Publications by authors named "Mary E Wilson"

187 Publications

Airborne transmission of SARS-CoV-2.

Science 2020 10 5;370(6514):303-304. Epub 2020 Oct 5.

Institute for Applied Environmental Health, University of Maryland, College Park, MD 20742, USA.

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http://dx.doi.org/10.1126/science.abf0521DOI Listing
October 2020

Complement receptor 3 mediates ruffle-like, actin-rich aggregates during phagocytosis of Leishmania infantum metacyclics.

Exp Parasitol 2021 Jan 8;220:107968. Epub 2020 Aug 8.

Department of Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA; Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, 52242, USA; Veterans' Affairs Medical Center, Iowa City, IA, 52242, USA.

The parasitic protozoan Leishmania infantum resides primarily in macrophages throughout mammalian infection. Infection is initiated by deposition of the metacyclic promastigote into the dermis of a mammalian host by the sand fly vector. Promastigotes enter macrophages by ligating surface receptors such as complement receptor 3 (CR3), inducing phagocytosis of the parasite. At the binding site of metacyclic promastigotes, we observed large asymmetrical aggregates of macrophage membrane with underlying actin, resembling membrane ruffles. Actin accumulation was observed at the point of initial contact, before phagosome formation and accumulation of peri-phagosomal actin. Ruffle-like structures did not form during phagocytosis of attenuated promastigotes or during phagocytosis of the intracellular amastigote form of L. infantum. Entry of promastigotes through massive actin accumulation was associated with a subsequent delay in fusion of the parasitophorous vacuole (PV) with the lysosomal markers LAMP-1 and Cathepsin D. Actin accumulation was also associated with entry through CR3, since macrophages from CD11b knockout (KO) mice did not form massive aggregates of actin during phagocytosis of metacyclic promastigotes. Furthermore, intracellular survival of L. infantum was significantly decreased in CD11b KO compared to wild type macrophages, although entry rates were similar. We conclude that both promastigote virulence and host cell CR3 are needed for the formation of ruffle-like membrane structures at the site of metacyclic promastigote phagocytosis, and that formation of actin-rich aggregates during entry correlates with the intracellular survival of virulent promastigotes.
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http://dx.doi.org/10.1016/j.exppara.2020.107968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750307PMC
January 2021

Anti-Interleukin-10 Unleashes Transcriptional Response to Leishmanial Antigens in Visceral Leishmaniasis Patients.

J Infect Dis 2021 Feb;223(3):517-521

Department of Pathology, University of Cambridge, Cambridge, United Kingdom.

Visceral leishmaniasis (VL; Leishmania donovani) cases produce interferon-γ and tumor necrosis factor in response to soluble leishmanial antigen (SLA) in whole-blood assays. Using transcriptional profiling, we demonstrate the impact of interleukin-10 (IL-10), a cytokine implicated in VL, on this response. SLA stimulation identified 28 differentially expressed genes (DEGs), 17/28 in a single network with TNF as hub. SLA plus anti-IL-10 produced 454 DEGs, 292 in a single network with TNF, IFNG, NFKBIA, IL6, and IL1B as hubs in concert with a remarkable chemokine/cytokine storm. Our data demonstrate the singular effect of IL-10 as a potent immune modulator in VL.
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http://dx.doi.org/10.1093/infdis/jiaa381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881328PMC
February 2021

Re-starting travel in the era of COVID-19: preparing anew.

J Travel Med 2020 Aug;27(5)

Travel Medicine Center, Mount Auburn Hospital, Cambridge, MA, USA.

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http://dx.doi.org/10.1093/jtm/taaa108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337735PMC
August 2020

Generation and Characterization of a Dual-Reporter Transgenic Line Expressing eGFP and Luciferase.

Front Cell Infect Microbiol 2019 22;9:468. Epub 2020 Jan 22.

Instituto Gonçalo Moniz, FIOCRUZ, Salvador, Brazil.

In this study, we generated a transgenic strain of , an etiological agent associated with a diversity of clinical manifestations of leishmaniasis ranging from localized cutaneous to mucocutaneous to disseminated disease. Transgenic parasites expressing reporter proteins are valuable tools for studies of parasite biology, host-pathogen interactions, and anti-parasitic drug development. To this end, we constructed an line stably expressing the reporters eGFP and luciferase (eGFP-LUC . The integration cassette co-expressing the two reporters was targeted to the ribosomal locus () of the parasite genome. Transgenic parasites were characterized for their infectivity and stability both and . Parasite maintenance in axenic long-term culture in the absence of selective drugs did not alter expression of the two reporters or infection of BALB/c mice, indicating stability of the integrated cassette. Infectivity of eGFP-LUC, , both and was similar to that obtained with the parental wild type strain. The possibility of tracking and quantification using fluorescence and luminescence broadens the scope of research involving this neglected species, despite its importance in terms of public health concerning the leishmaniasis burden.
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http://dx.doi.org/10.3389/fcimb.2019.00468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987073PMC
August 2020

What goes on board aircraft? Passengers include Aedes, Anopheles, 2019-nCoV, dengue, Salmonella, Zika, et al.

Authors:
Mary E Wilson

Travel Med Infect Dis 2020 Jan - Feb;33:101572. Epub 2020 Feb 5.

Clinical Professor of Epidemiology and Biostatistics, School of Medicine, University of California, San Francisco, USA; Adjunct Professor of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.tmaid.2020.101572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7128115PMC
March 2020

Travellers give wings to novel coronavirus (2019-nCoV).

J Travel Med 2020 03;27(2)

Travel Medicine Center, Mount Auburn Hospital, 330 Mt Auburn St, Cambridge, MA 02138, USA.

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http://dx.doi.org/10.1093/jtm/taaa015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7107561PMC
March 2020

Yellow fever control: current epidemiology and vaccination strategies.

Trop Dis Travel Med Vaccines 2020 10;6. Epub 2020 Jan 10.

3Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA USA.

Yellow fever (YF) outbreaks continue, have expanded into new areas and threaten large populations in South America and Africa. Predicting where epidemics might occur must take into account local mosquito populations and specific YF virus strain, as well as ecoclimatic conditions, sociopolitical and demographic factors including population size, density, and mobility, and vaccine coverage. Populations of and from different regions vary in susceptibility to and capacity to transmit YF virus. YF virus cannot be eliminated today because the virus circulates in animal reservoirs, but human disease could be eliminated with wide use of the vaccine. WHO EYE (Eliminate Yellow Fever Epidemics) is a welcome plan to control YF, with strategies to be carried out from 2017 to 2026: to expand use of YF vaccine, to prevent international spread, and to contain outbreaks rapidly. YF vaccination is the mainstay in controlling YF outbreaks, but global supply is insufficient. Therefore, dose-sparing strategies have been proposed including fractional dosing and intradermal administration. Fractional dosing has been effectively used in outbreak control but currently does not satisfy International Health Regulations; special documentation is needed for international travel. Vector control is another facet in preventing YF outbreaks, and novel methods are being considered and proposed.
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http://dx.doi.org/10.1186/s40794-020-0101-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954598PMC
January 2020

The afterlife of antibiotics.

Authors:
Mary E Wilson

J Travel Med 2020 02;27(1)

Clinical Professor of Epidemiology and Biostatistics, School of Medicine, University of California, San Francisco, CA, Adjunct Professor of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

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http://dx.doi.org/10.1093/jtm/taz102DOI Listing
February 2020

Bayesian compartmental models and associated reproductive numbers for an infection with multiple transmission modes.

Biometrics 2020 09 16;76(3):711-721. Epub 2019 Dec 16.

Department of Epidemiology, University of Iowa College of Public Health, Iowa City, Iowa.

Zoonotic visceral leishmaniasis (ZVL) is a serious neglected tropical disease that is endemic in 98 countries. ZVL is primarily transmitted via a sand fly vector. In the United States, it is enzootic in some canine populations; it is transmitted from infectious mother to pup transplacentally, and vector-borne transmission is absent. This absence affords a unique opportunity to study (1) vertical transmission dynamics in dogs and (2) the importance of vertical transmission in maintaining an infectious reservoir in the presence of a vector. In this paper, we present Bayesian compartmental models and reproductive number formulations to examine (1) and (2), providing a mechanism to plan and evaluate interventions in regions where both transmission modes are present. First, we propose an individual-level susceptible, infectious, removed (SIR) model to study the effect of maternal infection status during pregnancy on pup infection progression. We provide evidence that pups born to diagnostically positive mothers during pregnancy are more likely to become diagnostically positive both earlier in life, and at some point during their lifetime, than those born to diagnostically negative mothers. Second, we propose a population-level SIR model to study the impact of a vertically maintained reservoir on propagating infection in a naive canine population through emergent vector transmission using simulation studies. We also present reproductive numbers to quantify contributions of vertically infected and vector-infected dogs to maintaining infection in the population. We show that a vertically maintained canine reservoir can propagate infection in a theoretical naive population in the presence of a vector.
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http://dx.doi.org/10.1111/biom.13192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673222PMC
September 2020

Bayesian compartmental model for an infectious disease with dynamic states of infection.

J Appl Stat 2019 10;46(6):1043-1065. Epub 2018 Oct 10.

Department of Epidemiology, University of Iowa College of Public Health, USA.

Population-level proportions of individuals that fall at different points in the spectrum [of disease severity], from asymptomatic infection to severe disease, are often difficult to observe, but estimating these quantities can provide information about the nature and severity of the disease in a particular population. Logistic and multinomial regression techniques are often applied to infectious disease modeling of large populations and are suited to identifying variables associated with a particular disease or disease state. However, they are less appropriate for estimating infection state prevalence over time because they do not naturally accommodate known disease dynamics like duration of time an individual is infectious, heterogeneity in the risk of acquiring infection, and patterns of seasonality. We propose a Bayesian compartmental model to estimate latent infection state prevalence over time that easily incorporates known disease dynamics. We demonstrate how and why a stochastic compartmental model is a better approach for determining infection state proportions than multinomial regression is by using a novel method for estimating Bayes factors for models with high-dimensional parameter spaces. We provide an example using visceral leishmaniasis in Brazil and present an empirically-adjusted reproductive number for the infection.
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http://dx.doi.org/10.1080/02664763.2018.1531979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752225PMC
October 2018

Arbovirus on board - Predicting dengue importation into China.

Authors:
Mary E Wilson

Travel Med Infect Dis 2019 Sep - Oct;31:101476. Epub 2019 Sep 6.

Epidemiology and Biostatistics, School of Medicine, University of California, San Francisco, USA; Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.tmaid.2019.101476DOI Listing
October 2019

Zika circulation, congenital syndrome, and current guidelines: making sense of it all for the traveller.

Curr Opin Infect Dis 2019 10;32(5):381-389

Purpose Of Review: Zika virus (ZIKV) swept through the Americas and led to recognition of its neurotropism. Zika circulation elsewhere in the world, nonvector transmission including maternal-fetal/sexual/transfusion routes, and additional reports on congenital Zika syndrome (CZS) and Guillain-Barré syndrome (GBS) have been published.

Recent Findings: In 2018-2019, ZIKV transmission occurred in Cuba, India, and is suspected to appear sporadically in other countries. Maternal-fetal ZIKV transmission appears to occur in about 26% of ZIKV-infected pregnant women. The US ZIKV Pregnancy and Infant Registry identified 6% of live births to have at least one ZIKV-associated birth defect; 9% had at least one neurodevelopmental abnormality; 1% had both. Infectious virus was rarely isolated from semen of ZIKV-infected male patients beyond day 38 after symptom onset. Brazilian blood donations had low ZIKV prevalence in 2015-2016; in the United States, screening donations was cost-effective only in the high mosquito season in Puerto Rico.

Summary: ZIKV transmission continues; many countries with competent mosquitoes are at risk. Transmission can occur without detection where surveillance is poor and laboratory capacity limited. Travelers are important sentinels. Variations exist among ZIKV strains and Aedes mosquitoes that influence competence for transmission. Maternal-fetal transmission results in significant rates of abnormality. Identification of infectious virus in semen clarifies sexual transmission risk, with updated recommendations for preconception planning. ZIKV neurotropism requires further research and long-term follow-up.
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http://dx.doi.org/10.1097/QCO.0000000000000575DOI Listing
October 2019

Leishmania major degrades murine CXCL1 - An immune evasion strategy.

PLoS Negl Trop Dis 2019 07 1;13(7):e0007533. Epub 2019 Jul 1.

Inflammation Program, University of Iowa, Iowa City, IA, United States of America.

Leishmaniasis is a global health problem with an estimated report of 2 million new cases every year and more than 1 billion people at risk of contracting this disease in endemic areas. The innate immune system plays a central role in controlling L. major infection by initiating a signaling cascade that results in production of pro-inflammatory cytokines and recruitment of both innate and adaptive immune cells. Upon infection with L. major, CXCL1 is produced locally and plays an important role in the recruitment of neutrophils to the site of infection. Herein, we report that L. major specifically targets murine CXCL1 for degradation. The degradation of CXCL1 is not dependent on host factors as L. major can directly degrade recombinant CXCL1 in a cell-free system. Using mass spectrometry, we discovered that the L. major protease cleaves at the C-terminal end of murine CXCL1. Finally, our data suggest that L. major metalloproteases are involved in the direct cleavage and degradation of CXCL1, and a synthetic peptide spanning the CXCL1 cleavage site can be used to inhibit L. major metalloprotease activity. In conclusion, our study has identified an immune evasion strategy employed by L. major to evade innate immune responses in mice, likely reservoirs in the endemic areas, and further highlights that targeting these L. major metalloproteases may be important in controlling infection within the reservoir population and transmittance of the disease.
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http://dx.doi.org/10.1371/journal.pntd.0007533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625741PMC
July 2019

Coinfection with Leishmania major and Staphylococcus aureus enhances the pathologic responses to both microbes through a pathway involving IL-17A.

PLoS Negl Trop Dis 2019 05 20;13(5):e0007247. Epub 2019 May 20.

Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, United States of America.

Cutaneous leishmaniasis (CL) is a parasitic disease causing chronic, ulcerating skin lesions. Most humans infected with the causative Leishmania protozoa are asymptomatic. Leishmania spp. are usually introduced by sand flies into the dermis of mammalian hosts in the presence of bacteria from either the host skin, sand fly gut or both. We hypothesized that bacteria at the dermal inoculation site of Leishmania major will influence the severity of infection that ensues. A C57BL/6 mouse ear model of single or coinfection with Leishmania major, Staphylococcus aureus, or both showed that single pathogen infections caused localized lesions that peaked after 2-3 days for S. aureus and 3 weeks for L. major infection, but that coinfection produced lesions that were two-fold larger than single infection throughout 4 weeks after coinfection. Coinfection increased S. aureus burdens over 7 days, whereas L. major burdens (3, 7, 28 days) were the same in singly and coinfected ears. Inflammatory lesions throughout the first 4 weeks of coinfection had more neutrophils than did singly infected lesions, and the recruited neutrophils from early (day 1) lesions had similar phagocytic and NADPH oxidase capacities. However, most neutrophils were apoptotic, and transcription of immunomodulatory genes that promote efferocytosis was not upregulated, suggesting that the increased numbers of neutrophils may, in part, reflect defective clearance and resolution of the inflammatory response. In addition, the presence of more IL-17A-producing γδ and non-γδ T cells in early lesions (1-7 days), and L. major antigen-responsive Th17 cells after 28 days of coinfection, with a corresponding increase in IL-1β, may recruit more naïve neutrophils into the inflammatory site. Neutralization studies suggest that IL-17A contributed to an enhanced inflammatory response, whereas IL-1β has an important role in controlling bacterial replication. Taken together, these data suggest that coinfection of L. major infection with S. aureus exacerbates disease, both by promoting more inflammation and neutrophil recruitment and by increasing neutrophil apoptosis and delaying resolution of the inflammatory response. These data illustrate the profound impact that coinfecting microorganisms can exert on inflammatory lesion pathology and host adaptive immune responses.
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http://dx.doi.org/10.1371/journal.pntd.0007247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527190PMC
May 2019

Determinants for progression from asymptomatic infection to symptomatic visceral leishmaniasis: A cohort study.

PLoS Negl Trop Dis 2019 03 27;13(3):e0007216. Epub 2019 Mar 27.

Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India.

Background: Asymptomatic Leishmania donovani infections outnumber clinical presentations, however the predictors for development of active disease are not well known. We aimed to identify serological, immunological and genetic markers for progression from L. donovani infection to clinical Visceral Leishmaniasis (VL).

Methods: We enrolled all residents >2 years of age in 27 VL endemic villages in Bihar (India). Blood samples collected on filter paper on two occasions 6-12 months apart, were tested for antibodies against L. donovani with rK39-ELISA and DAT. Sero converters, (negative for both tests in the first round but positive on either of the two during the second round) and controls (negative on both tests on both occasions) were followed for three years. At the start of follow-up venous blood was collected for the following tests: DAT, rK39- ELISA, Quantiferon assay, SNP/HLA genotyping and L.donovani specific quantitative PCR.

Results: Among 1,606 subjects enrolled,17 (8/476 seroconverters and 9/1,130 controls) developed VL (OR 3.1; 95% CI 1.1-8.3). High DAT and rK39 ELISA antibody titers as well as positive qPCR were strongly and significantly associated with progression from seroconversion to VL with odds ratios of 19.1, 30.3 and 20.9 respectively. Most VL cases arose early (median 5 months) during follow-up.

Conclusion: We confirmed the strong association between high DAT and/or rK39 titers and progression to disease among asymptomatic subjects and identified qPCR as an additional predictor. Low predictive values do not warrant prophylactic treatment but as most progressed to VL early during follow-up, careful oberservation of these subjects for at least 6 months is indicated.
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http://dx.doi.org/10.1371/journal.pntd.0007216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453476PMC
March 2019

Sex-Related Differences in Immune Response and Symptomatic Manifestations to Infection with Species.

J Immunol Res 2019 10;2019:4103819. Epub 2019 Jan 10.

Department of Biology, University of Northern Iowa, Cedar Falls, IA 50614, USA.

Worldwide, an estimated 12 million people are infected with spp. and an additional 350 million are at risk of infection. Leishmania are intracellular parasites that cause disease by suppressing macrophage microbicidal responses. Infection can remain asymptomatic or lead to a spectrum of diseases including cutaneous, mucocutaneous, and visceral leishmaniasis. Ultimately, the combination of both pathogen and host factors determines the outcome of infection. Leishmaniasis, as well as numerous other infectious diseases, exhibits sex-related differences that cannot be explained solely in terms of environmental exposure or healthcare access. Furthermore, transcriptomic evidence is revealing that biological sex is a variable impacting physiology, immune response, drug metabolism, and consequently, the progression of disease. Herein, we review the distribution, morbidity, and mortality among male and female leishmaniasis patients. Additionally, we discuss experimental findings and new avenues of research concerning sex-specific responses in cutaneous and visceral leishmaniasis. The limitations of current therapies and the emergence of drug-resistant parasites underscore the need for new treatments that could harness the host immune response. As such, understanding the mechanisms driving the differential immune response and disease outcome of males versus females is a necessary step in the development of safer and more effective treatments against leishmaniasis.
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http://dx.doi.org/10.1155/2019/4103819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348913PMC
March 2019

RNA inhibitors of nuclear proteins responsible for multiple organ dysfunction syndrome.

Nat Commun 2019 01 10;10(1):116. Epub 2019 Jan 10.

Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA.

The development of multiple organ dysfunction syndrome (MODS) following infection or tissue injury is associated with increased patient morbidity and mortality. Extensive cellular injury results in the release of nuclear proteins, of which histones are the most abundant, into the circulation. Circulating histones are implicated as essential mediators of MODS. Available anti-histone therapies have failed in clinical trials due to off-target effects such as bleeding and toxicity. Here, we describe a therapeutic strategy for MODS based on the neutralization of histones by chemically stabilized nucleic acid bio-drugs (aptamers). Systematic evolution of ligands by exponential enrichment technology identified aptamers that selectively bind those histones responsible for MODS and do not bind to serum proteins. We demonstrate the efficacy of histone-specific aptamers in human cells and in a murine model of MODS. These aptamers could have a significant therapeutic benefit in the treatment of multiple diverse clinical conditions associated with MODS.
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http://dx.doi.org/10.1038/s41467-018-08030-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328615PMC
January 2019

Epidemiological characteristics and determinants of dengue transmission during epidemic and non-epidemic years in Fortaleza, Brazil: 2011-2015.

PLoS Negl Trop Dis 2018 12 3;12(12):e0006990. Epub 2018 Dec 3.

Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.

Background: After being eliminated during the 1950s, dengue reemerged in Brazil in the 1980s. Since then, incidence of the disease has increased, as serotypes move within and between cities. The co-circulation of multiple serotypes contributes to cycles of epidemic and interepidemic years, and a seasonal pattern of transmission is observed annually. Little is known regarding possible differences in the epidemiology of dengue under epidemic and interepidemic scenarios. This study addresses this gap and aims to assess the epidemiological characteristics and determinants of epidemic and interepidemic dengue transmission, utilizing data from the 5th largest city in Brazil (Fortaleza), at fine spatial and temporal scales.

Methods/principal Findings: Longitudinal models of monthly rates of confirmed dengue cases were used to estimate the differential contribution of contextual factors to dengue transmission in Fortaleza between 2011 and 2015. Models were stratified by annual climatological schedules and periods of interepidemic and epidemic transmission, controlling for social, economic, structural, entomological, and environmental factors. Results revealed distinct seasonal patterns between interepidemic and epidemic years, with persistent transmission after June in interepidemic years. Dengue was strongly associated with violence across strata, and with poverty and irregular garbage collection during periods of low transmission, but not with other indicators of public service provision or structural deprivation. Scrapyards and sites associated with tire storage were linked to incidence differentially between seasons, with the strongest associations during transitional precipitation periods. Hierarchical clustering analysis suggests that the dengue burden concentrates in the southern periphery of the city, particularly during periods of minimal transmission.

Conclusions/significance: Our findings have direct programmatic implications. Vector control operations must be sustained after June even in non-epidemic years. More specifically, scrapyards and sites associated with tires (strongly associated with incidence during periods of minimal transmission), require sustained entomological surveillance, particularly during interepidemic intervals and in the urban periphery. Intersectoral collaborations that address urban violence are critical for facilitating the regular activities of vector control agents.
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http://dx.doi.org/10.1371/journal.pntd.0006990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292645PMC
December 2018

Early Suppression of Macrophage Gene Expression by .

Front Microbiol 2018 15;9:2464. Epub 2018 Oct 15.

Serviço de Imunologia, Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil.

is an intracellular parasite that resides mostly in macrophages. Both the parasite genome and the clinical disease manifestations show considerable polymorphism. Clinical syndromes caused by include localized cutaneous (CL), mucosal (ML), and disseminated leishmaniasis (DL). Our prior studies showed that genetically distinct clades associate with different clinical types. Herein, we hypothesized that: (1) induces changes in macrophage gene expression that facilitates infection; (2) infection of macrophages with strains associated with CL (clade B), ML (clade C), or DL (clade A) will differentially affect host cell gene expression, reflecting their different pathogenic mechanisms; and (3) differences between the strains will be reflected by differences in macrophage gene expression after initial exposure to the parasite. Human monocyte derived macrophages were infected with isolates from clades A, B, or C. Patterns of gene expression were compared using Affymetrix DNA microarrays. Many transcripts were significantly decreased by infection with all isolates. The most dramatically decreased transcripts encoded proteins involved in signaling pathways, apoptosis, or mitochondrial oxidative phosphorylation. Some transcripts encoding stress response proteins were up-regulated. Differences between clades were observed in the magnitude of change, rather than the identity of transcripts. Isolates from subjects with metastatic disease (ML and DL) induced a greater magnitude of change than isolates from CL. We conclude that enhances its intracellular survival by inhibiting macrophage pathways leading to microbicidal activity. Parasite strains destined for dissemination may exert a more profound suppression than less invasive strains that remain near the cutaneous site of inoculation.
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http://dx.doi.org/10.3389/fmicb.2018.02464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196312PMC
October 2018

Surveillance of travel-related infections in China.

Lancet Public Health 2018 08 20;3(8):e356-e357. Epub 2018 Jul 20.

School of Medicine, University of California, San Francisco, San Francisco, CA, USA; Harvard TH Chan School of Public Health, Boston, MA, USA.

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http://dx.doi.org/10.1016/S2468-2667(18)30136-1DOI Listing
August 2018

Extracellular release of virulence factor major surface protease via exosomes in Leishmania infantum promastigotes.

Parasit Vectors 2018 Jun 19;11(1):355. Epub 2018 Jun 19.

Department of Biomedical Sciences and One Health Center for Zoonoses and Tropical Veterinary Medicine, Ross University School of Veterinary Medicine, St. Kitts & Nevis, West Indies, USA.

Background: The Leishmania spp. protozoa are introduced into humans through a sand fly blood meal, depositing the infectious metacyclic promastigote form of the parasite into human skin. Parasites enter a variety of host cells, although a majority are found in macrophages where they replicate intracellularly during chronic leishmaniasis. Symptomatic leishmaniasis causes considerable human morbidity in endemic regions. The Leishmania spp. evade host microbicidal mechanisms partially through virulence-associated proteins such as the major surface protease (MSP or GP63), to inactivate immune factors in the host environment. MSP is a metalloprotease encoded by a tandem array of genes belonging to three msp gene classes, whose mRNAs are differentially expressed in different life stages of the parasite. Like other cells, Leishmania spp. release small membrane-bound vesicles called exosomes into their environment. The purpose of this study was to detect MSP proteins in exosomal vesicles of Leishmania spp. protozoa.

Methods: Using mass spectrometry data we determined the profile of MSP class proteins released in L. infantum exosomes derived from promastigotes in their avirulent procyclic (logarithmic) stage and virulent stationary and metacyclic stages. MSP protein isoforms belonging to each of the three msp gene classes could be identified by unique peptides.

Results: Metacyclic promastigote exosomes contained the highest, and logarithmic exosomes had the lowest abundance of total MSP. Among the MSP classes, MSPC class had the greatest variety of isoforms, but was least abundant in all exosomes. Nonetheless, all MSP classes were present at higher levels in exosomes released from stationary or metacyclic promastigotes than logarithmic promastigotes.

Conclusions: The data suggest the efficiency of exosome release may be more important than the identity of MSP isoform in determining the MSP content of Leishmania spp. exosomes.
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http://dx.doi.org/10.1186/s13071-018-2937-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006689PMC
June 2018

Reply: regarding business travelers.

J Travel Med 2018 01;25(1)

Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

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http://dx.doi.org/10.1093/jtm/tay031DOI Listing
January 2018

Changing demographics of visceral leishmaniasis in northeast Brazil: Lessons for the future.

PLoS Negl Trop Dis 2018 03 6;12(3):e0006164. Epub 2018 Mar 6.

Health Graduate Program, Health Science Center; Federal University of Rio Grande do Norte, Natal, RN, Brazil.

Background: Visceral leishmaniasis (VL) caused by Leishmania infantum became a disease of urban areas in Brazil in the last 30 years and there has been an increase in asymptomatic L. infantum infection with these areas.

Methodology/principal Findings: A retrospective study of human VL was performed in the state of Rio Grande do Norte, Brazil, for the period of 1990-2014. The data were divided into five-time periods. For all VL cases, data on sex, age, nutritional status and childhood vaccination were collected. Geographic information system tools and statistical models were used to analyze the dispersion of human VL. The mean annual incidence of VL was 4.6 cases/100,000 inhabitants, with total 3,252 cases reported. The lethality rate was 6.4%. Over time the annual incidence of VL decreased in the 0-4 years (p<0.0001) and 5-9 (p <0.0001) age groups, but increased in ages 20-39 (p<0.001) and >40 years (p<0.0001). VL occurred more often in males (β2 = 2.5; p<0.0001). The decreased incidence of VL in children was associated with improved nutritional status and childhood immunizations including measles, poliomyelitis, BCG, and hepatitis B. Human VL correlated temporally and geographically with canine L. infantum infection (p = 0.002, R2 = 0.438), with rainfall and with Lutzomyia longipalpis density (r = 0.762). Overall, the incidence of VL decreased, while VL-AIDS increased, especially between 2010-2014. VL was more frequently found in areas that lacked urban infrastructure, detected by lack of garbage collection and sewers, whereas HIV infection was associated with higher levels of schooling and evidence of higher socioeconomic status.

Conclusion/significance: The demographics of VL in northeastern Brazil have changed. Disease incidence has decreased in children and increased in adults. They were associated with improvements in nutrition, socioeconomic status and immunization rates. Concurrent VL-AIDS poses a serious challenge for the future.
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http://dx.doi.org/10.1371/journal.pntd.0006164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839541PMC
March 2018

Business travel-associated illness: a GeoSentinel analysis.

J Travel Med 2018 01;25(1)

Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: Analysis of a large cohort of business travelers will help clinicians focus on frequent and serious illnesses. We aimed to describe travel-related health problems in business travelers.

Methods: GeoSentinel Surveillance Network consists of 64 travel and tropical medicine clinics in 29 countries; descriptive analysis was performed on ill business travelers, defined as persons traveling for work, evaluated after international travel 1 January 1997 through 31 December 2014.

Results: Among 12 203 business travelers seen 1997-2014 (14 045 eligible diagnoses), the majority (97%) were adults aged 20-64 years; most (74%) reported from Western Europe or North America; two-thirds were male. Most (86%) were outpatients. Fewer than half (45%) reported a pre-travel healthcare encounter. Frequent regions of exposure were sub-Saharan Africa (37%), Southeast Asia (15%) and South Central Asia (14%). The most frequent diagnoses were malaria (9%), acute unspecified diarrhea (8%), viral syndrome (6%), acute bacterial diarrhea (5%) and chronic diarrhea (4%). Species was reported for 973 (90%) of 1079 patients with malaria, predominantly Plasmodium falciparum acquired in sub-Saharan Africa. Of 584 (54%) with malaria chemoprophylaxis information, 92% took none or incomplete courses. Thirteen deaths were reported, over half of which were due to malaria; others succumbed to pneumonia, typhoid fever, rabies, melioidosis and pyogenic abscess.

Conclusions: Diarrheal illness was a major cause of morbidity. Malaria contributed substantial morbidity and mortality, particularly among business travelers to sub-Saharan Africa. Underuse or non-use of chemoprophylaxis contributed to malaria cases. Deaths in business travelers could be reduced by improving adherence to malaria chemoprophylaxis and targeted vaccination for vaccine-preventable diseases. Pre-travel advice is indicated for business travelers and is currently under-utilized and needs improvement.
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http://dx.doi.org/10.1093/jtm/tax097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824651PMC
January 2018

Changing epidemiology of visceral leishmaniasis in northeastern Brazil: a 25-year follow-up of an urban outbreak.

Trans R Soc Trop Med Hyg 2017 10;111(10):440-447

Health Graduate Program, Health Science Center, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte, Brazil.

Background: Visceral leishmaniasis (VL) continues to be a deadly parasitic disease in Brazil but the epidemiology has changed. The objective of this study was to assess the evolution of urban VL in the city of Natal, Brazil, over the past 25 y.

Methods: A retrospective study of human VL was performed, considering reported cases over the past 25 y in Natal. Analyses considered the spatial distribution of VL cases, human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) co-infection, Leishmania infantum infection in dogs, density of the insect vector (Lutzomyia longipalpis) and socio-economic factors.

Results: Paralleling migration of the population, VL cases changed from mostly rural to predominantly urban regions. The incidence of human VL was highest during the initial years (1990-1994) of our study. Human VL was positively associated with a high density of L. longipalpis, a high prevalence of canine L. infantum infection and HIV/AIDS co-infection. The average age at diagnosis increased over prior years and males were more frequently affected. The overall fatality rate was 6%. Socio-economic variables indicative of poverty were associated with a greater incidence of VL and clusters of VL.

Conclusion: VL has become endemic in Natal. The disease is associated with poverty and male gender. Surprisingly, there has been an increase in the age at diagnosis.
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http://dx.doi.org/10.1093/trstmh/trx080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5914331PMC
October 2017

Nlrp12 Mediates Adverse Neutrophil Recruitment during Influenza Virus Infection.

J Immunol 2018 02 27;200(3):1188-1197. Epub 2017 Dec 27.

Interdisciplinary Program in Immunology, University of Iowa Carver College of Medicine, Iowa City, IA 52242;

Exaggerated inflammatory responses during influenza A virus (IAV) infection are typically associated with severe disease. Neutrophils are among the immune cells that can drive this excessive and detrimental inflammation. In moderation, however, neutrophils are necessary for optimal viral control. In this study, we explore the role of the nucleotide-binding domain leucine-rich repeat containing receptor family member Nlrp12 in modulating neutrophilic responses during lethal IAV infection. mice are protected from lethality during IAV infection and show decreased vascular permeability, fewer pulmonary neutrophils, and a reduction in levels of neutrophil chemoattractant CXCL1 in their lungs compared with wild-type mice. neutrophils and dendritic cells within the IAV-infected lungs produce less CXCL1 than their wild-type counterparts. Decreased CXCL1 production by dendritic cells was not due to a difference in CXCL1 protein stability, but instead to a decrease in mRNA stability. Together, these data demonstrate a previously unappreciated role for Nlrp12 in exacerbating the pathogenesis of IAV infection through the regulation of CXCL1-mediated neutrophilic responses.
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http://dx.doi.org/10.4049/jimmunol.1700999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831365PMC
February 2018

Ending the Global Tuberculosis Epidemic by 2030 - The Moscow Declaration and achieving a Major Translational Change in Delivery of TB Healthcare.

Int J Infect Dis 2017 12 2;65:156-158. Epub 2017 Dec 2.

Division of Infection and Immunity, University College London, London, UK; National Institute of health Research, Biomedical Research Centre at UCL Hospitals, London, UK. Electronic address:

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http://dx.doi.org/10.1016/j.ijid.2017.11.029DOI Listing
December 2017

Epidemiological and Experimental Evidence for Sex-Dependent Differences in the Outcome of Infection.

Am J Trop Med Hyg 2018 01;98(1):142-145

Veterans' Affairs Medical Center, Iowa City, Iowa.

causes visceral leishmaniasis (VL) in Brazil. We previously observed that VL is more common in males than females living in endemic neighborhoods, despite similar exposure. Using a larger sample, we document that VL is more common in males than females, but only after puberty. BALB/c and C57BL/6 mouse models confirmed that there is a biological basis for male susceptibility to symptomatic VL, showing higher parasite burdens in males than females. Female C57BL/6 mice generated more antigen-induced cytokines associated with curative responses (interferon-γ, interleukin [IL]-1β). Males expressed higher levels of IL-10 and tumor necrosis factor, which are linked to exacerbated disease. Different parasite lines entered or survived at a higher rate in macrophages of male- than female-origin. These results suggest that males are inherently more susceptible to than females and that mice are a valid model to study this sex-dependent difference.
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http://dx.doi.org/10.4269/ajtmh.17-0563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928733PMC
January 2018

Dynamics of American tegumentary leishmaniasis in a highly endemic region for Leishmania (Viannia) braziliensis infection in northeast Brazil.

PLoS Negl Trop Dis 2017 Nov 2;11(11):e0006015. Epub 2017 Nov 2.

Serviço de Imunologia, Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Bahia, Brazil.

Background: American Tegumentary Leishmaniasis (ATL) caused by Leishmania braziliensis is endemic in Corte de Pedra, Northeast Brazil. Most L. braziliensis infections manifest as localized cutaneous leishmaniasis (CL). Disseminated manifestations include mucosal leishmaniasis (ML), present at a low constant level for several decades, and newly emerging disseminated leishmaniasis (DL). Surprisingly, DL has recently surpassed ML in its spatial distribution. This led us to hypothesize that distinct forms of ATL might spread in different patterns through affected regions.

Methodology/principal Findings: We explored the incidence and geographic dispersion of the three clinical types of ATL over a span of nearly two decades in Corte de Pedra. We obtained the geographic coordinates of the homes of patients with ATL during 1992-1996, 1999-2003 and 2008-2011. The progressive dispersion of ML or DL in each time period was compared to that of CL in 2008-2011 with the Cusick and Edward's geostatistical test. To evaluate whether ATL occurred as clusters, we compared each new case in 2008-2011 with the frequency of and distance from cases in the previous 3 to 12 months. The study revealed that DL, ML and CL actively spread within that region, but in distinct patterns. Whereas CL and DL propagated in clusters, ML occurred as sporadic cases. DL had a wider distribution than ML until 2003, but by 2011 both forms were distributed equally in Corte de Pedra. The incidence of ML fluctuated over time at a rate that was distinct from those of CL and DL.

Conclusions/significance: These findings suggest that CL and DL maintain endemic levels through successive outbreaks of cases. The sporadic pattern of ML cases may reflect the long and variable latency before infected patients develop clinically detectable mucosal involvement. Intimate knowledge of the geographic distribution of leishmaniasis and how it propagates within foci of active transmission may guide approaches to disease control.
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http://dx.doi.org/10.1371/journal.pntd.0006015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685640PMC
November 2017