Infectious disease
Abstract
Targeted metagenomic sequencing is an emerging strategy to survey disease- specific microbiome biomarkers for clinical diagnosis and prognosis. However, this approach often yields inconsistent or conflicting results due to inadequate study power and sequencing bias. We introduce Taxa4Meta, a bioinformatics pipeline explicitly designed to compensate for technical and demographic bias. We designed and validated Taxa4Meta for accurate taxonomic profiling of 16S rRNA amplicon data acquired from different sequencing strategies. Taxa4Meta offers significant potential in identifying clinical dysbiotic features that can reliably predict human disease, validated comprehensively via re-analysis of individual patient 16S datasets. We leveraged the power of Taxa4Meta's pan-microbiome profiling to generate 16S-based classifiers that exhibited excellent utility for stratification of diarrheal patients with Clostridioides difficile infection, irritable bowel syndrome or inflammatory bowel diseases, which represent common misdiagnoses and pose significant challenges for clinical management. We believe that Taxa4Meta represents a new "best practices" approach to individual microbiome surveys that can be used to define gut dysbiosis at a population-scale level.
Authors
Qinglong Wu, Shyam Badu, Sik Yu So, Todd J. Treangen, Tor C. Savidge
Abstract
Virophagy, the selective autophagosomal engulfment and lysosomal degradation of viral components, is crucial for neuronal cell survival and antiviral immunity. However, the mechanisms leading to viral antigen recognition and capture by autophagic machinery remain poorly understood. Here, we identified cyclin-dependent kinase-like 5 (CDKL5), known to function in neurodevelopment, as an essential regulator of virophagy. Loss of function mutations in CDKL5 are associated with a severe neurodevelopmental encephalopathy. We found deletion of CDKL5 or expression of a clinically-relevant pathogenic mutant of CDKL5 reduced virophagy of Sindbis virus (SINV), a neurotropic RNA virus, and increased intracellular accumulation of SINV capsid protein aggregates and cellular cytotoxicity. CDKL5 knockout mice displayed increased viral antigen accumulation and neuronal cell death after SINV infection and enhanced lethality after infection with several neurotropic viruses. Mechanistic studies demonstrated that CDKL5 directly binds the canonical selective autophagy receptor p62 and phosphorylates p62 at T269/S272 to promote its interaction with viral capsid aggregates. We found that CDKL5-mediated phosphorylation of p62 facilitated the formation of large p62 inclusion bodies that captured viral capsids to initiate capsid targeting to autophagic machinery. Overall, these findings identify a cell-autonomous innate immune mechanism for autophagy activation to clear intracellular toxic viral protein aggregates during infection.
Authors
Josephine W. Thinwa, Zhongju Zou, Emily Parks, Salwa Sebti, Kelvin K. Hui, Yongjie Wei, Mohammad Goodarzi, Vibha Singh, Greg Urquhart, Jenna L. Jewell, Julie K. Pfeiffer, Beth Levine, Tiffany A. Reese, Michael U. Shiloh
Abstract
The endothelium plays a critical role in the host response to infection, and has been a focus of investigation in sepsis. While it is appreciated that intravascular thrombus formation, severe inflammation, and loss of endothelial integrity impair tissue oxygenation during sepsis, the precise molecular mechanisms that lead to endothelial injury remain poorly understood. We demonstrate herein that endothelial ADAM10 is essential for the pathogenesis of Staphylococcus aureus sepsis, contributing to a-toxin (Hla)-mediated microvascular thrombus formation and lethality. As ADAM10 is essential for endothelial development and homeostasis, we examined whether other major human sepsis pathogens also rely on ADAM10-dependent pathways in pathogenesis. Mice harboring an endothelial-specific knockout of ADAM10 are protected against lethal Pseudomonas aeruginosa and Streptococcus pneumoniae sepsis, yet remain fully susceptible to Group B Streptococci and Candida albicans sepsis. These studies illustrate a previously unknown role for ADAM10 in sepsis-associated endothelial injury, and suggest that understanding pathogen-specific divergent host pathways in sepsis may enable more precise targeting of disease.
Authors
Danielle N. Alfano, Mark J. Miller, Juliane Bubeck Wardenburg
Abstract
The development of highly effective malaria vaccines and improvement of drug-treatment protocols to boost antiparasitic immunity are critical for malaria elimination. However, the rapid establishment of parasite-specific immune regulatory networks following exposure to malaria parasites hampers these efforts. Here, we identified stimulator of interferon genes (STING) as a critical mediator of type I interferon production by CD4+ T cells during blood-stage Plasmodium falciparum infection. The activation of STING in CD4+ T cells by cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) stimulated IFNB gene transcription, which promoted development of IL-10– and IFN-γ–coproducing CD4+ T (type I regulatory [Tr1]) cells. The critical role for type I IFN signaling for Tr1 cell development was confirmed in vivo using a preclinical malaria model. CD4+ T cell sensitivity to STING phosphorylation was increased in healthy volunteers following P. falciparum infection, particularly in Tr1 cells. These findings identified STING expressed by CD4+ T cells as an important mediator of type I IFN production and Tr1 cell development and activation during malaria.
Authors
Yulin Wang, Fabian De Labastida Rivera, Chelsea L. Edwards, Teija C.M. Frame, Jessica A. Engel, Luzia Bukali, Jinrui Na, Susanna S. Ng, Dillon Corvino, Marcela Montes de Oca, Patrick T. Bunn, Megan S.F. Soon, Dean Andrew, Jessica R. Loughland, Jia Zhang, Fiona H. Amante, Bridget E. Barber, James S. McCarthy, J. Alejandro Lopez, Michelle J. Boyle, Christian R. Engwerda
Abstract
Authors
Prashant Rai, Martin Sharpe, Charan K. Ganta, Paul J. Baker, Katrin D. Mayer-Barber, Brian E. Fee, Gregory A. Taylor, Michael B. Fessler
Abstract
Authors
Christoph Strumann, Otavio T. Ranzani, Jeanne Moor, Reinhard Berner, Nicole Toepfner, Cho-Ming Chao, Matthias B. Moor
Abstract
Biofilms are structured communities of microbial cells embedded in a self-produced matrix of extracellular polymeric substances. Biofilms are associated with many health issues in humans, including chronic wound infections and tooth decay. Current antimicrobials are often incapable of disrupting the polymeric biofilm matrix and reaching the bacteria within. Alternative approaches are needed. Here, we describe a unique structure of dextran coated gold in a gold cage nanoparticle that enables photoacoustic and photothermal properties for biofilm detection and treatment. Activation of these nanoparticles with a near infrared laser can selectively detect and kill biofilm bacteria with precise spatial control and in a short timeframe. We observe a strong biocidal effect against both Streptococcus mutans and Staphylococcus aureus biofilms in mouse models of oral plaque and wound infections respectively. These effects were over 100 times greater than that seen with chlorhexidine, a conventional antimicrobial agent. Moreover, this approach did not adversely affect surrounding tissues. We conclude that photothermal ablation using theranostic nanoparticles is a rapid, precise, and non-toxic method to detect and treat biofilm-associated infections.
Authors
Maryam Hajfathalian, Christiaan R. de Vries, Jessica C. Hsu, Ahmad Amirshaghaghi, Yuxi C. Dong, Zhi Ren, Yuan Liu, Yue Huang, Yong Li, Simon A.B. Knight, Pallavi Jonnalagadda, Aimen Zlitni, Elizabeth A. Grice, Paul L. Bollyky, Hyun Koo, David P. Cormode
Abstract
Multisystem inflammatory syndrome in children (MIS-C) is a rare but life-threatening hyperinflammatory condition induced by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes pediatric COVID-19 (pCOVID-19). The relationship of the systemic tissue injury to the pathophysiology of MIS-C is poorly defined. We leveraged the high sensitivity of epigenomic analyses of plasma cell-free DNA (cfDNA) and plasma cytokine measurements to identify the spectrum of tissue injury and glean mechanistic insights. Compared to pediatric healthy controls (pHC) and pCOVID-19, MIS-C patients had higher levels of cfDNA primarily derived from innate immune cells, megakaryocyte-erythroid precursor cells, and non-hematopoietic tissues such as hepatocytes, cardiac myocytes, and kidney cells. Non-hematopoietic tissue cfDNA levels demonstrated significant inter-individual variability, consistent with the heterogenous clinical presentation of MIS-C. In contrast, adaptive immune cell-derived cfDNA levels were comparable in MIS-C and pCOVID-19 patients. Indeed, the innate immune cells cfDNA in MIS-C correlated with levels of innate immune inflammatory cytokines and non-hematopoietic tissue-derived cfDNA, suggesting a primarily innate immunity-mediated response to account for multi-system pathology. These data provide insight into the pathogenesis of MIS-C and support the value of cfDNA as a sensitive biomarker to map tissue injury in MIS-C and likely other multi-organ inflammatory conditions.
Authors
Temesgen E. Andargie, Katerina Roznik, Neelam R. Redekar, Tom Hill, Weiqiang Zhou, Zainab Apalara, Hyesik Kong, Oren Gordon, Rohan Meda, Woojin Park, Trevor S. Johnston, Yi Wang, Sheila Brady, Hongkai Ji, Jack A. Yanovski, Moon Kyoo Jang, Clarence M. Lee, Andrew H. Karaba, Andrea L. Cox, Sean Agbor-Enoh
Abstract
BACKGROUND. The biology of Plasmodium vivax is markedly different to that of P. falciparum; how this shapes the immune response to infection remains unclear. To address this shortfall, we inoculated human volunteers with a clonal field isolate of P. vivax and tracked their response through infection and convalescence. METHODS. Participants were injected intravenously with blood-stage parasites and infection dynamics were tracked in real-time by quantitative PCR. Whole blood samples were used for high dimensional protein analysis, RNA-sequencing and Cytometry by Time Of Flight (CyTOF), and temporal changes in the host response to P. vivax were quantified by linear regression. Comparative analyses with P. falciparum were then undertaken using analogous datasets derived from prior controlled human malaria infection studies. RESULTS.P. vivax rapidly induced a type I inflammatory response that coincided with hallmark features of clinical malaria. This acute phase response shared remarkable overlap with that induced by P. falciparum but was significantly elevated (at RNA and protein level) leading to an increased incidence of pyrexia. In contrast, T cell activation and terminal differentiation was significantly increased in volunteers infected with P. falciparum. Heterogeneous CD4+ T cells were found to dominate this adaptive response and phenotypic analysis revealed unexpected features normally associated with cytotoxicity and autoinflammatory disease. CONCLUSION.P. vivax triggers increased systemic interferon signaling (cf P. falciparum), which likely explains its reduced pyrogenic threshold. In contrast, P. falciparum drives T cell activation far in excess of P. vivax, which may partially explain why falciparum malaria more frequently causes severe disease. TRIAL REGISTRATION. ClinicalTrials.gov NCT03797989 FUNDING. Supported by the European Union's Horizon 2020 Research and Innovation programme, the Wellcome Trust and the Royal Society.
Authors
Florian A. Bach, Diana Muñoz Sandoval, Michalina Mazurczyk, Yrene Themistocleous, Thomas A. Rawlinson, Adam C. Harding, Alison Kemp, Sarah E. Silk, Jordan R. Barrett, Nick J. Edwards, Alasdair C. Ivens, Julian C. Rayner, Angela M. Minassian, Giorgio Napolitani, Simon J. Draper, Philip J. Spence
Abstract
BACKGROUND. Autoimmune diseases often have strong genetic associations with specific HLA-DR alleles. The synovial lesion in chronic inflammatory forms of arthritis shows marked up-regulation of HLA-DR molecules, including in post-infectious Lyme arthritis (LA). However, the identity of HLA-DR-presented peptides and therefore, the reasons for these associations have frequently remained elusive. METHODS. Using immunopeptidomics to detect HLA-DR-presented peptides from synovial tissue, we identified T cell epitopes from 3 extracellular matrix (ECM) proteins in patients with post-infectious LA, identified potential Borreliella burgdorferi (Bb)-mimic epitopes, and characterized T and B cell responses to these peptides or proteins. RESULTS. Of 24 post-infectious LA patients, 58% had CD4+ T cell responses to ≥1 epitope of 3 ECM proteins, fibronectin-1, laminin B2, and/or collagen Vα1, and 17% of 52 such patients had antibody responses to >1 of these proteins. Patients with autoreactive T cell responses had significantly increased frequencies of HLA-DRB1*04 or DRB1*1501 alleles and more prolonged arthritis. When tetramer reagents were loaded with ECM or corresponding Bb-mimic peptides, binding was only with the autoreactive T cells. A high percentage of ECM-autoreactive CD4+ T cells in synovial fluid were T-bet-expressing Th1 cells, a small percentage were RoRyt-expressing Th17 cells, and a minimal percentage were FoxP3-expressing Treg cells. CONCLUSION. Autoreactive, proinflammatory CD4+ T cells and autoantibodies develop to ECM proteins in a subgroup of post-infectious LA patients who have specific HLA-DR alleles. Rather than the traditional molecular mimicry model, we propose that epitope spreading provides the best explanation for this example of infection-induced autoimmunity.
Authors
Korawit Kanjana, Klemen Strle, Robert B. Lochhead, Annalisa Pianta, Laura M. Mateyka, Qi Wang, Sheila L. Arvikar, David E. Kling, Cameron A. DeAngelo, Lucy Curham, Alan G. Barbour, Catherine E. Costello, James J. Moon, Allen C. Steere
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