HspX-mediated protection against tuberculosis depends on its chaperoning of a mycobacterial molecule

Department of Microbiology, Mycobacteria Research Laboratories, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA.
Immunology and Cell Biology (Impact Factor: 4.21). 07/2012; 90(10). DOI: 10.1038/icb.2012.34
Source: PubMed

ABSTRACT New approaches consisting of 'multistage' vaccines against (TB) are emerging that combine early antigenic proteins with latency-associated antigens. In this study, HspX was tested for its potential to elicit both short- and long-term protective immune responses. HspX is a logical component in vaccine strategies targeting protective immune responses against primary infection, as well as against reactivation of latent infection, because as previously shown, it is produced during latency, and as our studies show, it elicits protection within 30 days of infection. Recent studies have shown that the current TB vaccine, bacilli Calmette-Guerin (BCG), does not induce strong interferon-γ T-cell responses to latency-associated antigens like HspX, which may be in part why BCG fails to protect against reactivation disease. We therefore tested HspX protein alone as a prophylactic vaccine and as a boost to BCG vaccination, and found that HspX purified from M. tuberculosis cell lysates protected mice against aerosol challenge and improved the protective efficacy of BCG when used as a booster vaccine. Native HspX was highly immunogenic and protective, in a dose-dependent manner, in both short- and long-term infection models. Based on these promising findings, HspX was produced as a recombinant protein in E. coli, as this would enable facile purification; however, recombinant HspX (rHspX) alone consistently failed to protect against aerosol challenge. Incubation of rHspX with mycobacterial cell lysate and re-purification following incubation restored the capacity of the protein to confer protection. These data suggest the possibility that the native form may chaperone an immunogenic and protective antigen that is mycobacteria-specific.Immunology and Cell Biology advance online publication, 17 July 2012; doi:10.1038/icb.2012.34.

Download full-text


Available from: Karen M Dobos, Aug 09, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Adjuvants were reintroduced into modern immunology as the dirty little secret of immunologists by Janeway and thus began the molecular definition of innate immunity. It is now clear that the binding of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) on antigen presenting cells (APCs) activates the innate immune response and provides the host with a rapid mechanism for detecting infection by pathogens and initiates adaptive immunity. Ironically, in addition to advancing the basic science of immunology, Janeway's revelation on induction of the adaptive system has also spurred an era of rational vaccine design that exploits PRRs. Thus, defined PAMPs that bind to known PRRs are being specifically coupled to antigens to improve their immunogenicity. However, while PAMPs efficiently activate the innate immune response, they do not mediate the capture of antigen that is required to elicit the specific responses of the acquired immune system. Heat shock proteins (HSPs) are molecular chaperones that are found complexed to client polypeptides and have been studied as potential cancer vaccines. In addition to binding PRRs and activating the innate immune response, HSPs have been shown to both induce the maturation of APCs and provide chaperoned polypeptides for specific triggering of the acquired immune response.
    05/2013; 2013:461230. DOI:10.1155/2013/461230
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mycobacterium tuberculosis, the causative agent of tuberculosis, has developed various mechanisms to survive and cause disease in the human host. Incomplete understanding of the complex microbe-host interactions has hindered the identification of suitable biomarkers to expedite the development of diagnostic tools, drugs and vaccines. The field effectiveness of directly observed therapy-short course has been compromised by the intrinsic limitations of sputum microscopy and suboptimal adherence to the long duration of treatment, amidst the human immunodeficiency virus (HIV)-TB syndemic and various socio-economic constraints. While molecular tools are transforming the diagnostic processes, especially for multidrug-resistant (MDR)-TB, drug development and service provision for MDR-TB seriously lag behind. Inappropriate management of detected MDR-TB cases may amplify drug resistance, jeopardizing future control. Targeted screening and treatment of latent infection with M. tuberculosis with the currently available immunodiagnostic tools and treatment regimens aims more for personal protection than major epidemiological impact or elimination. The interferon-γ release assays are not affected by cross-reaction to the bacillus Calmette-Guérin (BCG) vaccine, and are increasingly used for such screening before initiation of biologics for treatment of rheumatoid arthritis and other autoimmune disorders. BCG offers only partial and unreliable protection against pulmonary tuberculosis in adults, the crucial transmission link for this airborne infection. Systems biology and vaccinomics may speed up vaccine research. The successful development of a fully effective tuberculosis vaccine that targets both growing bacteria and non-growing persisters may reflect a major breakthrough, as natural infection does not induce sufficient immunity to prevent reinfection.
    Respirology 07/2013; 18(7). DOI:10.1111/resp.12156 · 3.50 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Contemporary coral reef research has firmly established that a genomic approach is urgently needed to better understand the effects of anthropogenic environmental stress and global climate change on coral holobiont interactions. Here we present KEGG orthology-based annotation of the complete genome sequence of the scleractinian coral Acropora digitifera and provide the first comprehensive view of the genome of a reef-building coral by applying advanced bioinformatics.Description: Sequences from the KEGG database of protein function were used to construct hidden Markov models. These models were used to search the predicted proteome of A. digitifera to establish complete genomic annotation. The annotated dataset is published in ZoophyteBase, an open access format with different options for searching the data. A particularly useful feature is the ability to use a Google-like search engine that links query words to protein attributes. We present features of the annotation that underpin the molecular structure of key processes of coral physiology that include (1) regulatory proteins of symbiosis, (2) planula and early developmental proteins, (3) neural messengers, receptors and sensory proteins, (4) calcification and Ca2+-signalling proteins, (5) plant-derived proteins, (6) proteins of nitrogen metabolism, (7) DNA repair proteins, (8) stress response proteins, (9) antioxidant and redox-protective proteins, (10) proteins of cellular apoptosis, (11) microbial symbioses and pathogenicity proteins, (12) proteins of viral pathogenicity, (13) toxins and venom, (14) proteins of the chemical defensome and (15) coral epigenetics. We advocate that providing annotation in an open-access searchable database available to the public domain will give an unprecedented foundation to interrogate the fundamental molecular structure and interactions of coral symbiosis and allow critical questions to be addressed at the genomic level based on combined aspects of evolutionary, developmental, metabolic, and environmental perspectives.
    BMC Genomics 07/2013; 14(1):509. DOI:10.1186/1471-2164-14-509 · 4.04 Impact Factor
Show more