Four ways researchers are responding to the COVID-19 outbreak
19-02-2020 – Amanda B. Keener
Dynamic imaging in patients with tuberculosis reveals heterogeneous drug exposures in pulmonary lesions
17-02-2020 – Alvaro A. Ordonez,Hechuan Wang,Gesham Magombedze,Camilo A. Ruiz-Bedoya,Shashikant Srivastava,Allen Chen,Elizabeth W. Tucker,Michael E. Urbanowski,Lisa Pieterse,E. Fabian Cardozo,Martin A. Lodge,Maunank R. Shah,Daniel P. Holt,William B. Mathews,Robert F. Dannals,Jogarao V. S. Gobburu,Charles A. Peloquin,Steven P. Rowe,Tawanda Gumbo,Vijay D. Ivaturi,Sanjay K. Jain
Tuberculosis (TB) is the leading cause of death from a single infectious agent, requiring at least 6 months of multidrug treatment to achieve cure
Effect of salt substitution on community-wide blood pressure and hypertension incidence
17-02-2020 – Antonio Bernabe-Ortiz,Víctor G. Sal y Rosas,Vilarmina Ponce-Lucero,María K. Cárdenas,Rodrigo M. Carrillo-Larco,Francisco Diez-Canseco,M. Amalia Pesantes,Katherine A. Sacksteder,Robert H. Gilman,J. Jaime Miranda
Replacement of regular salt with potassium-enriched substitutes reduces blood pressure in controlled situations, mainly among people with hypertension. We report on a population-wide implementation of this strategy in a stepped-wedge cluster randomized trial (NCT01960972). The regular salt in enrolled households was retrieved and replaced, free of charge, with a combination of 75% Na
Cl and 25% KCl. A total of 2,376 participants were enrolled in 6 villages in Tumbes, Peru. The fully adjusted intention-to-treat analysis showed an average reduction of 1.29 mm Hg (95% confidence interval (95% CI) (-2.17, -0.41)) in systolic and 0.76 mm Hg (95% CI (-1.39, -0.13)) in diastolic blood pressure. Among participants without hypertension at baseline, in the time- and cluster-adjusted model, the use of the salt substitute was associated with a 51% (95% CI (29%, 66%)) reduced risk of developing hypertension compared with the control group. In 24-h urine samples, there was no evidence of differences in sodium levels (mean difference 0.01; 95% CI (0.25, -0.23)), but potassium levels were higher at the end of the study than at baseline (mean difference 0.63; 95% CI (0.78, 0.47)). Our results support a case for implementing a pragmatic, population-wide, salt-substitution strategy for reducing blood pressure and hypertension incidence.
A controlled human Schistosoma mansoni infection model to advance novel drugs, vaccines and diagnostics
17-02-2020 – Marijke C. C. Langenberg,Marie-Astrid Hoogerwerf,Jan Pieter R. Koopman,Jacqueline J. Janse,Janneke Kos-van Oosterhoud,Carola Feijt,Simon P. Jochems,Claudia J. de Dood,Roos van Schuijlenburg,Arifa Ozir-Fazalalikhan,Mikhael D. Manurung,Erliyani Sartono,Martha T. van der Beek,Béatrice M. F. Winkel,Petra H. Verbeek-Menken,Koen A. Stam,Fijs W. B. van Leeuwen,Pauline Meij,Angela van Diepen,Lisette van Lieshout,Govert J. van Dam,Paul L. A. M. Corstjens,Cornelis H. Hokke,Maria Yazdanbakhsh,Leo G. Visser,Meta Roestenberg
Schistosomiasis treatment relies on the use of a single drug, praziquantel, which is insufficient to control transmission in highly endemic areas
Interleukin-22-mediated host glycosylation prevents Clostridioides difficile infection by modulating the metabolic activity of the gut microbiota
17-02-2020 – Hiroko Nagao-Kitamoto,Jhansi L. Leslie,Sho Kitamoto,Chunsheng Jin,Kristina A. Thomsson,Merritt G. Gillilland III,Peter Kuffa,Yoshiyuki Goto,Robert R. Jenq,Chiharu Ishii,Akiyoshi Hirayama,Anna M. Seekatz,Eric C. Martens,Kathryn A. Eaton,John Y. Kao,Shinji Fukuda,Peter D. R. Higgins,Niclas G. Karlsson,Vincent B. Young,Nobuhiko Kamada
The involvement of host immunity in the gut microbiota-mediated colonization resistance to Clostridioides difficile infection (CDI) is incompletely understood. Here, we show that interleukin (IL)-22, induced by colonization of the gut microbiota, is crucial for the prevention of CDI in human microbiota-associated (HMA) mice. IL-22 signaling in HMA mice regulated host glycosylation, which enabled the growth of succinate-consuming bacteria Phascolarctobacterium spp. within the gut microbiome. Phascolarctobacterium reduced the availability of luminal succinate, a crucial metabolite for the growth of C. difficile, and therefore prevented the growth of C. difficile. IL-22-mediated host N-glycosylation is likely impaired in patients with ulcerative colitis (UC) and renders UC-HMA mice more susceptible to CDI. Transplantation of healthy human-derived microbiota or Phascolarctobacterium reduced luminal succinate levels and restored colonization resistance in UC-HMA mice. IL-22-mediated host glycosylation thus fosters the growth of commensal bacteria that compete with C. difficile for the nutritional niche.
An immune-cell signature of bacterial sepsis
17-02-2020 – Miguel Reyes,Michael R. Filbin,Roby P. Bhattacharyya,Kianna Billman,Thomas Eisenhaure,Deborah T. Hung,Bruce D. Levy,Rebecca M. Baron,Paul C. Blainey,Marcia B. Goldberg,Nir Hacohen
Dysregulation of the immune response to bacterial infection can lead to sepsis, a condition with high mortality. Multiple whole-blood gene-expression studies have defined sepsis-associated molecular signatures, but have not resolved changes in transcriptional states of specific cell types. Here, we used single-cell RNA-sequencing to profile the blood of people with sepsis (n = 29) across three clinical cohorts with corresponding controls (n = 36). We profiled total peripheral blood mononuclear cells (PBMCs, 106,545 cells) and dendritic cells (19,806 cells) across all subjects and, on the basis of clustering of their gene-expression profiles, defined 16 immune-cell states. We identified a unique CD14
Engineered immunogen binding to alum adjuvant enhances humoral immunity
17-02-2020 – Tyson J. Moyer,Yu Kato,Wuhbet Abraham,Jason Y. H. Chang,Daniel W. Kulp,Nicki Watson,Hannah L. Turner,Sergey Menis,Robert K. Abbott,Jinal N. Bhiman,Mariane B. Melo,Hayley A. Simon,Sara Herrera-De la Mata,Shu Liang,Gregory Seumois,Yash Agarwal,Na Li,Dennis R. Burton,Andrew B. Ward,William R. Schief,Shane Crotty,Darrell J. Irvine
Adjuvants are central to the efficacy of subunit vaccines. Aluminum hydroxide (alum) is the most commonly used vaccine adjuvant, yet its adjuvanticity is often weak and mechanisms of triggering antibody responses remain poorly understood. We demonstrate that site-specific modification of immunogens with short peptides composed of repeating phosphoserine (pSer) residues enhances binding to alum and prolongs immunogen bioavailability. The pSer-modified immunogens formulated in alum elicited greatly increased germinal center, antibody, neutralizing antibody, memory and long-lived plasma cell responses compared to conventional alum-adsorbed immunogens. Mechanistically, pSer-immunogen:alum complexes form nanoparticles that traffic to lymph nodes and trigger B cell activation through multivalent and oriented antigen display. Direct uptake of antigen-decorated alum particles by B cells upregulated antigen processing and presentation pathways, further enhancing B cell activation. These data provide insights into mechanisms of action of alum and introduce a readily translatable approach to significantly improve humoral immunity to subunit vaccines using a clinical adjuvant.