Publications by authors named "Alan L Rothman"

146 Publications

Longitudinal Analysis of Dengue Virus-Specific Memory T Cell Responses and Their Association With Clinical Outcome in Subsequent DENV Infection.

Front Immunol 2021 28;12:710300. Epub 2021 Jul 28.

Department of Cell and Molecular Biology, Institute for Immunology and Informatics, University of Rhode Island, Providence, RI, United States.

Memory T cells resulting from primary dengue virus (DENV) infection are hypothesized to influence the clinical outcome of subsequent DENV infection. However, the few studies involving prospectively collected blood samples have found weak and inconsistent associations with outcome and variable temporal trends in DENV-specific memory T cell responses between subjects. This study used both and cultured ELISPOT assays to further evaluate the associations between DENV serotype-cross-reactive memory T cells and severity of secondary infection. Using ELISPOT assays, frequencies of memory T cells secreting IFN-γ in response to DENV structural and non-structural peptide pools were low in PBMC from multiple time points prior to symptomatic secondary DENV infection and showed a variable response to infection. There were no differences in responses between subjects who were not hospitalized (NH, n=6) and those who were hospitalized with dengue hemorrhagic fever (hDHF, n=4). In contrast, responses in cultured ELISPOT assays were more reliably detectable prior to secondary infection and showed more consistent increases after infection. Responses in cultured ELISPOT assays were higher in individuals with hDHF (n=8) compared to NH (n=9) individuals before the secondary infection, with no difference between these groups after infection. These data demonstrate an association of pre-existing DENV-specific memory responses with the severity of illness in subsequent DENV infection, and suggest that frequencies of DENV-reactive T cells measured after short-term culture may be of particular importance for assessing the risk for more severe dengue disease.
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http://dx.doi.org/10.3389/fimmu.2021.710300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355709PMC
July 2021

Viral Suppression of RIPK1-Mediated Signaling.

mBio 2021 Aug 10;12(4):e0172321. Epub 2021 Aug 10.

Institute for Immunology and Informatics, University of Rhode Island, Providence, Rhode Island, USA.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) has emerged as a key upstream regulator of cell death and inflammation. RIPK1-mediated signaling governs the outcome of signaling pathways initiated by tumor necrosis factor receptor 1 (TNFR1), Toll-like receptor 3 (TLR3), TLR4, retinoic acid-inducible gene 1 (RIG-I)/melanoma differentiation-associated protein 5 (MDA-5), and Z-binding protein 1 (ZBP1) by signaling for NF-κB activation, mitogen-associated protein kinase (MAPK) and interferon regulatory factor 3/7 (IRF3/7) phosphorylation, and cell death via apoptosis and necroptosis. Both cell death and inflammatory responses play a major role in controlling virus infections. Therefore, viruses have evolved multifaceted mechanisms to exploit host immune responses by targeting RIPK1. This review focuses on the current understanding of RIPK1-mediated inflammatory and cell death pathways and multiple mechanisms by which viruses manipulate these pathways by targeting RIPK1. We also discuss gaps in our knowledge regarding RIPK1-mediated signaling pathways and highlight potential avenues for future research.
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http://dx.doi.org/10.1128/mBio.01723-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406217PMC
August 2021

The impact of dengue illness on social distancing and caregiving behavior.

PLoS Negl Trop Dis 2021 Jul 19;15(7):e0009614. Epub 2021 Jul 19.

Department of Global Community Health and Behavioral Sciences, Tulane School of Public Health and Tropical Medicine, New Orleans, Louisiana, United States of America.

Background: Human mobility among residential locations can drive dengue virus (DENV) transmission dynamics. Recently, it was shown that individuals with symptomatic DENV infection exhibit significant changes in their mobility patterns, spending more time at home during illness. This change in mobility is predicted to increase the risk of acquiring infection for those living with or visiting the ill individual. It has yet to be considered, however, whether social contacts are also changing their mobility, either by socially distancing themselves from the infectious individual or increasing contact to help care for them. Social, or physical, distancing and caregiving could have diverse yet important impacts on DENV transmission dynamics; therefore, it is necessary to better understand the nature and frequency of these behaviors including their effect on mobility.

Methodology And Principal Findings: Through community-based febrile illness surveillance and RT-PCR infection confirmation, 67 DENV positive (DENV+) residents were identified in the city of Iquitos, Peru. Using retrospective interviews, data were collected on visitors and home-based care received during the illness. While 15% of participants lost visitors during their illness, 22% gained visitors; overall, 32% of all individuals (particularly females) received visitors while symptomatic. Caregiving was common (90%), particularly caring by housemates (91%) and caring for children (98%). Twenty-eight percent of caregivers changed their behavior enough to have their work (and, likely, mobility patterns) affected. This was significantly more likely when caring for individuals with low "health-related quality of well-being" during illness (Fisher's Exact, p = 0.01).

Conclusions/significance: Our study demonstrates that social contacts of individuals with dengue modify their patterns of visitation and caregiving. The observed mobility changes could impact a susceptible individual's exposure to virus or a presymptomatic/clinically inapparent individual's contribution to onward transmission. Accounting for changes in social contact mobility is imperative in order to get a more accurate understanding of DENV transmission.
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http://dx.doi.org/10.1371/journal.pntd.0009614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354465PMC
July 2021

Evaluation of the extended efficacy of the Dengvaxia vaccine against symptomatic and subclinical dengue infection.

Nat Med 2021 08 24;27(8):1395-1400. Epub 2021 Jun 24.

Institute for Immunology and Informatics, Department of Cell and Molecular Biology, University of Rhode Island, Providence, RI, USA.

More than half of the world's population lives in areas at risk for dengue virus infection. A vaccine will be pivotal to controlling spread, however, the only licensed vaccine, Dengvaxia, has been shown to increase the risk of severe disease in a subset of individuals. Vaccine efforts are hampered by a poor understanding of antibody responses, including those generated by vaccines, and whether antibody titers can be used as a marker of protection from infection or disease. Here we present the results of an ancillary study to a phase III vaccine study (n = 611). All participants received three doses of either Dengvaxia or placebo and were followed for 6 years. We performed neutralization tests on annual samples and during confirmed dengue episodes (n = 16,508 total measurements). We use mathematical models to reconstruct long-term antibody responses to vaccination and natural infection, and to identify subclinical infections. There were 87 symptomatic infections reported, and we estimated that there were a further 351 subclinical infections. Cumulative vaccine efficacy was positive for both subclinical and symptomatic infection, although the protective effect of the vaccine was concentrated in the first 3 years following vaccination. Among individuals with the same antibody titer, we found no difference between the risk of subsequent infection or disease between placebo and vaccine recipients, suggesting that antibody titers are a good predictor of both protection and disease risk.
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http://dx.doi.org/10.1038/s41591-021-01392-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364868PMC
August 2021

Correlation between reported dengue illness history and seropositivity in rural Thailand.

PLoS Negl Trop Dis 2021 Jun 15;15(6):e0009459. Epub 2021 Jun 15.

State University of New York Upstate Medical University, Syracuse, New York, United States of America.

In the latest World Health Organization (WHO) recommendation for Dengvaxia implementation, either serological testing or a person's history of prior dengue illness may be used as supporting evidence to identify dengue virus (DENV)-immune individuals eligible for vaccination, in areas with limited capacity for laboratory confirmation. This analysis aimed to estimate the concordance between self-reported dengue illness histories and seropositivity in a prospective cohort study for dengue virus infection in Kamphaeng Phet province, a dengue-endemic area in northern Thailand. The study enrolled 2,076 subjects from 516 multigenerational families, with a median age of 30.6 years (range 0-90 years). Individual and family member dengue illness histories were obtained by questionnaire. Seropositivity was defined based on hemagglutination inhibition (HAI) assays. Overall seropositivity for DENV was 86.5% among those aged 9-45 years, which increased with age. 18.5% of participants reported a history of dengue illness prior to enrollment; 30.1% reported a previous DENV infection in the family, and 40.1% reported DENV infection in either themselves or a family member. Relative to seropositivity by HAI in the vaccine candidate group, the sensitivity and specificity of individual prior dengue illness history were 18.5% and 81.6%, respectively; sensitivity and specificity of reported dengue illness in a family member were 29.8% and 68.0%, and of either the individual or a family member were 40.1% and 60.5%. Notably, 13.4% of individuals reporting prior dengue illness were seronegative. Given the high occurrence of asymptomatic and mild DENV infection, self-reported dengue illness history is poorly sensitive for prior exposure and may misclassify individuals as 'exposed' when they were not. This analysis highlights that a simple, highly sensitive, and highly specific test for determining serostatus prior to Dengvaxia vaccination is urgently needed.
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http://dx.doi.org/10.1371/journal.pntd.0009459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232416PMC
June 2021

Immune-Based Interventions Against Infectious Disease - Impact of a Phase I Center for Biomedical Research Excellence in Translational Infectious Diseases Immunology.

R I Med J (2013) 2021 Mar 1;104(2):34-38. Epub 2021 Mar 1.

Center for International Health Research, Lifespan, and Department of Pathology and Laboratory Medicine, Brown University, Providence, RI.

In 2011, faculty from the University of Rhode Island (URI)'s Institute for Immunology and Informatics and Lifespan's Center for International Health Research collaborated to develop a successful application for a Phase I Center of Biomedical Research Excellence around the scientific theme of translational infectious diseases immunology. From 2013 to 2020, this COBRE supported significant discoveries in research on dengue, HIV, and malaria, among other diseases, and facilitated the career development of several independent Rhode Island (RI)-based early-stage investigators. Our experience illustrates both the potential and challenges for investigators with shared scientific interests to leverage the NIH COBRE program to enhance cross-institutional interactions.
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March 2021

Effect of low-passage number on dengue consensus genomes and intra-host variant frequencies.

J Gen Virol 2021 03 16;102(3). Epub 2021 Feb 16.

Walter Reed Army Institute of Research, Silver Spring, MD, USA.

Intra-host single nucleotide variants (iSNVs) have been increasingly used in genomic epidemiology to increase phylogenetic resolution and reconstruct fine-scale outbreak dynamics. These analyses are preferably done on sequence data from direct clinical samples, but in many cases due to low viral loads, there might not be enough genetic material for deep sequencing and iSNV determination. Isolation of the virus from clinical samples with low-passage number increases viral load, but few studies have investigated how dengue virus (DENV) culture isolation from a clinical sample impacts the consensus sequence and the intra-host virus population frequencies. In this study, we investigate consensus and iSNV frequency differences between DENV sequenced directly from clinical samples and their corresponding low-passage isolates. Twenty five DENV1 and DENV2 positive sera and their corresponding viral isolates ( inoculation and C6/36 passage) were obtained from a prospective cohort study in the Philippines. These were sequenced on MiSeq with minimum nucleotide depth of coverage of 500×, and iSNVs were detected using LoFreq. For both DENV1 and DENV2, we found a maximum of one consensus nucleotide difference between clinical sample and isolate. Interestingly, we found that iSNVs with frequencies ≥5 % were often preserved between the samples, and that the number of iSNV positions, and sample diversity, at this frequency cutoff did not differ significantly between the sample pairs (clinical sample and isolate) in either DENV1 or DENV2 data. Our results show that low-passage DENV isolate consensus genomes are largely representative of their direct sample parental viruses, and that low-passage isolates often mirror high frequency within-host variants from direct samples.
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http://dx.doi.org/10.1099/jgv.0.001553DOI Listing
March 2021

Temporally integrated single cell RNA sequencing analysis of PBMC from experimental and natural primary human DENV-1 infections.

PLoS Pathog 2021 01 29;17(1):e1009240. Epub 2021 Jan 29.

Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.

Dengue human infection studies present an opportunity to address many longstanding questions in the field of flavivirus biology. However, limited data are available on how the immunological and transcriptional response elicited by an attenuated challenge virus compares to that associated with a wild-type DENV infection. To determine the kinetic transcriptional signature associated with experimental primary DENV-1 infection and to assess how closely this profile correlates with the transcriptional signature accompanying natural primary DENV-1 infection, we utilized scRNAseq to analyze PBMC from individuals enrolled in a DENV-1 human challenge study and from individuals experiencing a natural primary DENV-1 infection. While both experimental and natural primary DENV-1 infection resulted in overlapping patterns of inflammatory gene upregulation, natural primary DENV-1 infection was accompanied with a more pronounced suppression in gene products associated with protein translation and mitochondrial function, principally in monocytes. This suggests that the immune response elicited by experimental and natural primary DENV infection are similar, but that natural primary DENV-1 infection has a more pronounced impact on basic cellular processes to induce a multi-layered anti-viral state.
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http://dx.doi.org/10.1371/journal.ppat.1009240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875406PMC
January 2021

Disease-driven reduction in human mobility influences human-mosquito contacts and dengue transmission dynamics.

PLoS Comput Biol 2021 01 19;17(1):e1008627. Epub 2021 Jan 19.

Program of Population Biology, Ecology and Evolution, Emory University, Atlanta, Georgia, United States of America.

Heterogeneous exposure to mosquitoes determines an individual's contribution to vector-borne pathogen transmission. Particularly for dengue virus (DENV), there is a major difficulty in quantifying human-vector contacts due to the unknown coupled effect of key heterogeneities. To test the hypothesis that the reduction of human out-of-home mobility due to dengue illness will significantly influence population-level dynamics and the structure of DENV transmission chains, we extended an existing modeling framework to include social structure, disease-driven mobility reductions, and heterogeneous transmissibility from different infectious groups. Compared to a baseline model, naïve to human pre-symptomatic infectiousness and disease-driven mobility changes, a model including both parameters predicted an increase of 37% in the probability of a DENV outbreak occurring; a model including mobility change alone predicted a 15.5% increase compared to the baseline model. At the individual level, models including mobility change led to a reduction of the importance of out-of-home onward transmission (R, the fraction of secondary cases predicted to be generated by an individual) by symptomatic individuals (up to -62%) at the expense of an increase in the relevance of their home (up to +40%). An individual's positive contribution to R could be predicted by a GAM including a non-linear interaction between an individual's biting suitability and the number of mosquitoes in their home (>10 mosquitoes and 0.6 individual attractiveness significantly increased R). We conclude that the complex fabric of social relationships and differential behavioral response to dengue illness cause the fraction of symptomatic DENV infections to concentrate transmission in specific locations, whereas asymptomatic carriers (including individuals in their pre-symptomatic period) move the virus throughout the landscape. Our findings point to the difficulty of focusing vector control interventions reactively on the home of symptomatic individuals, as this approach will fail to contain virus propagation by visitors to their house and asymptomatic carriers.
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http://dx.doi.org/10.1371/journal.pcbi.1008627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845972PMC
January 2021

Heterogeneity of Dengue Illness in Community-Based Prospective Study, Iquitos, Peru.

Emerg Infect Dis 2020 09;26(9):2077-2086

Measuring heterogeneity of dengue illness is necessary to define suitable endpoints in dengue vaccine and therapeutic trials and will help clarify behavioral responses to illness. To quantify heterogeneity in dengue illness, including milder cases, we developed the Dengue Illness Perceptions Response (IPR) survey, which captured detailed symptom data, including intensity, duration, and character, and change in routine activities caused by illness. During 2016-2019, we collected IPR data daily during the acute phase of illness for 79 persons with a positive reverse transcription PCR result for dengue virus RNA. Most participants had mild ambulatory disease. However, we measured substantial heterogeneity in illness experience, symptom duration, and maximum reported intensity of individual symptoms. Symptom intensity was a more valuable predicter of major activity change during dengue illness than symptom presence or absence alone. These data suggest that the IPR measures clinically useful heterogeneity in dengue illness experience and its relation to altered human behavior.
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http://dx.doi.org/10.3201/eid2609.191472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454099PMC
September 2020

T lymphocyte responses to flaviviruses - diverse cell populations affect tendency toward protection and disease.

Curr Opin Virol 2020 08 15;43:28-34. Epub 2020 Aug 15.

Institute for Immunology and Informatics and Department of Cell and Molecular Biology, University of Rhode Island, 80 Washington Street, Providence, RI 02903 USA. Electronic address:

Dengue virus (DENV), Yellow Fever virus, West Nile virus, Japanese encephalitis virus and Zika virus are medically important flaviviruses transmitted to humans by mosquitoes and circulate in overlapping geographic areas. Cross-reactive immune responses have been demonstrated among the flaviviruses, particularly the four DENV serotypes. The immunological imprint left by a flavivirus infection can therefore have profound effects on the responses to subsequent infections. In this review we summarize recent research focusing on T cell responses to DENV using clinical samples from prospective cohort studies in Asia. These data suggest that durability of different T cell populations after natural infection or vaccination is an important consideration for the outcome of subsequent flavivirus exposures and we argue for continued investigation in the context of longitudinal cohort studies.
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http://dx.doi.org/10.1016/j.coviro.2020.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655706PMC
August 2020

Major Histocompatibility Complex Class I Chain-Related A and B (MICA and MICB) Gene, Allele, and Haplotype Associations With Dengue Infections in Ethnic Thais.

J Infect Dis 2020 08;222(5):840-846

Department of Transfusion Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.

Background: Major histocompatibility complex class I chain-related (MIC) A and B (MICA and MICB) are polymorphic stress molecules recognized by natural killer cells. This study was performed to analyze MIC gene profiles in hospitalized Thai children with acute dengue illness.

Methods: MIC allele profiles were determined in a discovery cohort of patients with dengue fever or dengue hemorrhagic fever (DHF) (n = 166) and controls (n = 149). A replication cohort of patients with dengue (n = 222) was used to confirm specific MICB associations with disease.

Results: MICA*045 and MICB*004 associated with susceptibility to DHF in secondary dengue virus (DENV) infections (odds ratio [OR], 3.22; [95% confidence interval (CI), 1.18-8.84] and 1.99 [1.07-2.13], respectively), and MICB*002 with protection from DHF in secondary DENV infections (OR, 0.41; 95% CI, .21-.68). The protective effect of MICB*002 against secondary DHF was confirmed in the replication cohort (OR, 0.43; 95% CI, .22-.82) and was stronger when MICB*002 is present in individuals also carrying HLA-B*18, B*40, and B*44 alleles which form the B44 supertype of functionally related alleles (0.29, 95% CI, .14-.60).

Conclusions: Given that MICB*002 is a low expresser of soluble proteins, these data indicate that surface expression of MICB*002 with B44 supertype alleles on DENV-infected cells confer a protective advantage in controlling DENV infection using natural killer cells.
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http://dx.doi.org/10.1093/infdis/jiaa134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399699PMC
August 2020

Measuring health related quality of life for dengue patients in Iquitos, Peru.

PLoS Negl Trop Dis 2020 07 28;14(7):e0008477. Epub 2020 Jul 28.

Department of Global Community Health and Behavioral Sciences, Tulane School of Public Health and Tropical Medicine, New Orleans, Louisiana, United States of America.

Previous studies measuring the health-related quality of life (HRQoL) of individuals with dengue focused on treatment seeking populations. However, the vast majority of global dengue cases are unlikely to be detected by health systems. Representative measurements of HRQoL should therefore include patients with disease not likely to trigger treatment-seeking behavior. This study based in Iquitos, Peru used the Quality of Wellbeing Scale-Self Administered, a survey that enquires about not only physical health, but also psychological health, self-care, mobility, and usual social activities, and rates HRQoL between 0 (death) and 1 (optimum function), to evaluate the impact of dengue on HRQoL. In order to enroll treatment and non treatment-seeking participants, three modalities of participant recruitment were used. In addition to clinic and community-based febrile surveillance, a contact-cluster methodology was also employed to identify infected individuals less likely to seek treatment. We measured changes in HRQoL and identified common areas of health impairment in 73 virologically confirmed dengue cases at 3 time points during the participant's illness; the early-acute (days 0-6 post symptom onset), late-acute (days 7-20), and convalescent illness phases (days 21 +). Participants reported HRQoL related impairments at significantly higher frequency during the early-acute versus convalescent illness phase (Fisher's exact: P<0.01). There was substantial heterogeneity in scores during each illness phase with median scores in the early-acute, late-acute and convalescent phases of 0.56 (IQR: 0.41-0.64), 0.70 (IQR: 0.57-0.94), and 1 (IQR: 0.80-1.00), respectively. In all illness phases participants recruited in clinics had on average the lowest HRQoL scores where as those recruited in the contact clusters had the highest. Only 1 individual who was recruited in the contact-clusters had no reduction in HRQoL score during their illness. These data illustrate that dengue should be considered as a disease that may have significant implications for not only physical health but also psychological health and social functioning. The impact of dengue on the HRQoL of non-treatment-seeking individuals, although lower than the impact among treatment-seeking individuals, is not necessarily trivial.
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http://dx.doi.org/10.1371/journal.pntd.0008477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413550PMC
July 2020

Next-generation sequencing of 11 HLA loci in a large dengue vaccine cohort from the Philippines.

Hum Immunol 2020 Aug 9;81(8):437-444. Epub 2020 Jul 9.

U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA. Electronic address:

HLA genotyping by next-generation sequencing (NGS) has evolved with significant advancements in the last decade. Here we describe full-length HLA genotyping of 11 loci in 612 individuals comprising a dengue vaccine cohort from Cebu province in the Philippines. The multi-locus individual tagging NGS (MIT-NGS) method that we developed initially for genotyping 4-6 loci in one MiSeq run was expanded to 11 loci including HLA-A, B, C, DPA1, DPB1, DQA1, DQB1, DRB1, and DRB3/4/5. This change did not affect the overall coverage or depth of the sequencing reads. HLA alleles with frequencies greater than 10% were A*11:01:01, A*24:02:01, A*24:07:01, A*34:01:01, B*38:02:01, B*15:35, B*35:05:01, C*07:02:01, C*04:01:01, DPA1*02:02:02, DPB1*05:01:01, DPB1*01:01:01, DQA1*01:02:01, DQA1*06:01:01, DQB1*05:02:01, DQB1*03:01:01, DRB1*15:02:01, DRB1*12:02:01, DRB3*03:01:03, DRB4*01:03:01, and DRB5*01:01:01. Improvements in sequencing library preparation provide uniform and even coverage across all exons and introns. This has led to a marked reduction in allele imbalance and dropout. Furthermore, including more loci, such as DRB3/4/5, decreases cross-mapping and incorrect allele assignment at the DRB1 locus. The increased number of loci sequenced for each sample does not reduce the number of samples that can be multiplexed on a single MiSeq run and is therefore more cost-efficient. We believe that such improvements will help HLA genotyping by NGS to gain momentum over other conventional methods by increasing confidence in the calls.
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http://dx.doi.org/10.1016/j.humimm.2020.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442730PMC
August 2020

Analysis of cell-associated DENV RNA by oligo(dT) primed 5' capture scRNAseq.

Sci Rep 2020 06 3;10(1):9047. Epub 2020 Jun 3.

Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA.

Dengue is one of the most widespread vector-borne viral diseases in the world. However, the size, heterogeneity, and temporal dynamics of the cell-associated viral reservoir during acute dengue virus (DENV) infection remains unclear. In this study, we analyzed cells infected in vitro with DENV and PBMC from an individual experiencing a natural DENV infection utilizing 5' capture single cell RNA sequencing (scRNAseq). Both positive- and negative-sense DENV RNA was detected in reactions containing either an oligo(dT) primer alone, or in reactions supplemented with a DENV-specific primer. The addition of a DENV-specific primer did not increase the total amount of DENV RNA captured or the fraction of cells identified as containing DENV RNA. However, inclusion of a DENV-specific cDNA primer did increase the viral genome coverage immediately 5' to the primer binding site. Furthermore, while the majority of intracellular DENV sequence captured in this analysis mapped to the 5' end of the viral genome, distinct patterns of enhanced coverage within the DENV polyprotein coding region were observed. The 5' capture scRNAseq analysis of PBMC not only recapitulated previously published reports by detecting virally infected memory and naïve B cells, but also identified cell-associated genomic variants not observed in contemporaneous serum samples. These results demonstrate that oligo(dT) primed 5' capture scRNAseq can detect DENV RNA and quantify virus-infected cells in physiologically relevant conditions, and provides insight into viral sequence variability within infected cells.
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http://dx.doi.org/10.1038/s41598-020-65939-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270085PMC
June 2020

Transcriptional and clonal characterization of B cell plasmablast diversity following primary and secondary natural DENV infection.

EBioMedicine 2020 Apr 18;54:102733. Epub 2020 Apr 18.

Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United States.

Antibody-mediated humoral immunity is thought to play a central role in mediating the immunopathogenesis of acute DENV infection, but limited data are available on the diversity, specificity, and functionality of the antibody response at the molecular level elicited by primary or secondary DENV infection. In order to close this functional gap in our understanding of DENV-specific humoral immunity, we utilized high-throughput single cell RNA sequencing to investigate B cells circulating in both primary and secondary natural DENV infections. We captured full-length paired immunoglobulin receptor sequence data from 9,027 B cells from a total of 6 subjects, including 2,717 plasmablasts. In addition to IgG and IgM class-switched cells, we unexpectedly found a high proportion of the DENV-elicited plasmablasts expressing IgA, principally in individuals with primary DENV infections. These IgA class-switched cells were extensively hypermutated even in individuals with a serologically confirmed primary DENV infection. Utilizing a combination of conventional biochemical assays and high-throughput shotgun mutagenesis, we determined that DENV-reactive IgA class-switched antibodies represent a significant fraction of DENV-reactive Igs generated in response to DENV infection, and that they exhibit a comparable epitope specificity to DENV-reactive IgG antibodies. These results provide insight into the molecular-level diversity of DENV-elicited humoral immunity and identify a heretofore unappreciated IgA plasmablast response to DENV infection.
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http://dx.doi.org/10.1016/j.ebiom.2020.102733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170960PMC
April 2020

An Innovative, Prospective, Hybrid Cohort-Cluster Study Design to Characterize Dengue Virus Transmission in Multigenerational Households in Kamphaeng Phet, Thailand.

Am J Epidemiol 2020 07;189(7):648-659

Difficulties inherent in the identification of immune correlates of protection or severe disease have challenged the development and evaluation of dengue vaccines. There persist substantial gaps in knowledge about the complex effects of age and sequential dengue virus (DENV) exposures on these correlations. To address these gaps, we were conducting a novel family-based cohort-cluster study for DENV transmission in Kamphaeng Phet, Thailand. The study began in 2015 and is funded until at least 2023. As of May 2019, 2,870 individuals in 485 families were actively enrolled. The families comprise at least 1 child born into the study as a newborn, 1 other child, a parent, and a grandparent. The median age of enrolled participants is 21 years (range 0-93 years). Active surveillance is performed to detect acute dengue illnesses, and annual blood testing identifies subclinical seroconversions. Extended follow-up of this cohort will detect sequential infections and correlate antibody kinetics and sequence of infections with disease outcomes. The central goal of this prospective study is to characterize how different DENV exposure histories within multigenerational family units, from DENV-naive infants to grandparents with multiple prior DENV exposures, affect transmission, disease, and protection at the level of the individual, household, and community.
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http://dx.doi.org/10.1093/aje/kwaa008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393304PMC
July 2020

Cell-Mediated Immunity Generated in Response to a Purified Inactivated Vaccine for Dengue Virus Type 1.

mSphere 2020 01 22;5(1). Epub 2020 Jan 22.

Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.

Dengue is the most prevalent arboviral disease afflicting humans, and a vaccine appears to be the most rational means of control. Dengue vaccine development is in a critical phase, with the first vaccine licensed in some countries where dengue is endemic but demonstrating insufficient efficacy in immunologically naive populations. Since virus-neutralizing antibodies do not invariably correlate with vaccine efficacy, other markers that may predict protection, including cell-mediated immunity, are urgently needed. Previously, the Walter Reed Army Institute of Research developed a monovalent purified inactivated virus (PIV) vaccine candidate against dengue virus serotype 1 (DENV-1) adjuvanted with alum. The PIV vaccine was safe and immunogenic in a phase I dose escalation trial in healthy, flavivirus-naive adults in the United States. From that trial, peripheral blood mononuclear cells obtained at various time points pre- and postvaccination were used to measure DENV-1-specific T cell responses. After vaccination, a predominant CD4 T cell-mediated response to peptide pools covering the DENV-1 structural proteins was observed. Over half (13/20) of the subjects produced interleukin-2 (IL-2) in response to DENV peptides, and the majority (17/20) demonstrated peptide-specific CD4 T cell proliferation. In addition, analysis of postvaccination cell culture supernatants demonstrated an increased rate of production of cytokines, including gamma interferon (IFN-γ), IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Overall, the vaccine was found to have elicited DENV-specific CD4 T cell responses as measured by enzyme-linked immunosorbent spot (ELISpot), intracellular cytokine staining (ICS), lymphocyte proliferation, and cytokine production assays. Thus, together with antibody readouts, the use of a multifaceted measurement of cell-mediated immune responses after vaccination is a useful strategy for more comprehensively characterizing immunity generated by dengue vaccines. Dengue is a tropical disease transmitted by mosquitoes, and nearly half of the world's population lives in areas where individuals are at risk of infection. Several vaccines for dengue are in development, including one which was recently licensed in several countries, although its utility is limited to people who have already been infected with one of the four dengue viruses. One major hurdle to understanding whether a dengue vaccine will work for everyone-before exposure-is the necessity of knowing which marker can be measured in the blood to signal that the individual has protective immunity. This report describes an approach measuring multiple different parts of immunity in order to characterize which signals one candidate vaccine imparted to a small number of human volunteers. This approach was designed to be able to be applied to any dengue vaccine study so that the data can be compared and used to inform future vaccine design and/or optimization strategies.
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http://dx.doi.org/10.1128/mSphere.00671-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977178PMC
January 2020

Dengue illness impacts daily human mobility patterns in Iquitos, Peru.

PLoS Negl Trop Dis 2019 09 23;13(9):e0007756. Epub 2019 Sep 23.

Program of Population Biology, Ecology and Evolution, Emory University, Atlanta, Georgia, United States of America.

Background: Human mobility plays a central role in shaping pathogen transmission by generating spatial and/or individual variability in potential pathogen-transmitting contacts. Recent research has shown that symptomatic infection can influence human mobility and pathogen transmission dynamics. Better understanding the complex relationship between symptom severity, infectiousness, and human mobility requires quantification of movement patterns throughout infectiousness. For dengue virus (DENV), human infectiousness peaks 0-2 days after symptom onset, making it paramount to understand human movement patterns from the beginning of illness.

Methodology And Principal Findings: Through community-based febrile surveillance and RT-PCR assays, we identified a cohort of DENV+ residents of the city of Iquitos, Peru (n = 63). Using retrospective interviews, we measured the movements of these individuals when healthy and during each day of symptomatic illness. The most dramatic changes in mobility occurred during the first three days after symptom onset; individuals visited significantly fewer locations (Wilcoxon test, p = 0.017) and spent significantly more time at home (Wilcoxon test, p = 0.005), compared to when healthy. By 7-9 days after symptom onset, mobility measures had returned to healthy levels. Throughout an individual's symptomatic period, the day of illness and their subjective sense of well-being were the most significant predictors for the number of locations and houses they visited.

Conclusions/significance: Our study is one of the first to collect and analyze human mobility data at a daily scale during symptomatic infection. Accounting for the observed changes in human mobility throughout illness will improve understanding of the impact of disease on DENV transmission dynamics and the interpretation of public health-based surveillance data.
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http://dx.doi.org/10.1371/journal.pntd.0007756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776364PMC
September 2019

Longitudinal Analysis of Memory B and T Cell Responses to Dengue Virus in a 5-Year Prospective Cohort Study in Thailand.

Front Immunol 2019 13;10:1359. Epub 2019 Jun 13.

Institute for Immunology and Informatics, University of Rhode Island, Providence, RI, United States.

Prior exposure to dengue virus (DENV) has a profound impact on the outcome of infection, which varies according to the interval between infections. Antibodies secreted by B cells and cytokines secreted by T cells are thought to contribute both to protective immunity against DENV and the pathogenesis of dengue disease. We analyzed peripheral blood mononuclear cells (PBMC) collected from Thai children over a 5-year prospective cohort study to define the dynamics of DENV-specific memory B and T cell responses and the impact of symptomatic or subclinical DENV infections. To measure B cell responses, PBMC were stimulated with IL-2 plus R848 and culture supernatants were tested for DENV-binding antibodies by ELISA. To measure T cell responses, PBMC were stimulated in dual-color ELISPOT assays with overlapping peptide pools of structural and non-structural proteins from the four DENV types. B cell responses were low to one or more DENV types prior to symptomatic infection and increased with reactivity to all four types after infection. Subjects who had a subclinical infection or who did not experience a DENV infection during the study period showed strong memory B cell responses to all four DENV types. T cell responses to DENV peptides demonstrated a cytokine hierarchy of IFN-γ > IL-2 > IFN-γ/IL-2. T cell responses were low or absent prior to secondary infections. The trends in T cell responses to DENV peptides over 3 year post-infection were highly variable, but subjects who had experienced a secondary DENV1 infection showed higher cytokine responses compared to subjects who had experienced a secondary DENV2 or subclinical infection. The longitudinal nature of our study demonstrates persistent memory B cell responses over years and a lasting but variable impact of secondary DENV infection on DENV-specific T cell responses.
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http://dx.doi.org/10.3389/fimmu.2019.01359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585174PMC
October 2020

Protective versus pathologic pre-exposure cytokine profiles in dengue virus infection.

PLoS Negl Trop Dis 2018 12 17;12(12):e0006975. Epub 2018 Dec 17.

Institute for Immunology and Informatics, Department of Cell and Molecular Biology, University of Rhode Island, Providence, Rhode Island, United States of America.

Background: Hyperendemic circulation of all four types of dengue virus (DENV-1-4) has expanded globally, fueling concern for increased incidence of severe dengue. While the majority of DENV infections are subclinical, epidemiologic studies suggest that type-cross-reactive immunity can influence disease outcome in subsequent infections. The mechanisms controlling these differential clinical outcomes remain poorly defined.

Methodology/principal Findings: Blood samples were collected from a cohort of school-aged Thai children who subsequently experienced a subclinical DENV infection or developed dengue illness. PBMC collected prior to infection were stimulated in vitro with DENV and the secretion of 30 cytokines was measured using a multiplexed, bead-based array. Significant differences were found in cytokine production based on both the type of DENV used for stimulation and the occurrence of clinical illness. Secretion of IL-15 and MCP-1 was significantly higher by PBMC of subjects who later developed symptomatic DENV infection. In addition, IL-6 was produced by PBMC from all subjects who subsequently developed symptomatic infection, versus 59% of subjects who had subclinical infection. Secretion of IL-12, IL-2R, MIP-1α, RANTES, GM-CSF, and TNFα was significantly lower by PBMC from subjects with symptomatic infection.

Conclusions/significance: These data demonstrate significant differences in pre-existing immune responses to DENV associated with the clinical outcome of subsequent infection. The finding of higher levels of some cytokines in subjects with symptomatic infection and higher levels of other cytokines in subjects with subclinical infection supports the existence of both protective and pathologic immune profiles. Clinical-immunological correlations identified in the context of natural DENV infection may be useful for evaluating immune responses to dengue vaccines.
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http://dx.doi.org/10.1371/journal.pntd.0006975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312351PMC
December 2018

Multiplexed FluoroSpot for the Analysis of Dengue Virus- and Zika Virus-Specific and Cross-Reactive Memory B Cells.

J Immunol 2018 12 9;201(12):3804-3814. Epub 2018 Nov 9.

Institute for Immunology and Informatics, Department of Cell and Molecular Biology, University of Rhode Island, Providence, RI 02903;

Dengue virus (DENV) and Zika virus (ZIKV) are mosquito-borne pathogens that have a significant impact on human health. Immune sera, mAbs, and memory B cells (MBCs) isolated from patients infected with one DENV type can be cross-reactive with the other three DENV serotypes and even more distantly related flaviviruses such as ZIKV. Conventional ELISPOTs effectively measure Ab-secreting B cells but because they are limited to the assessment of a single Ag at a time, it is challenging to distinguish serotype-specific and cross-reactive MBCs in the same well. We developed a novel multifunction FluoroSpot assay using fluorescently labeled DENV and ZIKV (FLVs) that measures the cross-reactivity of Abs secreted by single B cells. Conjugation efficiency and recognition of FLVs by virus-specific Abs were confirmed by flow cytometry. Using a panel of DENV immune, ZIKV immune, and naive PBMC, FLVs were able to simultaneously detect DENV serotype-specific, ZIKV-specific, DENV serotype cross-reactive, and DENV/ZIKV cross-reactive Abs secreted by individual MBCs. Our findings indicate that the FLVs are sensitive and specific tools to detect specific and cross-reactive MBCs. These reagents will allow the assessment of the breadth as well as the durability of DENV/ZIKV B cell responses following vaccination or natural infection. This novel approach using FLVs in a FluoroSpot assay can be applied to other diseases such as influenza in which prior immunity with homosubtype- or heterosubtype-specific MBCs may influence subsequent infections.
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http://dx.doi.org/10.4049/jimmunol.1800892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289764PMC
December 2018

Use of structural equation models to predict dengue illness phenotype.

PLoS Negl Trop Dis 2018 10 1;12(10):e0006799. Epub 2018 Oct 1.

Institute for Immunology and Informatics, Department of Cell and Molecular Biology, University of Rhode Island, Providence, RI, United States of America.

Background: Early recognition of dengue, particularly patients at risk for plasma leakage, is important to clinical management. The objective of this study was to build predictive models for dengue, dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS) using structural equation modelling (SEM), a statistical method that evaluates mechanistic pathways.

Methods/findings: We performed SEM using data from 257 Thai children enrolled within 72 h of febrile illness onset, 156 with dengue and 101 with non-dengue febrile illnesses. Models for dengue, DHF, and DSS were developed based on data obtained three and one day(s) prior to fever resolution (fever days -3 and -1, respectively). Models were validated using data from 897 subjects who were not used for model development. Predictors for dengue and DSS included age, tourniquet test, aspartate aminotransferase, and white blood cell, % lymphocytes, and platelet counts. Predictors for DHF included age, aspartate aminotransferase, hematocrit, tourniquet test, and white blood cell and platelet counts. The models showed good predictive performances in the validation set, with area under the receiver operating characteristic curves (AUC) at fever day -3 of 0.84, 0.67, and 0.70 for prediction of dengue, DHF, and DSS, respectively. Predictive performance was comparable using data based on the timing relative to enrollment or illness onset, and improved closer to the critical phase (AUC 0.73 to 0.94, 0.61 to 0.93, and 0.70 to 0.96 for dengue, DHF, and DSS, respectively).

Conclusions: Predictive models developed using SEM have potential use in guiding clinical management of suspected dengue prior to the critical phase of illness.
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http://dx.doi.org/10.1371/journal.pntd.0006799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6181434PMC
October 2018

Activation of Peripheral T Follicular Helper Cells During Acute Dengue Virus Infection.

J Infect Dis 2018 10;218(10):1675-1685

Institute for Immunology and Informatics, Department of Cell and Molecular Biology, University of Rhode Island, Providence.

Background: Follicular helper T cells (TFH) are specialized CD4 T cells required for B-cell help and antibody production.

Methods: Given the postulated role of immune activation in dengue disease, we measured the expansion and activation of TFH in the circulation (peripheral TFH [pTFH]) collected from Thai children with laboratory-confirmed acute dengue virus (DENV) infection.

Results: We found significant expansion and activation of pTFH subsets during acute infection with the highest frequencies of activated pTFH (PD1hi pTFH and PD1+CD38+ pTFH) detected during the critical phase of illness. Numbers of activated pTFH were higher in patients with secondary compared with primary infections and in patients with more severe disease. We also found a positive correlation between the frequencies of activated pTFH and the frequencies of plasmablasts.

Conclusions: To our knowledge, this is the first ex vivo analysis of pTFH activation during acute DENV infection. Overall, our study supports the model that pTFH contribute to disease evolution during the critical stage of illness.
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http://dx.doi.org/10.1093/infdis/jiy360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927865PMC
October 2018

Reconstruction of antibody dynamics and infection histories to evaluate dengue risk.

Nature 2018 05 23;557(7707):719-723. Epub 2018 May 23.

Mathematical Modelling of Infectious Diseases Unit, Institut Pasteur, Paris, France.

As with many pathogens, most dengue infections are subclinical and therefore unobserved . Coupled with limited understanding of the dynamic behaviour of potential serological markers of infection, this observational problem has wide-ranging implications, including hampering our understanding of individual- and population-level correlates of infection and disease risk and how these change over time, between assay interpretations and with cohort design. Here we develop a framework that simultaneously characterizes antibody dynamics and identifies subclinical infections via Bayesian augmentation from detailed cohort data (3,451 individuals with blood draws every 91 days, 143,548 haemagglutination inhibition assay titre measurements). We identify 1,149 infections (95% confidence interval, 1,135-1,163) that were not detected by active surveillance and estimate that 65% of infections are subclinical. After infection, individuals develop a stable set point antibody load after one year that places them within or outside a risk window. Individuals with pre-existing titres of ≤1:40 develop haemorrhagic fever 7.4 (95% confidence interval, 2.5-8.2) times more often than naive individuals compared to 0.0 times for individuals with titres >1:40 (95% confidence interval: 0.0-1.3). Plaque reduction neutralization test titres ≤1:100 were similarly associated with severe disease. Across the population, variability in the size of epidemics results in large-scale temporal changes in infection and disease risk that correlate poorly with age.
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http://dx.doi.org/10.1038/s41586-018-0157-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6064976PMC
May 2018

Case Management of Dengue: Lessons Learned.

J Infect Dis 2017 03;215(suppl_2):S79-S88

Dengue Unit, Queen Sirikit National Institute of Child Health, Bangkok, Thailand ; and.

The global burden of dengue and its geographic distribution have increased over the past several decades. The introduction of dengue in new areas has often been accompanied by high case-fatality rates. Drawing on the experience in managing dengue cases at the Queen Sirikit National Institute of Child Health in Bangkok, Thailand, this article provides the authors' perspectives on key clinical lessons to improve dengue-related outcomes. Parallels between this clinical experience and outcomes reported in randomized controlled trials, results of efforts to disseminate practice recommendations, and suggestions for areas for further research are also discussed.
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http://dx.doi.org/10.1093/infdis/jiw609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5853291PMC
March 2017

Immune-mediated cytokine storm and its role in severe dengue.

Semin Immunopathol 2017 07 11;39(5):563-574. Epub 2017 Apr 11.

Institute for Immunology and Informatics, University of Rhode Island, 80 Washington St., Rm 302F, Providence, RI, 02903, USA.

Dengue remains one of the most important mosquito-borne diseases worldwide. Infection with one of the serologically related dengue viruses (DENVs) can lead to a wide range of clinical manifestations and severity. Severe dengue is characterized by plasma leakage and abnormal bleeding that can lead to shock and death. There is currently no specific treatment for severe dengue due to gaps in understanding of the underlying mechanisms. The transient period of vascular leakage is usually followed by a rapid recovery and is suggestive of the effects of short-lived biological mediators. Both the innate and the adaptive immune systems are activated in severe dengue and contribute to the cytokine production. We discuss the immunological events elicited during a DENV infection and identify candidate cytokines that may play a key role in the severe manifestations of dengue and possible interventions.
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http://dx.doi.org/10.1007/s00281-017-0625-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496927PMC
July 2017

Dengue virus induces mitochondrial elongation through impairment of Drp1-triggered mitochondrial fission.

Virology 2017 01 4;500:149-160. Epub 2016 Nov 4.

Institute for Immunology and Informatics, Department of Cell and Molecular Biology, University of Rhode Island, Providence, RI 02903, United States. Electronic address:

Mitochondria are highly dynamic organelles that undergo continuous cycles of fission and fusion to maintain essential cellular functions. An imbalance between these two processes can result in many pathophysiological outcomes. Dengue virus (DENV) interacts with cellular organelles, including mitochondria, to successfully replicate in cells. This study used live-cell imaging and found an increase in mitochondrial length and respiration during DENV infection. The level of mitochondrial fission protein, Dynamin-related protein 1 (Drp1), was decreased on mitochondria during DENV infection, as well as Drp1 phosphorylated on serine 616, which is important for mitochondrial fission. DENV proteins NS4b and NS3 were also associated with subcellular fractions of mitochondria. Induction of fission through uncoupling of mitochondria or overexpression of Drp1 wild-type and Drp1 with a phosphomimetic mutation (S616D) significantly reduced viral replication. These results demonstrate that DENV infection causes an imbalance in mitochondrial dynamics by inhibiting Drp1-triggered mitochondrial fission, which promotes viral replication.
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http://dx.doi.org/10.1016/j.virol.2016.10.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131733PMC
January 2017

Zika Virus: The Agent and Its Biology, With Relevance to Pathology.

Arch Pathol Lab Med 2017 Jan 20;141(1):33-42. Epub 2016 Oct 20.

From the Institute for Immunology and Informatics, Department of Cell and Molecular Biology, University of Rhode Island, Providence. Drs Medin and Rothman both contributed equally to the manuscript.

Once obscure, Zika virus (ZIKV) has attracted significant medical and scientific attention in the past year because of large outbreaks associated with the recent introduction of this virus into the Western hemisphere. In particular, the occurrence of severe congenital infections and cases of Guillain-Barré syndrome has placed this virus squarely in the eyes of clinical and anatomic pathologists. This review article provides a basic introduction to ZIKV, its genetics, its structural characteristics, and its biology. A multidisciplinary effort will be essential to establish clinicopathologic correlations of the basic virology of ZIKV in order to advance development of diagnostics, therapeutics, and vaccines.
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http://dx.doi.org/10.5858/arpa.2016-0409-RADOI Listing
January 2017
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