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Cohen S.B.,Cornell University | Cohen S.B.,Center for Infectious Disease Research | Denkers E.Y.,Cornell University
Journal of Immunology | Year: 2015

The function of mucosal dendritic cell (DC) subsets in immunity and inflammation is not well understood. In this study, we define four DC subsets present within the lamina propria and mesenteric lymph node compartments based on expression of CD103 and CD11b. Using IL-12p40 YFP (Yet40) reporter mice, we show that CD103+CD11b2 mucosal DCs are primary in vivo sources of IL-12p40; we also identified CD103-CD11b- mucosal DCs as a novel population producing this cytokine. Infection was preferentially found in CD11b+ DCs that were negative for CD103. Lamina propria DCs containing parasites were negative for IL-12p40. Instead, production of the cytokine was strictly a property of noninfected cells. We also show that vitamin A metabolism, as measured by ALDH activity, was preferentially found in CD103+CD11b+ DC and was strongly downregulated in all mucosal DC subsets during infection. Finally, overall apoptosis of lamina propria DC subsets was increased during infection. Combined, these results highlight the ability of intestinal Toxoplasma infection to alter mucosal DC activity at both the whole population level and at the level of individual subsets. © 2015 by The American Association of Immunologists, Inc.

Nachega J.B.,University of Cape Town | Uthman O.A.,University of Cape Town | Uthman O.A.,Keele University | Anderson J.,Johns Hopkins Hospital | And 10 more authors.
AIDS | Year: 2012

OBJECTIVE: To estimate antiretroviral therapy (ART) adherence rates during pregnancy and postpartum in high-income, middle-income, and low-income countries. DESIGN: Systematic review and meta-analysis. METHODS: MEDLINE, EMBASE, SCI Web of Science, NLM Gateway, and Google scholar databases were searched. We included all studies reporting adherence rates as a primary or secondary outcome among HIV-infected pregnant women. Two independent reviewers extracted data on adherence and study characteristics. A random-effects model was used to pool adherence rates; sensitivity, heterogeneity, and publication bias were assessed. RESULTS: Of 72 eligible articles, 51 studies involving 20153 HIV-infected pregnant women were included. Most studies were from United States (n=14, 27%) followed by Kenya (n=6, 12%), South Africa (n=5, 10%), and Zambia (n=5, 10%). The threshold defining good adherence to ART varied across studies (>80, >90, >95, 100%). A pooled analysis of all studies indicated a pooled estimate of 73.5% [95% confidence interval (CI) 69.3-77.5%] of pregnant women who had adequate (>80%) ART adherence. The pooled proportion of women with adequate adherence levels was higher during the antepartum (75.7%, 95% CI 71.5-79.7%) than during postpartum (53.0%, 95% CI 32.8-72.7%; P=0.005). Selected reported barriers for nonadherence included physical, economic and emotional stresses, depression (especially postdelivery), alcohol or drug use, and ART dosing frequency or pill burden. CONCLUSION: Our findings indicate that only 73.5% of pregnant women achieved optimal ART adherence. Reaching adequate ART adherence levels was a challenge in pregnancy, but especially during the postpartum period. Further research to investigate specific barriers and interventions to address them is urgently needed globally. Copyright © 2012 Lippincott Williams &Wilkins.

News Article
Site: www.nature.com

The World Health Organization (WHO) last week declared that the Ebola epidemic in West Africa no longer represents an international public-health emergency. But as experts also warned last week, there must be no let-up in improving readiness for the next Ebola outbreak — including the nightmare prospect of an epidemic in the megacities of Africa. An expert panel of researchers convened by the London-based Wellcome Trust and the Center for Infectious Disease Research and Policy at the University of Minnesota, Minneapolis, warned in particular that support for Ebola vaccine research must not be allowed to slip. Although a successful experimental Ebola vaccine has been developed, much work remains to be done if safe and effective vaccines are to be ready in sufficient amounts to quickly nip future outbreaks in the bud. “As Ebola infection rates come under control it’s a huge concern that complacency sets in, attention moves to more immediate threats, and Ebola vaccine development is left half-finished,” cautioned Jeremy Farrar, director of the Wellcome. Too often in the past, the world has stumbled from epidemic to epidemic, failing to learn the lessons of the last. Emergency responses to the latest threat capture headlines, research and political attention. But too often this attention quickly fades. Yellow fever, a virus that kills many of those it infects, is just one example of the failure to sustain control efforts. The virus is spread by Aedes aegypti, a mosquito adapted to live in urban areas. An ongoing yellow-fever outbreak in Angola, the first for nearly 30 years, began in December and has since spread within the country, infecting at least 490 people and killing 198. It now threatens the wider region. Yet mass vaccination and intensive mosquito-control programmes largely eliminated this vaccine-preventable mosquito-borne disease by the 1940s. In South America, where the disease was widespread, the mosquito vector was virtually wiped off the map by the 1970s. But the success of mosquito control led to complacency and scale-back. As a result, A. aegypti is now present across more of the continent than before control began. It is similarly resurgent in tropical and subtropical regions worldwide, resulting in sporadic outbreaks of yellow fever in at-risk countries. Moreover, the mosquito’s comeback has fuelled large urban outbreaks of dengue, chikungunya and now Zika viruses, with at least tens of millions of people infected. There’s a long list of other Aedes-borne viruses that are currently restricted to animal reservoirs in the wild. But some of these, including potentially deadly ones, will inevitably establish themselves in cities with Aedes mosquitoes. Given rampant urbanization throughout the tropics and subtropics, dense human and Aedes populations are ticking time bombs. The failure to sustain Aedes control illustrates the need for long-term persistence to curb epidemic threats. The Angola outbreak has already depleted an international emergency stockpile of 6 million doses of vaccine, leaving authorities scrambling to obtain extra vaccine from national immunization programmes. The WHO and other international agencies launched the Yellow Fever Initiative in 2006 to reboot yellow-fever mass-vaccination programmes and routine vaccination in the highest-risk African countries. But vaccine stocks are still insufficient, and vaccine coverage in many African countries too low, leaving many vulnerable. The problem, says one official associated with the initiative, is that yellow fever is a “forgotten disease”, which makes it difficult to attract sustained political interest and funding. Following the Ebola epidemic in West Africa, a slew of commissions and reports laid out a broad consensus on what needs to be done for a more proactive and sustained preparedness against epidemic threats. These measures include reinforcing public-health systems, surveillance and diagnostic capacities, and training health workers to identify and respond early to disease outbreaks. Weaknesses in these areas have been identified as factors that allowed what was a small Ebola outbreak to spiral out of control. Monitoring viruses in the wild, and a better understanding of how factors such as deforestation, and the hunting and consumption of bushmeat, influence spillover of animal viruses into humans, is key. So, too, is the pre-emptive development of drugs and vaccines against known potential epidemic threats. The Ebola epidemic has prompted vigorous discussion on all these points, on what shape or form any new global initiatives should take, and where the required multibillion-dollar investment will come from. The big risk is that as the Ebola epidemic fades from memory, the sustained political commitment and funding required will not materialize, and business as usual will resume. That must not be allowed to happen.

Havlir D.V.,University of California at San Francisco | Kendall M.A.,Harvard University | Ive P.,University of Witwatersrand | Swindells S.,University of Nebraska at Omaha | And 24 more authors.
New England Journal of Medicine | Year: 2011

BACKGROUND: Antiretroviral therapy (ART) is indicated during tuberculosis treatment in patients infected with human immunodeficiency virus type 1 (HIV-1), but the timing for the initiation of ART when tuberculosis is diagnosed in patients with various levels of immune compromise is not known. METHODS: We conducted an open-label, randomized study comparing earlier ART (within 2 weeks after the initiation of treatment for tuberculosis) with later ART (between 8 and 12 weeks after the initiation of treatment for tuberculosis) in HIV-1 infected patients with CD4+ T-cell counts of less than 250 per cubic millimeter and suspected tuberculosis. The primary end point was the proportion of patients who survived and did not have a new (previously undiagnosed) acquired immunodeficiency syndrome (AIDS)-defining illness at 48 weeks. RESULTS: A total of 809 patients with a median baseline CD4+ T-cell count of 77 per cubic millimeter and an HIV-1 RNA level of 5.43 log10 copies per milliliter were enrolled. In the earlier-ART group, 12.9% of patients had a new AIDS-defining illness or died by 48 weeks, as compared with 16.1% in the later-ART group (95% confidence interval [CI], -1.8 to 8.1; P = 0.45). Among patients with screening CD4+ T-cell counts of less than 50 per cubic millimeter, 15.5% of patients in the earlier-ART group versus 26.6% in the later-ART group had a new AIDS-defining illness or died (95% CI, 1.5 to 20.5; P = 0.02). Tuberculosis-associated immune reconstitution inflammatory syndrome was more common with earlier ART than with later ART (11% vs. 5%, P = 0.002). The rate of viral suppression at 48 weeks was 74% and did not differ between the groups (P = 0.38). CONCLUSIONS: Overall, earlier ART did not reduce the rate of new AIDS-defining illness and death, as compared with later ART. In persons with CD4+ T-cell counts of less than 50 per cubic millimeter, earlier ART was associated with a lower rate of new AIDS-defining illnesses and death. (Funded by the National Institutes of Health and others; ACTG A5221 ClinicalTrials.gov number, NCT00108862.) Copyright © 2011 Massachusetts Medical Society. All rights reserved.

Aachoui Y.,University of North Carolina at Chapel Hill | Kajiwara Y.,Mount Sinai School of Medicine | Leaf I.A.,Center for Infectious Disease Research | Mao D.,University of North Carolina at Chapel Hill | And 5 more authors.
Cell Host and Microbe | Year: 2015

The inflammatory caspases 1 and 11 are activated in response to different agonists and act independently to induce pyroptosis. In the context of IL-1β/IL-18 secretion, however, in vitro studies indicate that caspase-11 acts upstream of NLRP3 and caspase-1. By contrast, studying infection in vivo by the cytosol-invasive bacterium Burkholderia thailandensis, we find that caspase-1 activity is required upstream of caspase-11 to control infection. Caspase-1-activated IL-18 induces IFN-γ to prime caspase-11 and rapidly clear B. thailandensis infection. In the absence of IL-18, bacterial burdens persist, eventually triggering other signals that induce IFN-γ. Whereas IFN-γ was essential, endogenous type I interferons were insufficient to prime caspase-11. Although mice transgenic for caspase-4, the human ortholog of caspase-11, cleared B. thailandensis in vivo, they did not strictly require IFN-γ priming. Thus, caspase-1 provides priming signals upstream of caspase-11 but not caspase-4 during murine defense against a cytosol-invasive bacterium. © 2015 Elsevier Inc.

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