Microbiology & Immunology - Research Publications

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    Absence of an essential role for thymic stromal lymphopoietin receptor in murine B-cell development
    Carpino, N ; Thierfelder, WE ; Chang, MS ; Saris, C ; Turner, SJ ; Ziegler, SF ; Ihle, JN (AMER SOC MICROBIOLOGY, 2004-03)
    The murine cytokine thymic stromal lymphopoietin (TSLP) supports the development of B220+ IgM+ immature B cells and induces thymocyte proliferation in vitro. Human TSLP, by contrast, activates CD11c+ dendritic cells, but not B or T cells. Recent studies have demonstrated that the receptor for TSLP consists of a heterodimer of the interleukin 7 (IL-7) alpha chain and a novel protein that resembles the hematopoietic cytokine receptor common gamma chain. We examined signal transduction by the gamma-like chains using chimeric receptor proteins. The cytoplasmic domain of the human, but not of the murine, gamma-like chain, activates Jak2 and Stat5 and supports the proliferation of hematopoietic cell lines. In order to assess the role of the murine gamma-like chain in vivo, we generated gamma-like chain-deficient mice. Receptor-deficient mice are unresponsive to TSLP but exhibit no obvious phenotypic defects. In particular, hematopoietic cell development appeared normal. B-cell development, including the IgM+ compartment, was unaffected by loss of the TSLP pathway, as were T lymphopoiesis and lymphocyte proliferation in vitro. Cytokine receptors that utilize the common gamma chain signal through the lymphocyte-specific kinase Jak3. Mice deficient in Jak3 exhibit a SCID phenotype but harbor a residual B220+ splenic lymphocyte population. We demonstrate here that this residual lymphocyte population is lost in mice lacking both the gamma-like chain and Jak3.
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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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    Isolated core antibody hepatitis B in sub-Saharan African immigrants
    Gibney, KB ; Torresi, J ; Lemoh, C ; Biggs, BA (WILEY, 2008-09)
    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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    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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    Osteoclast Inhibitory Lectin, an Immune Cell Product That Is Required for Normal Bone Physiology in Vivo
    Kartsogiannis, V ; Sims, NA ; Quinn, JMW ; Ly, C ; Cipetic, M ; Poulton, IJ ; Walker, EC ; Saleh, H ; McGregor, NE ; Wallace, ME ; Smyth, MJ ; Martin, TJ ; Zhou, H ; Ng, KW ; Gillespie, MT (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2008-11-07)
    Osteoclast inhibitory lectin (OCIL or clrb) is a member of the natural killer cell C-type lectins that have a described role mostly in autoimmune cell function. OCIL was originally identified as an osteoblast-derived inhibitor of osteoclast formation in vitro. To determine the physiological function(s) of OCIL, we generated ocil(-/-) mice. These mice appeared healthy and were fertile, with no apparent immune function defect, and phenotypic abnormalities were limited to bone. Histomorphometric analysis revealed a significantly lower tibial trabecular bone volume and trabecular number in the 10- and 16-week-old male ocil(-/-) mice compared with wild type mice. Furthermore, ocil(-/-) mice showed reduced bone formation rate in the 10-week-old females and 16-week-old males while Static markers of bone formation showed no significant changes in male or female ocil(-/-) mice. Examination of bone resorption markers in the long bones of ocil(-/-) mice indicated a transient increase in osteoclast number per unit bone perimeter. Enhanced osteoclast formation was also observed when either bone marrow or splenic cultures were generated in vitro from ocil(-/-) mice relative to wild type control cultures. Loss of ocil therefore resulted in osteopenia in adult mice primarily as a result of increased osteoclast formation and/or decreased bone formation. The enhanced osteoclastic activity led to elevated serum calcium levels, which resulted in the suppression of circulating parathyroid hormone in 10-week-old ocil(-/-) mice compared with wild type control mice. Collectively, our data suggest that OCIL is a physiological negative regulator of bone.
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    DNA vaccine expressing conserved influenza virus proteins protective against H5N1 challenge infection in mice
    Epstein, SL ; Tumpey, TM ; Misplon, JA ; Lo, CY ; Cooper, LA ; Subbarao, K ; Renshaw, M ; Sambhara, S ; Katz, JM (CENTERS DISEASE CONTROL & PREVENTION, 2002-08)
    Influenza vaccination practice, which is based on neutralizing antibodies, requires being able to predict which viral strains will be circulating. If an unexpected strain, as in the 1997 H5N1 Hong Kong outbreak, or even a pandemic emerges, appropriate vaccines may take too long to prepare. Therefore, strategies based on conserved influenza antigens should be explored. We studied DNA vaccination in mice with plasmids expressing conserved nucleoprotein (NP) and matrix (M) from an H1N1 virus. After vaccination, mice were challenged with A/H5N1 viruses of low, intermediate, and high lethality. A/NP+A/M DNA vaccination reduced replication of A/Hong Kong/486/97 (HK/486), a nonlethal H5N1 strain, and protected against lethal challenge with more virulent A/Hong Kong/156/97 (HK/156). After HK/156 exposure, mice survived rechallenge with A/Hong Kong/483/97 (HK/483), although the DNA vaccination alone protected poorly against this highly virulent strain. In the absence of antigenically matched hemagglutinin-based vaccines, DNA vaccination with conserved influenza genes may provide a useful first line of defense against a rapidly spreading pandemic virus.
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    SARS vaccine protective in mice
    Stadler, K ; Roberts, A ; Becker, S ; Vogel, L ; Eickmann, M ; Kolesnikova, L ; Klenk, HD ; Murphy, B ; Rappuoli, R ; Abrignani, S ; Subbarao, K (CENTERS DISEASE CONTROL, 2005-08)
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    Vaccines for pandemic influenza
    Luke, CJ ; Subbarao, K (CENTERS DISEASE CONTROL & PREVENTION, 2006-01)
    Recent outbreaks of highly pathogenic avian influenza in Asia and associated human infections have led to a heightened level of awareness and preparation for a possible influenza pandemic. Vaccination is the best option by which spread of a pandemic virus could be prevented and severity of disease reduced. Production of live attenuated and inactivated vaccine seed viruses against avian influenza viruses, which have the potential to cause pandemics, and their testing in preclinical studies and clinical trials will establish the principles and ensure manufacturing experience that will be critical in the event of the emergence of such a virus into the human population. Studies of such vaccines will also add to our understanding of the biology of avian influenza viruses and their behavior in mammalian hosts.
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    Do apicomplexan parasite-encoded proteins act as both ligands and receptors during host cell invasion?
    Gilson, PR ; Crabb, BS (Faculty Opinions Ltd, 2009)
    Apicomplexan parasites are responsible for a wide range of diseases in animals, including humans, in whom Plasmodium species cause the devastating disease malaria. Several recent discoveries now indicate that these intracellular parasites may use a conserved mechanism to infect their host cells by using parasite-encoded proteins as both parasite ligands and receptors anchored to the host cells.
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    Reduced sensitivity of influenza A (H5N1) to oseltamivir
    McKimm-Breschkin, JL ; Selleck, PW ; Usman, TB ; Johnson, MA (CENTER DISEASE CONTROL, 2007-09)
    We tested the neuraminidase drug sensitivity of clade 1 and clade 2 influenza A (H5N1). All viruses demonstrated similar sensitivity to zanamivir, but compared with the 2004 clade 1 viruses, the Cambodian 2005 viruses were 6-fold less sensitive and the Indonesian clade 2 viruses were up to 30-fold less sensitive to oseltamivir.