Showing papers by "Tobias R. Kollmann published in 2012"

Uninfected but not unaffected: chronic maternal infections during pregnancy, fetal immunity, and susceptibility to postnatal infections

Abstract: Summary Chronic infections during pregnancy are highly prevalent in some parts of the world. Infections with helminths, Trypanosoma cruzi, Plasmodium spp, and HIV might affect the development of fetal immunity and susceptibility to postnatal infections independently of in-utero transmission of the pathogens. Fetal adaptive immune responses are common in neonates who have been exposed to maternal infection during pregnancy but not infected themselves. Such responses could affect the development of immunity to the homologous pathogens and their control during the first few years of life. Fetal innate and regulatory responses might also affect immunity to unrelated pathogens and responses to vaccines. Strategies to improve child health should integrate the possible clinical implications of in-utero exposure to chronic maternal infections.

HIV-exposed uninfected infants are at increased risk for severe infections in the first year of life.

Abstract: HIV-exposed uninfected (HEU) infants have higher infectious morbidity than HIV-unexposed uninfected (HUU) infants. We present the clinical outcomes from a pilot cohort study of 27 HEU and 28 HUU infants. In the absence of infant malnutrition or advanced maternal HIV, HEU infants experienced a 2.74 (0.85-8.78) times greater risk of hospitalization in the first year.

GLA-SE, a Synthetic Toll-like Receptor 4 Agonist, Enhances T-Cell Responses to Influenza Vaccine in Older Adults

Abstract: Background. The decline in influenza vaccine efficacy in older adults is associated with a limited ability of current split-virus vaccines (SVVs) to stimulate cytotoxic T lymphocyte (CTL) responses required for clinical protection against influenza. Methods. The Toll-like receptor 4 agonist glucopyranosyl lipid adjuvant–stable emulsion (GLA-SE) was combined with SVV to stimulate peripheral blood mononuclear cells (PBMCs) in vitro to determine the cytokine response in dendritic cell subsets. Stimulated PBMCs were then challenged with live influenza virus to mimic the response to natural infection following vaccination, using previously identified T-cell correlates of protection. Results. GLA-SE significantly increased the proportion of myeloid dendritic cells that produced tumor necrosis factor α, interleukin 6, and interleukin 12. When combined with SVV to stimulate PBMCs in vitro, this effect of GLA-SE was shown to regulate a T-helper 1 cell response upon challenge with live influenza virus; interleukin 10 production was suppressed, thus significantly increasing the interferon γ to interleukin 10 ratio and the cytolytic (granzyme B) response to influenza virus challenge, both of which have been shown to correlate with protection against influenza in older adults. Conclusions. Our findings suggest that a novel adjuvant, GLA-SE, combined with standard SVV has the potential to significantly improve vaccine-mediated protection against influenza in older adults.

Humanized TLR4/MD-2 Mice Reveal LPS Recognition Differentially Impacts Susceptibility to Yersinia pestis and Salmonella enterica

Abstract: Although lipopolysaccharide (LPS) stimulation through the Toll-like receptor (TLR)-4/MD-2 receptor complex activates host defense against Gram-negative bacterial pathogens, how species-specific differences in LPS recognition impact host defense remains undefined. Herein, we establish how temperature dependent shifts in the lipid A of Yersinia pestis LPS that differentially impact recognition by mouse versus human TLR4/MD-2 dictate infection susceptibility. When grown at 37°C, Y. pestis LPS is hypo-acylated and less stimulatory to human compared with murine TLR4/MD-2. By contrast, when grown at reduced temperatures, Y. pestis LPS is more acylated, and stimulates cells equally via human and mouse TLR4/MD-2. To investigate how these temperature dependent shifts in LPS impact infection susceptibility, transgenic mice expressing human rather than mouse TLR4/MD-2 were generated. We found the increased susceptibility to Y. pestis for “humanized” TLR4/MD-2 mice directly paralleled blunted inflammatory cytokine production in response to stimulation with purified LPS. By contrast, for other Gram-negative pathogens with highly acylated lipid A including Salmonella enterica or Escherichia coli, infection susceptibility and the response after stimulation with LPS were indistinguishable between mice expressing human or mouse TLR4/MD-2. Thus, Y. pestis exploits temperature-dependent shifts in LPS acylation to selectively evade recognition by human TLR4/MD-2 uncovered with “humanized” TLR4/MD-2 transgenic mice.

Ontogeny of Toll-Like Receptor Mediated Cytokine Responses of South African Infants throughout the First Year of Life

Abstract: The first year of life represents a time of marked susceptibility to infections; this is particularly true for regions in sub-Saharan Africa. As innate immunity directs the adaptive immune response, the observed increased risk for infection as well as a suboptimal response to vaccination in early life may be due to less effective innate immune function. In this study, we followed a longitudinal cohort of infants born and raised in South Africa over the first year of life, employing the most comprehensive analysis of innate immune response to stimulation published to date. Our findings reveal rapid changes in innate immune development over the first year of life. This is the first report depicting dramatic differences in innate immune ontogeny between different populations in the world, with important implications for global vaccination strategies.

Staphylococcus aureus nasal septal abscess complicated by extradural abscess in an infant.

Abstract: Nasal septal abscess (NSA) is an uncommon entity. We present a case of NSA in an infant to highlight that in a child with nasal obstruction, NSA needs to be considered and evaluated immediately, given its potentially dangerous course. This is followed by a review of the literature (based on a review of PubMed and EMBASE using the terms ‘‘nasal abscess,’’ ‘‘infant,’’ ‘‘child,’’ ‘‘pediatric,’’ and ‘‘extradural abscess’’). Finally, we present our recommended approach to pediatric NSA based on our experience and review of the literature. Case Presentation A 4-month-old girl presented to a hospital in British Columbia with a history of loose stools for 2 weeks and fever, poor feeding, and increased fussiness for 1 day. The baby was previously well, with normal growth. She was born at 37 weeks’ gestation. There was no consanguinity. Her mother’s antenatal blood screen for human immunodeficiency virus (HIV), hepatitis B, and rapid plasma reagin were all negative. There was no family history of immunodeficiency. The umbilical cord dropped off at 3 or 4 days. There was no history of recurrent skin boils. A detailed social and family history uncovered no concern of injury or suspicion of child abuse. At presentation, the white blood cell count was 22.6 3

Management of Multi-drug-resistant Tuberculosis in Children

Abstract: Drug-resistant tuberculosis (DR-TB) has emerged as the biggest impediment to maintaining effective global tuberculosis control. The incidence and prevalence of paediatric DR-TB, as well as the risk of disease progression and transmission, are not as low in children as previously thought. Here, the authors review what is known about the diagnosis and management of childhood DR-TB, including preventive chemoprophylaxis and infection control in healthcare settings. Specifically, the authors point out the challenging but central role of drug susceptibility testing and review the concepts guiding the design of optimal treatment plans. The authors also address the issues surrounding directly observed therapy and patient monitoring in paediatric DR-TB. Lastly, the authors address the four pillars of optimal infection control, and provide guidance on how they could be implemented in clinical settings for children with DR-TB.

Brief Report HIV-Exposed Uninfected Infants are at Increased Risk for Severe Infections in the First Year of Life

Abstract: SummaryHIV-exposed uninfected (HEU) infants have higher infectious morbidity than HIV-unexposed unin-fected (HUU) infants. We present the clinical outcomes from a pilot cohort study of 27 HEU and 28HUU infants. In the absence of infant malnutrition or advanced maternal HIV, HEU infants experi-enced a 2.74 (0.85–8.78) times greater risk of hospitalization in the first year.Key words: HIV-exposed infants, HIV, vertical transmission prevention, PMTCT, South Africa.IntroductionSouth Africa’s (SA) antenatal HIV seroprevalence is30% [1] with perinatal HIV infection reduced to<5% by vertical transmission prevention (VTP) [2].More than a quarter of SA’s newborns are HIVexposed but uninfected (HEU) and may haveincreased mortality and morbidity compared to in-fants born to HIV-uninfected mothers [3, 4].Avoidance of breastfeeding is catastrophic in areaswith high infectious disease burdens and malnutrition[5, 6]. But it is not only formula-fed HEU infants thatexperience more frequent infections and death [4, 7],the reasons for this being multi-factorial [5 ,8 9]. Thisreport compares infection-related outcomes of HEUand HIV-unexposed uninfected (HUU) infants in thefirst year of life.During this study, VTP prophylaxis in SA con-sisted of maternal and infant short-course zidovudinewith single-dose nevirapine. Maternal CD4 count<200 cells l