Doherty Institute - Research Publications

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    Prevalence of polymorphisms in DHFR, DHPS, PFMDR1 and PFCRT genes of Plasmodium falciparum isolates in Quang Tri Province, Vietnam
    Phuc, BQ ; Caruana, SR ; Cowman, AF ; Biggs, B-A ; Thanh, NV ; Tien, NT ; Thuan, LK (SEAMEO TROPMED Network, 2008-11)
    In 2002 an antimalarial drug resistance survey was carried out in a seasonally endemic area of Vietnam. Sulfadoxine/pyrimethamine (S/P) was the standard treatment recommended for uncomplicated Plasmodium falciparum malaria in that area at the time. Early or late treatment failure as defined by WHO was observed in 14.9% (7/47) of patients. Molecular analysis of treatment failure isolates identified that 5/6 carried two or more dhfr and dhps polymorphisms associated with S/P resistance. Chloroquine resistance-associated polymorphisms occurred in 38.5% (15/39) of the isolates. These results support the move to artemisinin-based combination therapy for malaria in Vietnam.
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    Vitamin D deficiency is associated with tuberculosis and latent tuberculosis infection in immigrants from Sub-Saharan Africa
    Gibney, KB ; MacGregor, L ; Leder, K ; Torresi, J ; Marshall, C ; Ebeling, PR ; Biggs, B-A (OXFORD UNIV PRESS INC, 2008-02-01)
    Among African immigrants in Melbourne, Victoria, Australia, we demonstrated lower geometric mean vitamin D levels in immigrants with latent tuberculosis infection than in those with no Mycobacterium tuberculosis infection (P=.007); such levels were also lower in immigrants with tuberculosis or past tuberculosis than in those with latent tuberculosis infection (P=.001). Higher vitamin D levels were associated with lower probability of any M. tuberculosis infection (P=.001) and lower probability of tuberculosis or past tuberculosis (compared with latent tuberculosis infection; P=.001).
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    Anemia, iron deficiency, meat consumption, and hookworm infection in women of reproductive age in northwest Vietnam
    Pasricha, S-R ; Caruana, SR ; Phuc, TQ ; Casey, GJ ; Jolley, D ; Kingsland, S ; Tien, NT ; MacGregor, L ; Montresor, A ; Biggs, B-A (AMER SOC TROP MED & HYGIENE, 2008-03)
    Iron deficiency anemia poses an important public health problem for women of reproductive age living in developing countries. We assessed the prevalence of iron deficiency and anemia and associated risk factors in a community-based sample of women living in a rural province of northwest Vietnam. A cross-sectional survey, comprised of written questionnaires and laboratory analysis of hemoglobin (Hb), ferritin, transferrin receptor, and stool hookworm egg count, was undertaken, and the soluble transferrin receptor/log ferritin index was calculated. Of 349 non-pregnant women, 37.53% were anemic (Hb < 12 g/dL), and 23.10% were iron deficient (ferritin < 15 ng/L). Hookworm infection was present in 78.15% of women, although heavy infection was uncommon (6.29%). Iron deficiency was more prevalent in anemic than non-anemic women (38.21% versus 14.08%, P < 0.001). Consumption of meat at least three times a week was more common in non-anemic women (51.15% versus 66.67%, P = 0.042). Mean ferritin was lower in anemic women (18.99 versus 35.66 ng/mL, P < 0.001). There was no evidence of a difference in prevalence (15.20% versus 17.23%, P = 0.629) or intensity (171.07 versus 129.93 eggs/g, P = 0.412) of hookworm infection between anemic and non-anemic women. Although intensity of hookworm infection and meat consumption were associated with indices of iron deficiency in a multiple regression model, their relationship with hemoglobin was not significant. Anemia, iron deficiency, and hookworm infection were prevalent in this population. Intake of meat was more clearly associated with hemoglobin and iron indices than hookworm. An approach to addressing iron deficiency in this population should emphasize both iron supplementation and deworming.
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    The Profile of Health Problems in African Immigrants Attending an Infectious Disease Unit in Melbourne, Australia
    Gibney, KB ; Mihrshahi, S ; Torresi, J ; Marshall, C ; Leder, K ; Biggs, B-A (AMER SOC TROP MED & HYGIENE, 2009-05)
    The number of African immigrants living in Western countries is increasing. A retrospective audit of sub-Saharan African patients attending the infectious diseases clinics of a Melbourne teaching hospital was performed. A total of 375 patients were included. Helicobacter pylori gastritis was diagnosed in 60% of those tested (35/58), schistosomiasis in 41% (84/206), chronic hepatitis B in 19% (32/167), and strongyloidiasis in 18% (32/179). Active tuberculosis (TB) affected 18% (51/276) and latent TB 55% (152/276). Pathologic parasites were detected in stool in 21% (31/145). Vitamin D deficiency (< 50 nmol/L) affected 73% (139/191), anemia 17% (52/312), iron deficiency 15% (22/151), and low neutrophil count 25% (78/312). Infectious diseases, vitamin D deficiency, anemia, and latent TB were common in sub-Saharan African immigrants. Clinicians need to be aware of these conditions to meet the health needs of this group. Comprehensive health checks should be encouraged for new arrivals, particularly from high-risk areas.
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    Public Health Response to Imported Case of Poliomyelitis, Australia, 2007
    Carnie, JA ; Lester, R ; Moran, R ; Brown, L ; Meagher, J ; Roberts, JA ; Thorley, BR (CENTERS DISEASE CONTROL & PREVENTION, 2009-11)
    Australia, along with 36 other countries in the Western Pacific Region, was declared free of poliomyelitis by the World Health Organization in October 2000. Yet, the persistence of wild poliovirus in the 4 remaining polio-endemic countries-Afghanistan, India, Nigeria, and Pakistan-poses a risk for its importation into all countries declared polio free. We describe the public health response and outcomes resulting from the importation of a wild poliovirus infection in Melbourne, Australia, in July 2007. This response, based on an assessment of the risk for transmission, included offering vaccination with inactivated polio vaccine to the contacts and placing the index patient in isolation and the household contacts in quarantine until consecutive fecal specimens were negative for poliovirus by culture. The experience gained from the polio importation event in Australia may assist other polio-free countries to prepare for, and respond to, a similar event. No secondary clinical cases resulted from this importation.
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    Using ELISPOT to Expose False Positive Skin Test Conversion in Tuberculosis Contacts
    Hill, PC ; Jeffries, DJ ; Brookes, RH ; Fox, A ; Jackson-Sillah, D ; Lugos, MD ; Donkor, SA ; de Jong, BC ; Corrah, T ; Adegbola, RA ; McAdam, KP ; Ratner, A (PUBLIC LIBRARY SCIENCE, 2007-01-31)
    BACKGROUND: Repeat tuberculin skin tests may be false positive due to boosting of waned immunity to past mycobacterial exposure. We evaluated whether an ELISPOT test could identify tuberculosis (TB) contacts with boosting of immunity to non-tuberculous mycobacterial exposure. METHODOLOGY/PRINCIPAL FINDINGS: We conducted tuberculin and ELISPOT tests in 1665 TB contacts: 799 were tuberculin test negative and were offered a repeat test after three months. Those with tuberculin test conversion had an ELISPOT, chest X-ray and sputum analysis if appropriate. We compared converters with non-converters, assessed the probability of each of four combinations of ELISPOT results over the two time points and estimated boosting with adjustment for ELISPOT sensitivity and specificity. 704 (72%) contacts had a repeat tuberculin test; 176 (25%) had test conversion, which increased with exposure to a case (p = 0.002), increasing age (p = 0.0006) and BCG scar (p = 0.06). 114 tuberculin test converters had ELISPOT results: 16(14%) were recruitment positive/follow-up positive, 9 (8%) positive/negative, 34 (30%) negative/positive, and 55 (48%) were negative/negative. There was a significant non-linear effect of age for ELISPOT results in skin test converters (p = 0.038). Estimates of boosting ranged from 32%-41% of skin test converters with increasing age. Three converters were diagnosed with TB, two had ELISPOT results: both were positive, including one at recruitment. CONCLUSIONS/SIGNIFICANCE: We estimate that approximately one third of tuberculin skin test conversion in Gambian TB case contacts is due to boosting of immunity to non-tuberculous mycobacterial exposure. Further longitudinal studies are required to confirm whether ELISPOT can reliably identify case contacts with tuberculin test conversion that would benefit most from prophylactic treatment.
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    Improved single-chain transactivators of the Tet-on gene expression system
    Zhou, X ; Symons, J ; Hoppes, R ; Krueger, C ; Berens, C ; Hillen, W ; Berkhout, B ; Das, AT (BIOMED CENTRAL LTD, 2007-01-19)
    BACKGROUND: The Tet-Off (tTA) and Tet-On (rtTA) regulatory systems are widely applied to control gene expression in eukaryotes. Both systems are based on the Tet repressor (TetR) from transposon Tn10, a dimeric DNA-binding protein that binds to specific operator sequences (tetO). To allow the independent regulation of multiple genes, novel Tet systems are being developed that respond to different effectors and bind to different tetO sites. To prevent heterodimerization when multiple Tet systems are expressed in the same cell, single-chain variants of the transactivators have been constructed. Unfortunately, the activity of the single-chain rtTA (sc-rtTA) is reduced when compared with the regular rtTA, which might limit its application. RESULTS: We recently identified amino acid substitutions in rtTA that greatly improved the transcriptional activity and doxycycline-sensitivity of the protein. To test whether we can similarly improve other TetR-based gene regulation systems, we introduced these mutations into tTA and sc-rtTA. Whereas none of the tested mutations improved tTA activity, they did significantly enhance sc-rtTA activity. We thus generated a novel sc-rtTA variant that is almost as active and dox-sensitive as the regular dimeric rtTA. This variant was also less sensitive to interference by co-expressed TetR-based tTS repressor protein and may therefore be more suitable for applications where multiple TetR-based regulatory systems are used. CONCLUSION: We developed an improved sc-rtTA variant that may replace regular rtTA in applications where multiple TetR-based regulatory systems are used.
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    Evolution of DC-SIGN use revealed by fitness studies of R5 HIV-I variants emerging during AIDS progression
    Borggren, M ; Repits, J ; Kuylenstierna, C ; Sterjovski, J ; Churchill, MJ ; Purcell, DFJ ; Karlsson, A ; Albert, J ; Gorry, PR ; Jansson, M (BMC, 2008-03-27)
    BACKGROUND: At early stages of infection CCR5 is the predominant HIV-1 coreceptor, but in approximately 50% of those infected CXCR4-using viruses emerge with disease progression. This coreceptor switch is correlated with an accelerated progression. However, those that maintain virus exclusively restricted to CCR5 (R5) also develop AIDS. We have previously reported that R5 variants in these "non-switch virus" patients evolve during disease progression towards a more replicative phenotype exhibiting altered CCR5 coreceptor interactions. DC-SIGN is a C-type lectin expressed by dendritic cells that HIV-1 may bind and utilize for enhanced infection of T cells in trans. To further explore the evolution of the R5 phenotype we analyzed sequential R5 isolates obtained before and after AIDS onset, i.e. at the chronic stage and during end-stage disease, with regard to efficiency of DC-SIGN use in trans-infections. RESULTS: Results from binding and trans-infection assays showed that R5 viruses emerging during end-stage AIDS disease displayed reduced ability to use DC-SIGN. To better understand viral determinants underlying altered DC-SIGN usage by R5 viruses, we cloned and sequenced the HIV-1 env gene. We found that end-stage R5 viruses lacked potential N-linked glycosylation sites (PNGS) in the gp120 V2 and V4 regions, which were present in the majority of the chronic stage R5 variants. One of these sites, amino acid position 160 (aa160) in the V2 region, also correlated with efficient use of DC-SIGN for binding and trans-infections. In fitness assays, where head-to-head competitions between chronic stage and AIDS R5 viruses were setup in parallel direct and DC-SIGN-mediated infections, results were further supported. Competitions revealed that R5 viruses obtained before AIDS onset, containing the V2 PNGS at aa160, were selected for in the trans-infection. Whereas, in agreement with our previous studies, the opposite was seen in direct target cell infections where end-stage viruses out-competed the chronic stage viruses. CONCLUSION: Results of our study suggest R5 virus variants with diverse fitness for direct and DC-SIGN-mediated trans-infections evolve within infected individuals at end-stage disease. In addition, our results point to the importance of a glycosylation site within the gp120 V2 region for efficient DC-SIGN use of HIV-1 R5 viruses.
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    Impact of Emerging Antiviral Drug Resistance on Influenza Containment and Spread: Influence of Subclinical Infection and Strategic Use of a Stockpile Containing One or Two Drugs
    McCaw, JM ; Wood, JG ; McCaw, CT ; McVernon, J ; Montgomery, JM (PUBLIC LIBRARY SCIENCE, 2008-06-04)
    BACKGROUND: Wide-scale use of antiviral agents in the event of an influenza pandemic is likely to promote the emergence of drug resistance, with potentially deleterious effects for outbreak control. We explored factors promoting resistance within a dynamic infection model, and considered ways in which one or two drugs might be distributed to delay the spread of resistant strains or mitigate their impact. METHODS AND FINDINGS: We have previously developed a novel deterministic model of influenza transmission that simulates treatment and targeted contact prophylaxis, using a limited stockpile of antiviral agents. This model was extended to incorporate subclinical infections, and the emergence of resistant virus strains under the selective pressure imposed by various uses of one or two antiviral agents. For a fixed clinical attack rate, R(0) rises with the proportion of subclinical infections thus reducing the number of infections amenable to treatment or prophylaxis. In consequence, outbreak control is more difficult, but emergence of drug resistance is relatively uncommon. Where an epidemic may be constrained by use of a single antiviral agent, strategies that combine treatment and prophylaxis are most effective at controlling transmission, at the cost of facilitating the spread of resistant viruses. If two drugs are available, using one drug for treatment and the other for prophylaxis is more effective at preventing propagation of mutant strains than either random allocation or drug cycling strategies. Our model is relatively straightforward, and of necessity makes a number of simplifying assumptions. Our results are, however, consistent with the wider body of work in this area and are able to place related research in context while extending the analysis of resistance emergence and optimal drug use within the constraints of a finite drug stockpile. CONCLUSIONS: Combined treatment and prophylaxis represents optimal use of antiviral agents to control transmission, at the cost of drug resistance. Where two drugs are available, allocating different drugs to cases and contacts is likely to be most effective at constraining resistance emergence in a pandemic scenario.
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    A Small Community Model for the Transmission of Infectious Diseases: Comparison of School Closure as an Intervention in Individual-Based Models of an Influenza Pandemic
    Milne, GJ ; Kelso, JK ; Kelly, HA ; Huband, ST ; McVernon, J ; Montgomery, JM (PUBLIC LIBRARY SCIENCE, 2008-12-23)
    BACKGROUND: In the absence of other evidence, modelling has been used extensively to help policy makers plan for a potential future influenza pandemic. METHOD: We have constructed an individual based model of a small community in the developed world with detail down to exact household structure obtained from census collection datasets and precise simulation of household demographics, movement within the community and individual contact patterns. We modelled the spread of pandemic influenza in this community and the effect on daily and final attack rates of four social distancing measures: school closure, increased case isolation, workplace non-attendance and community contact reduction. We compared the modelled results of final attack rates in the absence of any interventions and the effect of school closure as a single intervention with other published individual based models of pandemic influenza in the developed world. RESULTS: We showed that published individual based models estimate similar final attack rates over a range of values for R(0) in a pandemic where no interventions have been implemented; that multiple social distancing measures applied early and continuously can be very effective in interrupting transmission of the pandemic virus for R(0) values up to 2.5; and that different conclusions reached on the simulated benefit of school closure in published models appear to result from differences in assumptions about the timing and duration of school closure and flow-on effects on other social contacts resulting from school closure. CONCLUSION: Models of the spread and control of pandemic influenza have the potential to assist policy makers with decisions about which control strategies to adopt. However, attention needs to be given by policy makers to the assumptions underpinning both the models and the control strategies examined.