Microbiology & Immunology - Research Publications
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ItemmRNA vaccine against malaria tailored for liver-resident memory T cells(NATURE PORTFOLIO, 2023-09)Malaria is caused by Plasmodium species transmitted by Anopheles mosquitoes. Following a mosquito bite, Plasmodium sporozoites migrate from skin to liver, where extensive replication occurs, emerging later as merozoites that can infect red blood cells and cause symptoms of disease. As liver tissue-resident memory T cells (Trm cells) have recently been shown to control liver-stage infections, we embarked on a messenger RNA (mRNA)-based vaccine strategy to induce liver Trm cells to prevent malaria. Although a standard mRNA vaccine was unable to generate liver Trm or protect against challenge with Plasmodium berghei sporozoites in mice, addition of an agonist that recruits T cell help from type I natural killer T cells under mRNA-vaccination conditions resulted in significant generation of liver Trm cells and effective protection. Moreover, whereas previous exposure of mice to blood-stage infection impaired traditional vaccines based on attenuated sporozoites, mRNA vaccination was unaffected, underlining the potential for such a rational mRNA-based strategy in malaria-endemic regions.
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ItemDiscovery and Biosynthesis of the Cytotoxic Polyene Terpenomycin in Human Pathogenic Nocardia(AMER CHEMICAL SOC, 2023-07-27)Nocardia are opportunistic human pathogens that can cause a range of debilitating and difficult to treat infections of the lungs, brain, skin, and soft tissues. Despite their close relationship to the well-known secondary metabolite-producing genus, Streptomyces, comparatively few natural products are known from the Nocardia, and even less is known about their involvement in the pathogenesis. Here, we combine chemistry, genomics, and molecular microbiology to reveal the production of terpenomycin, a new cytotoxic and antifungal polyene from a human pathogenic Nocardia terpenica isolate. We unveil the polyketide synthase (PKS) responsible for terpenomycin biosynthesis and show that it combines several unusual features, including "split", skipped, and iteratively used modules, and the use of the unusual extender unit methoxymalonate as a starter unit. To link genes to molecules, we constructed a transposon mutant library in N. terpenica, identifying a terpenomycin-null mutant with an inactivated terpenomycin PKS. Our findings show that the neglected actinomycetes have an unappreciated capacity for the production of bioactive molecules with unique biosynthetic pathways waiting to be uncovered and highlights these organisms as producers of diverse natural products.
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ItemNo Preview AvailableHIV-1 INFECTION OF HUMAN MACROPHAGES IMPAIRS PHAGOCYTOSIS AND KILLING OF TOXOPLASMA-GONDII(AMER ASSOC IMMUNOLOGISTS, 1995-06-01)The susceptibility of patients with AIDS to certain opportunistic infections is due to defective cell-mediated immunity. The contribution of direct infection of macrophages with HIV-1 to this defect is unknown. To address this issue, we infected normal human monocyte-derived macrophages with a monocytotropic strain of HIV-1 and examined their ability to phagocytose and kill the opportunistic pathogen, Toxoplasma gondii. Phagocytosis of heat-killed T. gondii was reduced in HIV-infected macrophages compared with mock-infected controls. Opsonization of heat-killed T. gondii increased phagocytosis by both mock- and HIV-infected macrophages, but phagocytosis in HIV-infected cultures remained lower than in controls. Internalization of live T. gondii by macrophages was unaffected by HIV infection. Intracellular replication of live T. gondii was enhanced by HIV infection, as shown in four experiments, each using monocyte-derived macrophages from a different donor. Treatment of HIV-infected macrophages with IFN-gamma decreased parasite replication but not to control levels. These findings suggest that infection of macrophages by HIV may be a contributing factor to the reactivation of T. gondii infection in patients with AIDS.
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ItemNo Preview AvailableChromosome 9 from independent clones and isolates of Plasmodium falciparum undergoes subtelomeric deletions with similar breakpoints in vitro(Elsevier, 1990-04-01)We show that chromosome 9 in all isolates and clones of Plasmodium falciparum examined so far exists as one of two distinctly different forms, a large form about 1.9 megabases long or a smaller form about 25% shorter. Physical maps of chromosome 9 from independent clones with large and small forms of chromosome 9, and from an isolate with the large form and 3 derived clones with the small form reveal the underlying structural basis of this size polymorphism. The small form differs from the large only in that there are subtelomeric deletions at each end, one of these deletions involving about 0.45 megabases. Remarkably, the breakpoints map within about +/- 1% of the total chromosome length for each of these populations. We discuss some possible mechanisms for this.
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ItemNo Preview AvailableVitamin D deficiency is associated with tuberculosis and latent tuberculosis infection in immigrants from Sub-Saharan Africa(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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ItemNo Preview AvailableIsolated core antibody hepatitis B in sub-Saharan African immigrants(WILEY, 2008-09-01)Chronic hepatitis B virus (HBV) infection is a major health problem in sub-Saharan Africa, where prevalence is > or =8%, and is increasingly seen in African immigrants to developed countries. A retrospective audit of the medical records of 383 immigrants from sub-Saharan Africa attending the infectious diseases clinics at the Royal Melbourne Hospital was performed from 2003 to 2006. The HBV, human immunodeficiency virus (HIV) and hepatitis C virus (HCV) serological results are reported, with a focus on the isolated core antibody HBV pattern (detection of anti-HBc without detection of HBsAg or anti-HBs). Two-thirds (118/174, 68%) of those tested had evidence of HBV infection with detectable anti-HBc. Chronic HBV infection (serum HBsAg detected) was identified in 38/174 (22%) and resolved HBV infection (both serum anti-HBs and anti-HBc detected) in 45/174 (26%). The isolated core antibody pattern was identified in 35/174 (20%), of whom only 1/35 (3%) had detectable serum HBV DNA on PCR testing, indicating occult chronic HBV (OCHB). Only 8/56 (14%) patients with negative anti-HBc had serological evidence of vaccination (serum anti-HBs detected). HIV infection was detected in 26/223 (12%). HCV antibodies were detected in 10/241 (4%), of whom 8 (80%) had detectable HCV RNA. Viral co-infection was detected in only 2/131 (1.5%) patients tested for all three viruses. The isolated core antibody HBV pattern was common among sub-Saharan African patients in our study. These patients require assessment for OCHB infection and monitoring for complications of HBV.
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ItemThe Profile of Health Problems in African Immigrants Attending an Infectious Disease Unit in Melbourne, Australia(AMER SOC TROP MED & HYGIENE, 2009-05-01)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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ItemPublication speed: a balancing act between author urgency and editorial process(WILEY, 2022-07-18)
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ItemThe Implementation Experience of COVID-19 Rapid Antigen Testing in a Large-Scale Construction Project in Victoria, Australia(Springer, 2023-05-30)The coronavirus (COVID-19) pandemic has caused major disruptions to industries and workplaces. Rapid Antigen Tests (RATs) for COVID-19, which allow individuals to self-administer tests and receive timely results without laboratory testing, provide the opportunity for surveillance testing of asymptomatic individuals in non-medical settings. However, the literature offers few lessons regarding how to create enabling conditions for effective and sustainable implementation in a workplace setting. Guided by the RE-AIM framework, we assessed factors associated with the adoption, implementation, and maintenance of mandatory RAT in a large-scale construction project in Victoria, Australia. We used a mixed methods approach involving site observation, worker surveys (n = 30), and interviews with 51 site workers and managers to understand the implementation experience. Factors which facilitated adoption included easy, non-invasive testing procedure; sense of workplace safety; and strong backing by management and acceptance by workers that RATs helped limit COVID-19-related lost days of work. Gaps in knowledge and adherence to testing protocols, logistical challenges (test kit supply, observation of test results), and low appetite for long-term, mandatory testing emerged as challenges for effective implementation and sustainability. As RAT becomes normalized in a range of workplace settings, strategies will be required to support the sustainability of implementation, including longer-term acceptability of surveillance testing and adherence to testing protocols. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43477-023-00085-4.