultimately, the clinical outcomes in influenza-infected aged mice. In conclusion, ONP-302 improves outcomes in influenza-infected aged mice. Thus, our study provides fundamental information concerning a practical therapeutic which, if translated clinically, could improve disease outcomes for vulnerable older patients suffering from respiratory viral infections.
Authors
William J. Kelley, Kathleen M. Wragg, Judy Chen, Tushar Murthy, Qichen Xu, Michael T. Boyne II, Joseph R. Podojil, Adam Elhofy, Daniel R. Goldstein
Abstract
Chikungunya virus (CHIKV) is a re-emerging mosquito-borne alphavirus responsible for numerous outbreaks. Chikungunya can cause debilitating acute and chronic disease. Thus, the development of a safe and effective CHIKV vaccine is an urgent global health priority.This study evaluated the effectiveness of the live-attenuated CHIKV vaccine VLA1553 against WT CHIKV infection by using passive transfer of sera from vaccinated volunteers to non-human primates (NHP) subsequently exposed to WT CHIKV and established a serological surrogate of protection. We demonstrated that human VLA1553 sera transferred to NHPs conferred complete protection from CHIKV viremia and fever after challenge with homologous WT CHIKV. In addition, serum transfer protected animals from other CHIKV associated clinical symptoms and from CHIKV persistence in tissue. Based on this passive transfer study, a 50% micro plaque reduction neutralization test titer of ≥150 was determined as a surrogate of protection which was supported by analysis of samples from a sero-epidemiological study.In conclusion, considering the unfeasibility of an efficacy trial due to the unpredictability and explosive, rapidly moving nature of chikungunya outbreaks, the definition of a surrogate of protection for VLA1553 is an important step towards vaccine licensure to reduce the medical burden caused by chikungunya.
Authors
Pierre Roques, Andrea Fritzer, Nathalie Dereuddre-Bosquet, Nina Wressnigg, Romana Hochreiter, Laetitia Bossevot, Quentin Pascal, Fabienne Guehenneux, Annegret Bitzer, Irena Corbic Ramljak, Roger Le Grand, Urban Lundberg, Andreas Meinke
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