Publications by authors named "William A Petri"

284 Publications

Optimizing a Multi-Component Intranasal Vaccine Formulation Using a Design of Experiments Strategy.

Front Immunol 2021 25;12:683157. Epub 2021 Jun 25.

Infectious Disease Research Institute (IDRI), Seattle, WA, United States.

Amebiasis is a neglected tropical disease caused by a. Although the disease burden varies geographically, amebiasis is estimated to account for some 55,000 deaths and millions of infections globally per year. Children and travelers are among the groups with the greatest risk of infection. There are currently no licensed vaccines for prevention of amebiasis, although key immune correlates for protection have been proposed from observational studies in humans. We previously described the development of a liposomal adjuvant formulation containing two synthetic TLR ligands (GLA and 3M-052) that enhanced antigen-specific fecal IgA, serum IgG2a, a mixed IFNγ and IL-17A cytokine profile from splenocytes, and protective efficacy following intranasal administration with the LecA antigen. By applying a statistical design of experiments (DOE) and desirability function approach, we now describe the optimization of the dose of each vaccine formulation component (LecA, GLA, 3M-052, and liposome) as well as the excipient composition (acyl chain length and saturation; PEGylated lipid:phospholipid ratio; and presence of antioxidant, tonicity, or viscosity agents) to maximize desired immunogenicity characteristics while maintaining physicochemical stability. This DOE/desirability index approach led to the identification of a lead candidate composition that demonstrated immune response durability and protective efficacy in the mouse model, as well as an assessment of the impact of each active vaccine formulation component on protection. Thus, we demonstrate that both GLA and 3M-052 are required for statistically significant protective efficacy. We also show that immunogenicity and efficacy results differ in female male mice, and the differences appear to be at least partly associated with adjuvant formulation composition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2021.683157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268010PMC
June 2021

Associations of socioeconomic and other environmental factors with early brain development in Bangladeshi infants and children.

Dev Cogn Neurosci 2021 Aug 18;50:100981. Epub 2021 Jun 18.

Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Harvard Graduate School of Education, Cambridge, MA, USA. Electronic address:

Studies of infants growing up in high-income countries reveal developmental changes in electroencephalography (EEG) power whereby socioeconomic factors - specifically, low SES and low income - are associated with lower EEG power in infants aged newborn to nine months. In the current paper we explore relationships of spectral EEG power across three regions (frontal, central, and parietal) and four frequency bands (theta, alpha, beta, and gamma) with socioeconomic and psychosocial factors in a cohort of n = 160 6-month-old infants and n = 187 36-month-old children living in Dhaka, Bangladesh. Household wealth is assessed as a multi-dimensional composite score encompassing income, assets, and housing materials. Psychosocial factors include maternal perceived stress and family caregiving activities. Among the 6-month-old infants we do not observe any association of household wealth or psychosocial factors with EEG power. Among the 36-month-old children, we find that household wealth is negatively associated absolute power in the beta and gamma bands across frontal, central, and parietal electrodes. We also find that higher reports of maternal perceived stress are associated with more absolute theta power in frontal and central regions in the 36-month-old children. The finding of a negative relationship of household wealth with beta and gamma power in 36-month-old children differs from findings previously observed in infants in high-income countries. Overall, findings suggest that children's environment continues to influence the development of EEG oscillations and provide support for the utility of EEG to quantify developmental effects of early life experiences on neural functional outcomes in low income countries.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dcn.2021.100981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254021PMC
August 2021

IL-13 is a driver of COVID-19 severity.

JCI Insight 2021 Jun 29. Epub 2021 Jun 29.

Department of Medicine, University of Virginia School of Medicine, Charlottesville, United States of America.

Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here we report that elevated interleukin-13 (IL-13) was associated with the need for mechanical ventilation in two independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab, a mAb that blocks IL-13 and IL-4 signaling, had less severe disease. In SARS-CoV-2 infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti-IL-13 treatment in infected mice, hyaluronan synthase 1 (Has1) was the most downregulated gene and accumulation of the hyaluronan polysaccharide was decreased in the lung. In patients with COVID-19, hyaluronan was increased in the lungs and plasma. Blockade of the hyaluronan receptor, CD44, reduced mortality in infected mice, supporting the importance of hyaluronan as a pathogenic mediator. Finally, hyaluronan was directly induced in the lungs of mice by administration of IL-13, indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and hyaluronan has important implications for therapy of COVID-19 and potentially other pulmonary diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.150107DOI Listing
June 2021

Diverse Humoral Immune Responses in Younger and Older Adult COVID-19 Patients.

mBio 2021 06 29;12(3):e0122921. Epub 2021 Jun 29.

Antigen Discovery, Incorporated, Irvine, California, USA.

We sought to discover links between antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and patient clinical variables, cytokine profiles, and antibodies to endemic coronaviruses. Serum samples from 30 patients of younger (26 to 39 years) and older (69 to 83 years) age groups and with varying clinical severities ranging from outpatient to mechanically ventilated were collected and used to probe a novel multi-coronavirus protein microarray. This microarray contained variable-length overlapping fragments of SARS-CoV-2 spike (S), envelope (E), membrane (M), nucleocapsid (N), and open reading frame (ORF) proteins created through transcription and translation (IVTT). The array also contained SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), human coronavirus OC43 (HCoV-OC43), and HCoV-NL63 proteins. IgG antibody responses to specific epitopes within the S1 protein region spanning amino acids (aa) 500 to 650 and within the N protein region spanning aa 201 to 300 were found to be significantly higher in older patients and further significantly elevated in those older patients who were ventilated. Additionally, there was a noticeable overlap between antigenic regions and known mutation locations in selected emerging SARS-CoV-2 variants of current clinical consequence (B.1.1.7, B1.351, P.1, CAL20.C, and B.1.526). Moreover, the older age group displayed more consistent correlations of antibody reactivity with systemic cytokine and chemokine responses than the younger adult group. A subset of patients, however, had little or no response to SARS-CoV-2 antigens and disproportionately severe clinical outcomes. Further characterization of these slow-low-responding individuals with cytokine analysis revealed significantly higher interleukin-10 (IL-10), IL-15, and interferon gamma-induced protein 10 (IP-10) levels and lower epidermal growth factor (EGF) and soluble CD40 ligand (sCD40L) levels than those of seroreactive patients in the cohort. As numerous viral variants continue to emerge in the coronavirus disease 2019 (COVID-19) pandemic, determining antibody reactivity to SARS-CoV-2 epitopes becomes essential in discerning changes in the immune response to infection over time. This study enabled us to identify specific areas of antigenicity within the SARS-CoV-2 proteome, allowing us to detect correlations of epitopes with clinical metadata and immunological signals to gain holistic insight into SARS-CoV-2 infection. This work also emphasized the risk of mutation accumulation in viral variants and the potential for evasion of the adaptive immune responses in the event of reinfection. We additionally highlighted the correlation of antigenicity between structural proteins of SARS-CoV-2 and endemic HCoVs, raising the possibility of cross-protection between homologous lineages. Finally, we identified a subset of patients with minimal antibody reactivity to SARS-CoV-2 infection, prompting discussion of the potential consequences of this alternative immune response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mBio.01229-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262923PMC
June 2021

Nonsterile immunity to cryptosporidiosis in infants is associated with mucosal IgA against the sporozoite and protection from malnutrition.

PLoS Pathog 2021 Jun 28;17(6):e1009445. Epub 2021 Jun 28.

Department of Medicine, University of Virginia, Charlottesville, Virginia, United States of America.

We conducted a longitudinal study of cryptosporidiosis from birth to three years of age in an urban slum of Dhaka Bangladesh. Fecal DNA was extracted from monthly surveillance samples and diarrheal stool samples collected from 392 infants from birth to three years. A pan-Cryptosporidium qPCR assay was used to identify sub-clinical and symptomatic cryptosporidiosis. Anthropometric measurements were collected quarterly to assess child nutritional status. 31% (121/392) of children experienced a single and 57% (222/392) multiple infections with Cryptosporidium. Repeat infections had a lower burden of parasites in the stool (Cq slope = -1.85; p<0.0001) and were more likely to be sub-clinical (Chi square test for trend; p = 0.01). Repeat infections were associated with the development of growth faltering (Pearson correlation = -0.18; p = 0.0004). High levels of fecal IgA antibodies against the Cryptosporidium Cp23 sporozoite protein at one year of life were associated with a delay in reinfection and amelioration of growth faltering through three years of life (HAZ IgA high responders -1.323 ± 0.932 versus HAZ -1.731 ± 0.984 p = 0.0001). We concluded that nonsterile immunity to cryptosporidiosis in young children was associated with high levels of mucosal IgA anti-Cp23 and protection from diarrhea and growth faltering. Trial Registration: NCT02764918.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.ppat.1009445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270466PMC
June 2021

HLA class I and II associations with common enteric pathogens in the first year of life.

EBioMedicine 2021 May 25;67:103346. Epub 2021 Apr 25.

Department of Medicine, Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, VA, USA.. Electronic address:

Background: genetic susceptibility to infection is mediated by numerous host factors, including the highly diverse, classical human leukocyte antigen (HLA) genes, which are critical genetic determinants of immunity. We systematically evaluated the effect of HLA alleles and haplotypes on susceptibility to 12 common enteric infections in children during the first year of life in an urban slum of Dhaka, Bangladesh.

Methods: a birth cohort of 601 Bangladeshi infants was prospectively monitored for diarrhoeal disease. Each diarrhoeal stool sample was analyzed for enteric pathogens by multiplex TaqMan Array Card (TAC). High resolution genotyping of HLA class I (A and B) and II (DRB1, DQA1, and DQB1) genes was performed by next-generation sequencing. We compared the frequency of HLA alleles and haplotypes between infected and uninfected children.

Findings: we identified six individual allele associations and one five-locus haplotype association. One allele was associated with protection: A*24:02 - EAEC. Five alleles were associated with increased risk: A*24:17 - typical EPEC, B*15:01 - astrovirus, B*38:02 - astrovirus, B*38:02 - Cryptosporidium and DQA1*01:01 - Cryptosporidium. A single five-locus haplotype was associated with protection: A*11:01~B*15:02~DRB1*12:02~DQA1*06:01~DQB1*03:01- adenovirus 40/41.

Interpretation: our findings suggest a role for HLA in susceptibility to early enteric infection for five pathogens. Understanding the genetic contribution of HLA in susceptibility has important implications in vaccine design and understanding regional differences in incidence of enteric infection.

Funding: this research was supported by the National Institute of Health (NIH) and the Bill and Melinda Gates Foundation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2021.103346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093888PMC
May 2021

IL-13 is a driver of COVID-19 severity.

medRxiv 2021 Mar 1. Epub 2021 Mar 1.

Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville VA 22908 USA.

Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here we report that elevated interleukin-13 (IL-13) was associated with the need for mechanical ventilation in two independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab had less severe disease. In SARS-CoV-2 infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti-IL-13 treatment in infected mice, in the lung, hyaluronan synthase 1 ( ) was the most downregulated gene and hyaluronan accumulation was decreased. Blockade of the hyaluronan receptor, CD44, reduced mortality in infected mice, supporting the importance of hyaluronan as a pathogenic mediator, and indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and hyaluronan has important implications for therapy of COVID-19 and potentially other pulmonary diseases.

Summary: L-13 levels are elevated in patients with severe COVID-19. In a mouse model of disease, IL-13 neutralization results in reduced disease and lung hyaluronan deposition. Similarly, blockade of hyaluronan's receptor, CD44, reduces disease, highlighting a novel mechanism for IL-13-mediated pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2020.06.18.20134353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941663PMC
March 2021

Megasphaera in the stool microbiota is negatively associated with diarrheal cryptosporidiosis.

Clin Infect Dis 2021 Mar 4. Epub 2021 Mar 4.

Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, USA.

Background: The protozoan parasites in the Cryptosporidium genus cause both acute diarrheal disease and subclinical (i.e. non-diarrheal) disease. It is unclear if the microbiota can influence the manifestation of diarrhea during a Cryptosporidium infection.

Methods: To characterize the role of the gut microbiota in diarrheal cryptosporidiosis, the microbiome composition of both diarrheal and surveillance Cryptosporidium-positive fecal samples from 72 infants was evaluated using 16S rRNA gene sequencing. Additionally, the microbiome composition prior to infection was examined to test whether a preexisting microbiome profile could influence the Cryptosporidium infection phenotype.

Results: Fecal microbiome composition was associated with diarrheal symptoms at two timepoints. Megasphaera was significantly less abundant in diarrheal samples when compared to subclinical samples at the time of Cryptosporidium detection (log2(fold change) = -4.3, p=10 -10) and prior to infection (log2(fold change) = -2.0, p=10 -4); this assigned sequence variant was detected in 8 children who had diarrhea and 30 children without diarrhea. Random forest classification also identified Megasphaera abundance in the pre- and post-exposure microbiota as predictive of a subclinical infection.

Conclusions: Microbiome composition broadly, and specifically low Megasphaera abundance, was associated with diarrheal symptoms prior to and at the time of Cryptosporidium detection. This observation suggests that the gut microenvironment may play a role in determining the severity of a Cryptosporidium infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciab207DOI Listing
March 2021

Host Genome-Wide Association Study of Infant Susceptibility to -Associated Diarrhea.

Infect Immun 2021 May 17;89(6). Epub 2021 May 17.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA

is a leading cause of moderate-to-severe diarrhea globally and the causative agent of shigellosis and bacillary dysentery. Associated with 80 to 165 million cases of diarrhea and >13% of diarrheal deaths, in many regions, exposure is ubiquitous while infection is heterogenous. To characterize host-genetic susceptibility to -associated diarrhea, we performed two independent genome-wide association studies (GWAS) including Bangladeshi infants from the PROVIDE and CBC birth cohorts in Dhaka, Bangladesh. Cases were infants with -associated diarrhea ( = 143) and controls were infants with no -associated diarrhea in the first 13 months of life ( = 446). -associated diarrhea was identified via quantitative PCR (qPCR) threshold cycle ( ) distributions for the gene, carried by all four species and enteroinvasive Host GWAS were performed under an additive genetic model. A joint analysis identified protective loci on chromosomes 11 (rs582240, within the pseudogene; = 6.40 × 10; odds ratio [OR], 0.43) and 8 (rs12550437, within the lincRNA ; = 1.49 × 10; OR, 0.48). Conditional analyses identified two previously suggestive loci, a protective locus on chromosome 7 (rs10266841, within the 3' untranslated region [UTR] of ; = 1.48 × 10; OR, 0.44) and a risk-associated locus on chromosome 10 (rs2801847, an intronic variant within ; = 8.37 × 10; OR, 5.51). These loci have all been indirectly linked to bacterial type 3 secretion system (T3SS) activity, its components, and bacterial effectors delivered into host cells. Host genetic factors that may affect bacterial T3SS activity and are associated with the host response to -associated diarrhea may provide insight into vaccine and drug development efforts for -associated diarrheal disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/IAI.00012-21DOI Listing
May 2021

Host Protective Mechanisms to Intestinal Amebiasis.

Trends Parasitol 2021 02 23;37(2):165-175. Epub 2020 Oct 23.

Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, VA, USA. Electronic address:

The protozoan parasite Entamoeba histolytica is the causative agent of amebiasis, an infection that manifests as colitis and, in some cases, liver abscess. A better understanding of host protective factors is key to developing an effective remedy. Recently, significant advances have been made in understanding the mechanisms of MUC2 production by goblet cells upon amebic infection, regulation of antimicrobial peptide production by Paneth cells, the interaction of commensal microbiota with immune stimulation, and host genetics in conferring protection from amebiasis. In addition to host pathways that may serve as potential therapeutic targets, significant progress has also been made with respect to development of a vaccine against amebiasis. Here, we aim to highlight the current understanding and knowledge gaps critically.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pt.2020.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840892PMC
February 2021

Diarrheal Pathogens Associated with Growth and Neurodevelopment.

Clin Infect Dis 2021 Jan 5. Epub 2021 Jan 5.

Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA.

Background: Diarrheal pathogens have been associated with linear growth deficits. The effect of diarrheal pathogens on growth is likely due to inflammation which also adversely affects neurodevelopment. We hypothesized that diarrheagenic pathogens would be negatively associated with both growth and neurodevelopment.

Methods: We conducted a longitudinal birth cohort study of 250 children with diarrheal surveillance and measured pathogen burden in diarrheal samples using quantitative PCR. Pathogen attributable fraction estimates (AFe) of diarrhea over the first two years of life, corrected for socioeconomic variables, were used to predict both growth and scores on the Bayley III Scales of Infant and Toddler Development.

Results: 180 children were analyzed for growth and 162 for neurodevelopmental outcomes. Rotavirus, Campylobacter, and Shigella were the leading causes of diarrhea in year 1 while Shigella, Campylobacter, and ST-ETEC were the leading causes in year 2. Norovirus was the only pathogen associated with LAZ at 24 months and was positively associated (RC 0.42, CI 0.04, 0.80). Norovirus (RC 2.46, CI 0.05 - 4.87) was also positively associated with cognitive scores while sapovirus (RC -2.64, CI -4.80 - -0.48) and Typical EPEC (RC -4.14, CI -8.02 - -0.27) were inversely associated. No pathogens were associated with language or motor scores. Significant maternal, socioeconomic, and perinatal predictors were identified for both growth and neurodevelopment.

Conclusion: Maternal, prenatal, and socioeconomic factors were common predictors of growth and neurodevelopment. Only a limited number of diarrheal pathogens were associated with these outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciaa1938DOI Listing
January 2021

Clinical performance of the H. PYLORI QUIK CHEK™ and H. PYLORI CHEK™ assays, novel stool antigen tests for diagnosis of Helicobacter pylori.

Eur J Clin Microbiol Infect Dis 2021 May 3;40(5):1023-1028. Epub 2021 Jan 3.

Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA.

Infection with Helicobacter pylori is a global health issue, and rapid and accurate testing is a key to diagnosis. We aimed to assess the performance of two novel enzyme immunoassays (EIA), the H. PYLORI QUIK CHEK™ and the H. PYLORI CHEK™ assays, for the detection of H. pylori antigen in stool. Patients from five geographically diverse sites across the USA, Germany, and in Bangladesh were tested for infection with Helicobacter pylori with the two novel stool antigen tests and two commercially available stool antigen assays. All patients provided a stool sample and underwent esophagogastroduodenoscopy for biopsy. Results were compared to a clinical diagnosis using a composite reference method consisting of histological analysis and rapid urease testing of the biopsy. A total of 271 patients, 68.2% female and mean age of 46 years, were included. The overall prevalence of H. pylori infection was 24.1%. The sensitivity of the H. PYLORI QUIK CHEK™ and H. PYLORI CHEK™ was 92% and 91%, respectively. The specificity of H. PYLORI QUIK CHEK™ and H. PYLORI CHEK™ was 91% and 100%, respectively. No significant cross-reactivity against other gut pathogens was observed. The H. PYLORI QUIK CHEK™ and H. PYLORI CHEK™ assays demonstrate excellent clinical performance compared the composite reference method.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10096-020-04137-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778841PMC
May 2021

IgG Antibodies against SARS-CoV-2 Correlate with Days from Symptom Onset, Viral Load and IL-10.

medRxiv 2020 Dec 7. Epub 2020 Dec 7.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a pandemic of the respiratory disease coronavirus disease 2019 (COVID-19). Antibody testing is essential to identify persons exposed to the virus and potentially in predicting disease immunity. 183 COVID-19 patients (68 of whom required mechanical ventilation) and 41 controls were tested for plasma IgG, IgA and IgM against the SARS-CoV-2 S1, S2, receptor binding domain (RBD) and N proteins using the MILLIPLEX SARS-CoV-2 Antigen Panel. Plasma cytokines were concurrently measured using the MILLIPLEX® MAP Human Cytokine/Chemokine/Growth Factor Panel A. As expected the 183 COVID-19 positive patients had high levels of IgG, IgA and IgM anti-SARS-CoV-2 antibodies against each of the viral proteins. Sensitivity of anti-S1 IgG increased from 60% to 93% one week after symptom onset. S1-IgG and S1-IgA had specificities of 98% compared to the 41 COVID-19 negative patients. The 68 ventilated COVID-19 positive patients had higher antibody levels than the 115 COVID-19 positive patients who were not ventilated. IgG antibody levels against S1 protein had the strongest positive correlation to days from symptom onset. There were no statistically significant differences in IgG, IgA and IgM antibodies against S1 based on age. We found that patients with the highest levels of anti-SARS-CoV-2 antibodies had the lowest viral load in the nasopharynx. Finally there was a correlation of high plasma IL-10 with low anti-SARS-CoV-2 antibodies. Anti-SARS-CoV-2 antibody levels, as measured by a novel antigen panel, increased within days after symptom onset, achieving > 90% sensitivity and specificity within one week, and were highest in patients who required mechanical ventilation. Antibody levels were inversely associated with viral load but did not differ as a function of age. The correlation of high IL-10 with low antibody response suggests a potentially suppressive role of this cytokine in the humoral immune response in COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2020.12.05.20244541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7743087PMC
December 2020

Setting up a maternal and newborn registry applying electronic platform: an experience from the Bangladesh site of the global network for women's and children's health.

Reprod Health 2020 Nov 30;17(Suppl 2):148. Epub 2020 Nov 30.

Infectious Diseases & International Health, University of Virginia, Charlottesville, Virginia, USA.

Background: The Global Network for Women's and Children's Health Research (Global Network, GN) has established the Maternal Newborn Health Registry (MNHR) to assess MNH outcomes over time. Bangladesh is the newest country in the GN and has implemented a full electronic MNH registry system, from married women surveillance to pregnancy enrollment and subsequent follow ups.

Method: Like other GN sites, the Bangladesh MNHR is a prospective, population-based observational study that tracks pregnancies and MNH outcomes. The MNHR site is in the Ghatail and Kalihati sub-districts of the Tangail district. The study area consists of 12 registry clusters each of ~ 18,000-19,000 population. All pregnant women identified through a two-monthly house-to-house surveillance are enrolled in the registry upon consenting and followed up on scheduled visits until 42 days after pregnancy outcome. A comprehensive automated registry data capture system has been developed that allows for married women surveillance, pregnancy enrollment, and data collection during follow-up visits using a web-linked tablet-PC-based system.

Result: During March-May 2019, a total of 56,064 households located were listed in the Bangladesh MNH registry site. Of the total 221,462 population covered, 49,269 were currently married women in reproductive age (CMWRA). About 13% CMWRA were less susceptible to pregnancy. Large variability was observed in selected contraceptive usage across clusters. Overall, 5% of the listed CMWRAs were reported as currently pregnant.

Conclusion: In comparison to paper-pen capturing system electronic data capturing system (EDC) has advantages of less error-prone data collection, real-time data collection progress monitoring, data quality check and sharing. But the implementation of EDC in a resource-poor setting depends on technical infrastructure, skilled staff, software development, community acceptance and a data security system. Our experience of pregnancy registration, intervention coverage, and outcome tracking provides important contextualized considerations for both design and implementation of individual-level health information capturing and sharing systems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12978-020-00993-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708182PMC
November 2020

COVID-19-Lessons Learned and Questions Remaining.

Clin Infect Dis 2021 06;72(12):2225-2240

Department of Medicine, University of California, San Diego School of Medicine, San Diego, CA, USA.

In this article, the editors of Clinical Infectious Diseases review some of the most important lessons they have learned about the epidemiology, clinical features, diagnosis, treatment and prevention of SARS-CoV-2 infection and identify essential questions about COVID-19 that remain to be answered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciaa1654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797746PMC
June 2021

Asymptomatic Duodenitis and Helicobacter pylori associated Dyspepsia in 2-Year-Old Chronic Malnourished Bangladeshi Slum-Dwelling Children: A Cross-Sectional Study.

J Trop Pediatr 2021 01;67(1)

Nutrition and Clinical Services Division, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka 1212, Bangladesh.

Aim: There is insufficient knowledge on the * duodenal histology and Helicobacter pylori infection in malnourished Bangladeshi children. Therefore, we attempted to explore the prevalence of H. pylori infection and duodenal histopathology in 2-year-old chronic malnourished Bangladeshi slum-dwelling children and investigate their association with dyspeptic symptoms.

Methods: This cross-sectional study was conducted using the data of the Bangladesh Environmental Enteric Dysfunction study in an urban slum of Dhaka, Bangladesh. With a view to address the association of environmental enteric dysfunction (EED) with stunting, upper gastrointestinal endoscopy was performed on 54 chronic malnourished children {31 stunted [length-for-age Z-scores (LAZ) <-2] and 23 at risk of stunting (LAZ <-1 to -2)} aged between 12-24 months and the mucosal biopsies were subjected to histopathological examination after obtaining proper clinical history. Stool antigen for H. pylori (HpSA) was assessed to determine H. pylori status.

Results: In all, 83.3% (45/54) of the children had histopathological evidence of duodenitis. Chronic mild duodenitis was found to be the most prevalent form of duodenitis (53.7%) in the children. Only 8.9% (4/45) of the children with duodenitis had dyspepsia (p < 0.05). The 14.8% (8/54) of the children were found positive for H. pylori infection. Logistic regression analysis revealed children positive for HpSA had significant association with dyspepsia (OR 9.34; 95% CI 1.54-56.80).

Conclusions: The number of chronic malnourished children suffering from duodenitis was found to be very high. Majority of these children was asymptomatic. Children positive for HpSA had significant association with dyspeptic symptoms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/tropej/fmaa079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948384PMC
January 2021

Delayed Time to Cryptosporidiosis in Bangladeshi Children is Associated with Greater Fecal IgA against Two Sporozoite-Expressed Antigens.

Am J Trop Med Hyg 2021 01;104(1):229-232

1Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, Virginia.

Cryptosporidiosis is common in early childhood, and both diarrheal and subclinical infections are associated with adverse developmental outcomes. Improved therapeutic medications may help reduce the burden of cryptosporidial diarrhea; however, an effective vaccine would be better able to prevent the detrimental impact of both diarrheal and subclinical disease. A more complete understanding of naturally occurring immunity may further inform strategies to develop an effective vaccine. In this prospective cohort study of Bangladeshi children, greater fecal IgA at 12 months, but not plasma IgG, directed against two sporozoite-expressed, immunodominant and vaccine candidate antigens was associated with delayed time to subsequent cryptosporidiosis to 3 years of life. These findings extend prior work and further support the role of mucosal antibody responses in naturally developing protective immunity to .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4269/ajtmh.20-0657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790099PMC
January 2021

Clostridioides difficile binary toxin (CDT) is recognized by the TLR2/6 heterodimer to induce an NF-κB response.

J Infect Dis 2020 Oct 3. Epub 2020 Oct 3.

Department of Pathology, University of Virginia, Charlottesville, Virginia.

Clostridioides difficile infection (CDI) represents a significant burden on the health care system, one that is exacerbated by the emergence of binary toxin (CDT)-producing hypervirulent C. difficile strains. Previous work from our lab has shown that TLR2 recognizes CDT to induce inflammation. Here we explore the interactions of CDT with TLR2 and the impact on host immunity during CDI. We found that the TLR2/6 heterodimer, not TLR2/1, is responsible for CDT recognition, and that gene pathways including NF-κB and MAPK downstream of TLR2/6 are upregulated in mice with intact TLR2/6 signaling during CDI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jiaa620DOI Listing
October 2020

Type 2 cytokines IL-4 and IL-5 reduce severe outcomes from Clostridiodes difficile infection.

Anaerobe 2020 Dec 22;66:102275. Epub 2020 Sep 22.

Department of Medicine, University of Virginia, VA, USA; Department of Microbiology, Immunology and Cancer Biology, University of Virginia, VA, USA; Department of Pathology, University of Virginia, VA, USA. Electronic address:

Clostridiodes difficile infection (CDI) is the leading cause of hospital-acquired gastrointestinal infections in the U.S. While the immune response to C. difficile is not well understood, it has been shown that severe disease is accompanied by high levels of infiltrating immune cells and pro-inflammatory cytokine production. This study tests the roles of two type 2 cytokines, IL-4 and IL-5, in mediating protection in a murine model of disease. Administration of IL-5 protected from mortality due to CDI, and both IL-4 and IL-5 were protective against severe disease symptoms. Together, the results from this study increase our understanding of how type 2 immune signaling processes are protective from severe C. difficile infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.anaerobe.2020.102275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736165PMC
December 2020

Lewis Blood-group Antigens Are Associated With Altered Susceptibility to Shigellosis.

Clin Infect Dis 2021 06;72(11):e868-e871

Department of Medicine, Division of International Health and Infectious Diseases, University of Virginia School of Medicine, Charlottesville, Virginia, USA.

In a cohort of infants, we found that lack of the Lewis histo-blood group antigen was associated with increased susceptibility to shigellosis. Broadly inhibiting fucosylation in epithelial cells in vitro decreased invasion by Shigella flexneri. These results support a role for fucosylated glycans in susceptibility to shigellosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciaa1409DOI Listing
June 2021

Group penalized generalized estimating equation for correlated event-related potentials and biomarker selection.

BMC Med Res Methodol 2020 08 31;20(1):221. Epub 2020 Aug 31.

University of Virginia, Charlottesville, US.

Background: Event-related potentials (ERP) data are widely used in brain studies that measure brain responses to specific stimuli using electroencephalogram (EEG) with multiple electrodes. Previous ERP data analyses haven't accounted for the structured correlation among observations in ERP data from multiple electrodes, and therefore ignored the electrode-specific information and variation among the electrodes on the scalp. Our objective was to evaluate the impact of early adversity on brain connectivity by identifying risk factors and early-stage biomarkers associated with the ERP responses while properly accounting for structured correlation.

Methods: In this study, we extend a penalized generalized estimating equation (PGEE) method to accommodate structured correlation of ERPs that accounts for electrode-specific data and to enable group selection, such that grouped covariates can be evaluated together for their association with brain development in a birth cohort of urban-dwelling Bangladeshi children. The primary ERP responses of interest in our study are N290 amplitude and the difference in N290 amplitude.

Results: The selected early-stage biomarkers associated with the N290 responses are representatives of enteric inflammation (days of diarrhea, MIP1b, retinol binding protein (RBP), Zinc, myeloperoxidase (MPO), calprotectin, and neopterin), systemic inflammation (IL-5, IL-10, ferritin, C Reactive Protein (CRP)), socioeconomic status (household expenditure), maternal health (mother height) and sanitation (water treatment).

Conclusions: Our proposed group penalized GEE estimator with structured correlation matrix can properly model the complex ERP data and simultaneously identify informative biomarkers associated with such brain connectivity. The selected early-stage biomarkers offer a potential explanation for the adversity of neurocognitive development in low-income countries and facilitate early identification of infants at risk, as well as potential pathways for intervention.

Trial Registration: The related clinical study was retrospectively registered with https://doi.org/ClinicalTrials.gov , identifier NCT01375647, on June 3, 2011.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12874-020-01103-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457526PMC
August 2020

Ten simple rules for reading a scientific paper.

PLoS Comput Biol 2020 07 30;16(7):e1008032. Epub 2020 Jul 30.

Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pcbi.1008032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392212PMC
July 2020

Evaluation of K18- Mice as a Model of SARS-CoV-2 Infection.

Am J Trop Med Hyg 2020 Sep;103(3):1215-1219

Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia.

Murine models of SARS-CoV-2 infection are critical for elucidating the biological pathways underlying COVID-19. Because human angiotensin-converting enzyme 2 (ACE2) is the receptor for SARS-CoV-2, mice expressing the human gene have shown promise as a potential model for COVID-19. Five mice from the transgenic mouse strain K18- were intranasally inoculated with SARS-CoV-2 Hong Kong/VM20001061/2020. Mice were followed twice daily for 5 days and scored for weight loss and clinical symptoms. Infected mice did not exhibit any signs of infection until day 4, when no other obvious clinical symptoms other than weight loss were observed. By day 5, all infected mice had lost around 10% of their original body weight but exhibited variable clinical symptoms. All infected mice showed high viral titers in the lungs as well as altered lung histology associated with proteinaceous debris in the alveolar space, interstitial inflammatory cell infiltration, and alveolar septal thickening. Overall, these results show that the K18- transgenic background can be used to establish symptomatic SARS-CoV-2 infection and can be a useful mouse model for COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4269/ajtmh.20-0762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470527PMC
September 2020

Role of Microbiota-Derived Bile Acids in Enteric Infections.

Cell 2020 06;181(7):1452-1454

Department of Medicine, University of Virginia, PO Box 801340, Charlottesville, VA 22908-1340, USA. Electronic address:

In this issue of Cell, Alavi et al. report that infection by Vibrio cholerae is blocked by gut microbiome-mediated hydrolysis of bile acids. Cholera therefore joins amebic dysentery and Clostridioides difficile colitis as enteric infections profoundly influenced by the microbiome's impact on bile acid metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2020.05.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162987PMC
June 2020

TLR2 as a Therapeutic Target in Bacterial Infection.

Trends Mol Med 2020 08 17;26(8):715-717. Epub 2020 Jun 17.

Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA, USA; Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, USA; Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA. Electronic address:

Toll-like receptor (TLR) 2 recognizes and responds to threats early in bacterial infections and can influence the downstream immune response to the host's benefit or detriment. Therapeutic modulation of TLR2 signaling represents an underutilized opportunity to moderate the immune response to infection to promote an improved outcome for the host.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molmed.2020.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845793PMC
August 2020

Immune Profiling To Predict Outcome of Clostridioides difficile Infection.

mBio 2020 05 26;11(3). Epub 2020 May 26.

Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia, USA

There is a pressing need for biomarker-based models to predict mortality from and recurrence of infection (CDI). Risk stratification would enable targeted interventions such as fecal microbiota transplant, antitoxin antibodies, and colectomy for those at highest risk. Because severity of CDI is associated with the immune response, we immune profiled patients at the time of diagnosis. The levels of 17 cytokines in plasma were measured in 341 CDI inpatients. The primary outcome of interest was 90-day mortality. Increased tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), C-C motif chemokine ligand 5 (CCL-5), suppression of tumorigenicity 2 receptor (sST-2), IL-8, and IL-15 predicted mortality by univariate analysis. After adjusting for demographics and clinical characteristics, the mortality risk (as indicated by the hazard ratio [HR]) was higher for patients in the top 25th percentile for TNF-α (HR = 8.35, = 0.005) and IL-8 (HR = 4.45, = 0.01) and lower for CCL-5 (HR = 0.18,  ≤ 0.008). A logistic regression risk prediction model was developed and had an area under the receiver operating characteristic curve (AUC) of 0.91 for 90-day mortality and 0.77 for 90-day recurrence. While limited by being single site and retrospective, our work resulted in a model with a substantially greater predictive ability than white blood cell count. In conclusion, immune profiling demonstrated differences between patients in their response to CDI, offering the promise for precision medicine individualized treatment. infection is the most common health care-associated infection in the United States with more than 20% patients experiencing symptomatic recurrence. The complex nature of host-bacterium interactions makes it difficult to predict the course of the disease based solely on clinical parameters. In the present study, we built a robust prediction model using representative plasma biomarkers and clinical parameters for 90-day all-cause mortality. Risk prediction based on immune biomarkers and clinical variables may contribute to treatment selection for patients as well as provide insight into the role of immune system in pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mBio.00905-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251209PMC
May 2020

Gut microbiome communication with bone marrow regulates susceptibility to amebiasis.

J Clin Invest 2020 08;130(8):4019-4024

Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA.

The microbiome provides resistance to infection. However, the underlying mechanisms are poorly understood. We demonstrate that colonization with the intestinal bacterium Clostridium scindens protects from Entamoeba histolytica colitis via innate immunity. Introduction of C. scindens into the gut microbiota epigenetically altered and expanded bone marrow granulocyte-monocyte progenitors (GMPs) and resulted in increased intestinal neutrophils with subsequent challenge with E. histolytica. Introduction of C. scindens alone was sufficient to expand GMPs in gnotobiotic mice. Adoptive transfer of bone marrow from C. scindens-colonized mice into naive mice protected against amebic colitis and increased intestinal neutrophils. Children without E. histolytica diarrhea also had a higher abundance of Lachnoclostridia. Lachnoclostridia C. scindens can metabolize the bile salt cholate, so we measured deoxycholate and discovered that it was increased in the sera of C. scindens-colonized specific pathogen-free and gnotobiotic mice, as well as in children protected from amebiasis. Administration of deoxycholate alone increased GMPs and provided protection from amebiasis. We elucidated a mechanism by which C. scindens and the microbially metabolized bile salt deoxycholic acid alter hematopoietic precursors and provide innate protection from later infection with E. histolytica.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI133605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410058PMC
August 2020

Considering the Immune System during Fecal Microbiota Transplantation for Clostridioides difficile Infection.

Trends Mol Med 2020 05 17;26(5):496-507. Epub 2020 Feb 17.

Department of Microbiology, Immunology, and Cancer Biology, University of Virginia Health System, Charlottesville, Virginia 22908, USA; Department of Medicine, University of Virginia Health System, Charlottesville, Virginia 22908, USA; Department of Pathology, University of Virginia Health System, Charlottesville, Virginia 22908, USA.

Our understanding and utilization of fecal microbiota transplantation (FMT) has jump-started over the past two decades. Recent technological advancements in sequencing and metabolomics have allowed for better characterization of our intestinal microbial counterparts, triggering a surge of excitement in the fields of mucosal immunology and microbiology. This excitement is well founded, as demonstrated by 90% relapse-free cure rates in FMT treatment for recurrent Clostridioides difficile infections. Growing evidence suggests that in addition to bacterial factors, the host immune response during C. difficile infection greatly influences disease severity. In this review, we discuss recent advancements in understanding the interplay between immune cells and the microbiota and how they may relate to recovery from C. difficile through FMT therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molmed.2020.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198612PMC
May 2020

Mucosal immunity and the eradication of polio.

Science 2020 04;368(6489):362-363

Department of Medicine, University of Virginia, VA, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.abb8588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821416PMC
April 2020

New strategies for profiling and characterization of human milk oligosaccharides.

Glycobiology 2020 09;30(10):774-786

Complex Carbohydrate Research Center, The University of Georgia, Athens, GA 30602, USA.

Human breast milk is an incredibly rich and complex biofluid composed of proteins, lipids and complex carbohydrates, including a diverse repertoire of free human milk oligosaccharides (HMOs). Strikingly, HMOs are not digested by the infant but function as prebiotics for bacterial strains associated with numerous benefits. Considering the broad variety of beneficial effects of HMOs, and the vast number of factors that affect breast milk composition, the analysis of HMO diversity and complexity is of utmost relevance. Using human milk samples from a cohort of Bangladeshi mothers participating in a study on malnutrition and stunting in children, we have characterized breast milk oligosaccharide composition by means of permethylation followed by liquid chromatography coupled with high-resolution tandem mass spectrometry (LC-MS/MS) analysis. This approach identified over 100 different glycoforms and showed a wide diversity of milk composition, with a predominance of fucosylated and sialylated HMOs over nonmodified HMOs. We observed that these samples contain on average 80 HMOs, with the highest permethylated masses detected being >5000 mass units. Here we report an easily implemented method developed for the separation, characterization and relative quantitation of large arrays of HMOs, including higher molecular weight sialylated HMOs. Our ultimate goal is to create a simple, high-throughput method, which can be used for full characterization of sialylated and/or fucosylated HMOs. These results demonstrate how current analytical techniques can be applied to characterize human milk composition, providing new tools to help the scientific community shed new light on the impact of HMOs during infant development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/glycob/cwaa028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526734PMC
September 2020
-->