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      The Bacterial and Viral Complexity of Postinfectious Hydrocephalus in Uganda

      research-article
      1 , 2 , 23 , 3 , 2 , 23 , 4 , 5 , 3 , 4 , 6 , 7 , 8 , 9 , 9 , 8 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 2 , 17 , 18 , 8 , 19 , 20 , 21 , 2 , 22 , 23 , 24 , 8 , 8 , 25 , 10 , 22 , 26 , 8 , 27 , 8 , 2 , 15 , 28 , 8 , 4 , 6 , 29 , 3 , 30 , 31 , 32 , 29 , 8 , 33 , 34 , 35 , 36 , 2 , 23 , 3 , 4 , 6 , 19 , 37 , 38 ,
      Science translational medicine

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          Abstract

          Postinfectious hydrocephalus (PIH), often following neonatal sepsis, is the most common cause of pediatric hydrocephalus world-wide, yet the microbial pathogens remain uncharacterized. Characterization of the microbial agents causing PIH would lead to an emphasis shift from surgical palliation of cerebrospinal fluid (CSF) accumulation to prevention. We examined blood and CSF from 100 consecutive cases of PIH and control cases of non-postinfectious hydrocephalus (NPIH) in infants in Uganda. Genomic testing was undertaken for bacterial, fungal, and parasitic DNA, DNA and RNA sequencing for viral identification, and extensive bacterial culture recovery. We uncovered a major contribution to PIH from Paenibacillus, upon a background of frequent cytomegalovirus (CMV) infection. CMV was only found in CSF in PIH cases. A facultatively anaerobic isolate was recovered. Assembly of the genome revealed a strain of P. thiaminolyticus. In mice, this isolate designated strain Mbale, was lethal in contrast with the benign reference strain. These findings point to the value of an unbiased pan-microbial approach to characterize PIH in settings where the organisms remain unknown, and enables a pathway towards more optimal treatment and prevention of the proximate neonatal infections.

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          We have discovered a novel strain of bacteria upon a frequent viral background underlying postinfectious hydrocephalus in Uganda.

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          Most cited references45

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          Detection of four Plasmodium species in blood from humans by 18S rRNA gene subunit-based and species-specific real-time PCR assays.

          There have been reports of increasing numbers of cases of malaria among migrants and travelers. Although microscopic examination of blood smears remains the "gold standard" in diagnosis, this method suffers from insufficient sensitivity and requires considerable expertise. To improve diagnosis, a multiplex real-time PCR was developed. One set of generic primers targeting a highly conserved region of the 18S rRNA gene of the genus Plasmodium was designed; the primer set was polymorphic enough internally to design four species-specific probes for P. falciparum, P. vivax, P. malarie, and P. ovale. Real-time PCR with species-specific probes detected one plasmid copy of P. falciparum, P. vivax, P. malariae, and P. ovale specifically. The same sensitivity was achieved for all species with real-time PCR with the 18S screening probe. Ninety-seven blood samples were investigated. For 66 of them (60 patients), microscopy and real-time PCR results were compared and had a crude agreement of 86% for the detection of plasmodia. Discordant results were reevaluated with clinical, molecular, and sequencing data to resolve them. All nine discordances between 18S screening PCR and microscopy were resolved in favor of the molecular method, as were eight of nine discordances at the species level for the species-specific PCR among the 31 samples positive by both methods. The other 31 blood samples were tested to monitor the antimalaria treatment in seven patients. The number of parasites measured by real-time PCR fell rapidly for six out of seven patients in parallel to parasitemia determined microscopically. This suggests a role of quantitative PCR for the monitoring of patients receiving antimalaria therapy.
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            Reactivation of Multiple Viruses in Patients with Sepsis

            A current controversy is whether patients with sepsis progress to an immunosuppressed state. We hypothesized that reactivation of latent viruses occurred with prolonged sepsis thereby providing evidence of clinically-relevant immunosuppression and potentially providing a means to serially-monitor patients' immune status. Secondly, if viral loads are markedly elevated, they may contribute to morbidity and mortality. This study determined if reactivation of herpesviruses, polyomaviruses, and the anellovirus TTV occurred in sepsis and correlated with severity. Serial whole blood and plasma samples from 560 critically-ill septic, 161 critically-ill non-septic, and 164 healthy age-matched patients were analyzed by quantitative-polymerase-chain-reaction for cytomegalovirus (CMV), Epstein-Barr (EBV), herpes-simplex (HSV), human herpes virus-6 (HHV-6), and TTV. Polyomaviruses BK and JC were quantitated in urine. Detectable virus was analyzed with respect to secondary fungal and opportunistic bacterial infections, ICU duration, severity of illness, and survival. Patients with protracted sepsis had markedly increased frequency of detectable virus. Cumulative viral DNA detection rates in blood were: CMV (24.2%), EBV (53.2%), HSV (14.1%), HHV-6 (10.4%), and TTV (77.5%). 42.7% of septic patients had presence of two or more viruses. The 50% detection rate for herpesviruses was 5–8 days after sepsis onset. A small subgroup of septic patients had markedly elevated viral loads (>104–106 DNA copies/ml blood) for CMV, EBV, and HSV. Excluding TTV, DNAemia was uncommon in critically-ill non-septic patients and in age-matched healthy controls. Compared to septic patients without DNAemia, septic patients with viremia had increased fungal and opportunistic bacterial infections. Patients with detectable CMV in plasma had higher 90-day mortality compared to CMV-negative patients; p<0.05. Reactivation of latent viruses is common with prolonged sepsis, with frequencies similar to those occurring in transplant patients on immunosuppressive therapy and consistent with development of an immunosuppressive state. Whether reactivated latent viruses contribute to morbidity and mortality in sepsis remains unknown.
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              Direct and sensitive detection of a pathogenic protozoan, Toxoplasma gondii, by polymerase chain reaction.

              We applied the polymerase chain reaction to detection of the pathogenic protozoan Toxoplasma gondii based on our identification of a 35-fold-repetitive gene (the B1 gene) as a target. Using this procedure, we were able to amplify and detect the DNA of a single organism directly from a crude cell lysate. This level of sensitivity also allowed us to detect the B1 gene from purified DNA samples containing as few as 10 parasites in the presence of 100,000 human leukocytes. This is representative of the maximal cellular infiltration (10(5)/ml) in 1 ml of cerebrospinal fluid obtained from patients with toxoplasmic encephalitis. The B1 gene is present and conserved in all six T. gondii strains tested to date, including two isolates from patients with acquired immunodeficiency syndrome. No signal was detected by using this assay and DNAs from a variety of other organisms, including several which might be found in the central nervous system of an immunocompromised host. This combination of sensitivity and specificity should make detection of the B1 gene based on polymerase chain reaction amplification a very useful method for diagnosis of toxoplasmosis both in immunocompromised hosts and in congenitally infected fetuses.
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                Author and article information

                Journal
                101505086
                36963
                Sci Transl Med
                Sci Transl Med
                Science translational medicine
                1946-6234
                1946-6242
                6 July 2020
                30 September 2020
                30 March 2021
                : 12
                : 563
                : eaba0565
                Affiliations
                [1 ]Department of Biostatistics, Product Development, Genentech Inc.
                [2 ]Center for Infection and Immunity, Mailman School of Public Health, Columbia University
                [3 ]Institute for Personalized Medicine, Dept. of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine
                [4 ]Center for Neural Engineering, The Pennsylvania State University
                [5 ]Department of Medicine, The Pennsylvania State University College of Medicine
                [6 ]Department of Engineering Science and Mechanics, The Pennsylvania State University
                [7 ]Department of Public Health Sciences, The Pennsylvania State University College of Medicine
                [8 ]CURE Children’s Hospital of Uganda
                [9 ]Department of Pathology, The Pennsylvania State University College of Medicine
                [10 ]Department of Pediatrics, Mbarara University of Science and Technology
                [11 ]Department of Epidemiology, Mbarara University of Science and Technology
                [12 ]Department of Microbiology, Mbarara University of Science and Technology
                [13 ]MGH Medical Practice Evaluation Center, Division of Infectious Diseases, and Center for Global Health
                [14 ]Neonatal Unit, Department of Paediatrics and Child Health, Mbale Regional Referral Hospital, Mbale, Uganda
                [15 ]Mbale Clinical Research Institute, Mbale Regional Referral Hospital, Mbale, Uganda
                [16 ]University of Liverpool, Liverpool, UK
                [17 ]Biotia, 100 6th avenue, New York, NY, USA
                [18 ]Division of Pediatric Infectious Disease, The Pennsylvania State University College of Medicine
                [19 ]The Center for Infectious Disease Dynamics, The Pennsylvania State University
                [20 ]Departments of Biology and Statistics, The Pennsylvania State University
                [21 ]Institute for Translational Medicine, University of Liverpool
                [22 ]Department of Statistics, The Pennsylvania State University
                [23 ]Department of Epidemiology, Columbia University Mailman School of Public Health
                [24 ]Department of Neuroscience, Washington University School of Medicine
                [25 ]Department of Neurosurgery, University of Toronto
                [26 ]Department of Neurological Surgery, Washington University School of Medicine
                [27 ]Division of Newborn Medicine, Boston Children’s Hospital and Department of Pediatrics, Harvard Medical School
                [28 ]Busitema University, Faculty of Health Sciences, Mbale Campus 2
                [29 ]Department of Biostatistics, Harvard T.H. Chan School of Public Health
                [30 ]Department of Medicine, Washington University School of Medicine
                [31 ]Department of Women’s and Children’s Health, University of Liverpool and Liverpool Women’s Hospital for Liverpool Health Partners, Liverpool, UK
                [32 ]Department of Mechanical Engineering, The Pennsylvania State University
                [33 ]National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health
                [34 ]MGP MetaGénoPolis, INRA, Université Paris-Saclay
                [35 ]Department of Comparative Medicine, The Pennsylvania State University College of Medicine
                [36 ]Dept. of Neurosurgery, Boston Children’s Hospital, Harvard Medical School
                [37 ]Department of Neurosurgery, The Pennsylvania State University College of Medicine
                [38 ]Department of Physics, The Pennsylvania State University
                Author notes
                [*,§]

                Contributed Equally

                [†]

                Deceased

                Author contributions: The study was designed by J.K., and S.J.S. The manuscript was written by J.N.P, B.L.W., C.H., and S.J.S. The data analysis was performed by J.N.P., B.L.W., C.H., N.M., L.Z., S.M.K., M.P. Bacteriology was carried out by D.S.S.W., B.V.B., and J.B., and advised by M.Y.G. and M.A. Virology was performed by N.M. Wet lab technical analysis was performed by C.H., M.C-R., C.G., and J.N. Animal experiments were carried out by P.S., and histology performed by H.A. Independent laboratories were supervised by W.I.L. and J.B. Clinical work was performed by J.M., F.B., E.M-K., R.M., E.K., J.M., P.O-O., J.O., K.B., P.S. Project management was performed by S.S., E.M-K., J.K., E.K., K.S., A.D.W., M.G., T.W., W.I.L, J.B., and S.J.S. Bioinformatics was performed by J.N.P., L.Z., F.R., and J.Q. Neurosurgical consultation was performed by A.V.K., D.D.L., B.C.W., and S.J.S. Infectious disease consultation was provided by L.B. and J.E.E. Computer support by B.N.K. Immunology consultation was performed by S.U.M. and M.H. CSF proteomics was performed by A.M.I., R.T., and D.D.L. Statistical analysis was provided by J.N.P., M.H., and X.L., and geographical mapping performed by A.J.W. and P.S. All authors contributed to editing the manuscript.

                []To whom correspondence should be addressed: Steven J. Schiff, W311 Millennium Science Complex, The Pennsylvania State University, University Park, PA 16802 USA, 814-863-4210, steven.j.schiff@ 123456gmail.com
                Article
                PMC7774825 PMC7774825 7774825 nihpa1609375
                10.1126/scitranslmed.aba0565
                7774825
                32998967
                035a16b3-559a-4cf4-b599-480e0f18a944
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