Begell House Inc.
Critical Reviews™ in Immunology
CRI
1040-8401
30
2
2010
Novel Innate Immune Functions Revealed by Dynamic, Real-Time Live Imaging of Bacterial Infections
107-117
10.1615/CritRevImmunol.v30.i2.10
Keira
Melican
Swedish Medical Nanoscience Center, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
Jorrit
Boekel
Swedish Medical Nanoscience Center, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
Monica
Ryden-Aulin
Swedish Medical Nanoscience Center, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
Agneta
Richter-Dahlfors
Swedish Medical Nanoscience Center, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
multiphoton microscopy
two-photon microscopy
ischemia
UPEC
pyelonephritis
A bacterial infection is accompanied by dynamic alterations in tissue homeostasis within the infected organ. What starts as a local bacterium-host cell interaction at the site of infection changes over time to include distant signaling and the engagement of multiple cell types in an efort to eradicate the bacteria. Recent advancements in imaging technologies, such as multiphoton microscopy, provide new tools to visualize the realtime dynamics of infection within the living host. The use of live animal models means that all of the interplaying factors, such as the immune, lymphatic, nervous, and vascular systems, are present and can be accounted for. This review describes novel insights of innate immune defense mechanisms obtained using real-time visualization of the infected tissue in a live animal model. This emerging feld of "tissue microbiology" will provide data that, when combined with the massive knowledge base generated from research in "cellular microbiology," will provide a more complete picture of the complex infection process.
The Pathogenesis of Murine Coronavirus Infection of the Central Nervous System
119-130
10.1615/CritRevImmunol.v30.i2.20
Martin P.
Hosking
Department of Molecular Biology and Biochemistry, University of California, Irvine, California
Thomas E.
Lane
Department of Molecular Biology and Biochemistry, Institute for Immunology, and Sue and Bill Gross Stem Cell Center University of California, Irvine, California
host defense
viral infection
multiple sclerosis
demyelination
Mouse hepatitis virus (MHV) is a positive-strand RNA virus that causes an acute encephalomyelitis that later resolves into a chronic fulminating demyelinating disease. Cytokine production, chemokine secretion, and immune cell infiltration into the central nervous system are critical to control viral replication during acute infection. Despite potent antiviral T-lymphocyte activity, sterile immunity is not achieved, and MHV chronically persists within oligodendrocytes. Continued infiltration and activation of the immune system, a result of the lingering viral antigen and RNA within oligodendrocytes, lead directly to the development of an immune-mediated demyelination that bears remarkable similarities, both clinically and histologically, to the human demyelinating disease multiple sclerosis. MHV offers a unique model system for studying host defense during acute viral infection and immune-mediated demyelination during chronic infection.
Treatment of Hepatitis C Virus Infection With Interferon and Small Molecule Direct Antivirals: Viral Kinetics and Modeling
131-148
10.1615/CritRevImmunol.v30.i2.30
Libin
Rong
Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico
Alan S.
Perelson
Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico
virus dynamics
interferon
ribavirin
small molecule inhibitors
drug resistance
combination therapy
Hepatitis C virus (HCV) infection remains a threat to global public health. Treatment with pegylated interferon (IFN) plus ribavirin leads to a sustained virologic response in about 50% of patients. New therapies using direct antiviral agents have the potential to cure patients unresponsive to IFN-based therapies. Mathematical modeling has played an important role in studying HCV kinetics. Using models, one can evaluate the effectiveness of new treatment agents, estimate important parameters that govern virus-host interactions, explore possible mechanisms of drug action against HCV, investigate the development of drug resistance, and study quasispecies dynamics during therapy. Here we review our current knowledge of HCV kinetics under IFN-based therapy and newly developed antiviral agents specifically targeted to attack HCV, and show how mathematical models have helped to improve our understanding of HCV infection and treatment.
Staphylococcal Superantigen Super-Domains in Immune Evasion
149-165
10.1615/CritRevImmunol.v30.i2.40
Ries
Langley
The Maurice Wilkins Centre for Research, University of Auckland, New Zealand
Deepa
Patel
The Maurice Wilkins Centre for Research, University of Auckland, New Zealand
Nicola
Jackson
The Maurice Wilkins Centre for Research, University of Auckland, New Zealand
Fiona
Clow
The Maurice Wilkins Centre for Research, University of Auckland, New Zealand
John D.
Fraser
The Maurice Wilkins Centre for Research, University of Auckland, New Zealand
Staphylococcus
virulence
superantigen
complement
innate immunity
SSL
Staphylococcus aureus is a robust pathogen that is capable of growing in virtually any part of the human body, and can also survive and grow in many other species. S. aureus remains the most frequent cause of hospital-acquired infection and, with the emergence and spread of drug-resistant, hypervirulent, community-acquired strains, the specter looms of the ultimate superbug. S. aureus produces an array of immune evasion factors that target various components of host immune defense. Among them are the powerful superantigen (SAg) and SAg-like (SSL) molecules, which are coded for by genes scattered across several genomic and pathogenicity islands. The SAgs universally bind MHC (major histocompatibility complex) class II and T-cell receptors to induce profound T-cell activation, while the SSLs target a range of molecules regulating opsonophagocytosis and neutrophil function. Despite functional diferences, the SAgs and SSLs have clearly evolved from a single ancestral gene that now codes for a stable, two-domain protein, with each domain responsible for binding a diferent target molecule. This superstructure tolerates extensive surface variation, enabling a wide assortment of virulence factors targeting multiple steps in innate immunity. Notably, both the SAgs and the SSLs exhibit optimal activity for humans and non-human primates, clearly indicating that primates have been the preferred host for S. aureus evolution. This restricted function makes it difficult to assess their role in staphylococcal virulence using animal models of infection. This brief review focuses on the structural features of SAgs and SSLs and their individual functions as we currently understand them.
Mode of Action of Botulinum Neurotoxins: Current Vaccination Strategies and Molecular Immune Recognition
167-187
10.1615/CritRevImmunol.v30.i2.50
K. Roger
Aoki
Ailergan, Inc., 2525 DuPont Drive, Irvine, CA 92612, USA
Leonard A.
Smith
Integrated Toxicology Division, US Army Medical Research Institute of Infectious Diseases; Fort Detrick, MD 21702-5011, USA
M. Zouhair
Atassi
Baylor College of Medicine,
Houston, TX 77030, USA
Antigenic sites
antibodies
botulinum neurotoxin
cervical dystonia
epitopes
immunoresistance
mechanism of action
subunit
synthetic peptides
vaccines
The action of a botulinum neurotoxin (BoNT) commences by binding at the nerve terminal via its H- (heavy) chain to a cell-surface receptor, which consists of a ganglioside and a cell-surface protein. Binding enables the L-chain, a Zn2+-dependent endopeptidase, to be internalized and act intracellularly, cleaving one or more SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins required for vesicle docking and fusion, which results in reduced neurotransmitter release. Sprouts emerge at motor-nerve terminals that reestablish synaptic contact and lead to restoration of exocytosis. As the terminals recover, sprouts retreat and synaptic function is fully re-established. Neutralizing antibodies (Abs) induced by vaccination can prevent the neuronal changes produced by BoNT. Until recently, vaccines against BoNT have been based on toxins inactivated by treatment with formaldehyde (toxoids) and contain either one (monovalent) or five (pentavalent) toxoids, but formalin-based toxoids have many undesirable side effects. Availability of the gene sequences of BoNT serotypes enabled design of recombinant subunit vaccines that have included the C-terminal domain of the H chain (HC, its subdomains (HC-N and HC-C), the L- (catalytic) chain, and the L-chain expressed with the translocation domain (LCHN). Of these, the HC displays the highest protective ability. Recent vaccines have used whole toxins inactivated by three key mutations at the enzyme active site, which have been found to be very effective in mice against the correlated toxin. Immune responses to BoNTs A and B epitopes are under the host’s MHC (major histocompatibility complex) control. Anti-BoNT/A blocking Abs bind at sites that coincide or overlap with those that bind synaptosomes and to BoNT/B at sites that overlap with synaptotagmin-II and ganglioside-binding sites. Therefore, locations occupied by blocking Abs preclude the respective toxin from binding to its receptor and thus from binding to cell surface. Information on BoNT epitopes for blocking Abs, sites for binding to cell surface receptors, and T-cell epitopes that provide help to B cells making blocking Abs afford a prospect for rational design of stable synthetic vaccines. These constructs should be clinically useful for epitope-selective modulation of Ab responses to restore effective BoNT treatment in immunoresistant patients.
Induction of Th17 Cellular Immunity With a Novel Nanoemulsion Adjuvant
189-199
10.1615/CritRevImmunol.v30.i2.60
Anna U.
Bielinska
University of Michigan Nanotechnology Institute for Medicine and Biological Sciences and Department of Internal Medicine, Ann Arbor, Michigan
Michele
Gerber
University of Michigan Nanotechnology Institute for Medicine and Biological Sciences and Department of Internal Medicine, Ann Arbor, Michigan
Luz P.
Blanco
University of Michigan Nanotechnology Institute for Medicine and Biological Sciences and Department of Internal Medicine, Ann Arbor, Michigan
Paul E.
Makidon
University of Michigan Nanotechnology Institute for Medicine and Biological Sciences and Department of Internal Medicine, Ann Arbor, Michigan
Katarzyna W.
Janczak
University of Michigan Nanotechnology Institute for Medicine and Biological Sciences and Department of Internal Medicine, Ann Arbor, Michigan
Michael
Beer
University of Michigan Nanotechnology Institute for Medicine and Biological Sciences and Department of Internal Medicine, Ann Arbor, Michigan
Benjamin
Swanson
University of Michigan Nanotechnology Institute for Medicine and Biological Sciences and Department of Internal Medicine, Ann Arbor, Michigan
James R.
Baker, Jr.
University of Michigan Nanotechnology Institute for Medicine and Biological Sciences and Department of Internal Medicine, Ann Arbor, Michigan
mucosal adjuvant
nanoemulsion
T17
cellular immunity
T17 (T-helper-17) cytokine responses have been recently recognized as an important component for the protective immunity produced by vaccination. However, the mechanism by which immune adjuvants induce T17 immunity has not been defined. We have developed a novel mucosal nanoemulsion (NE) adjuvant that produces a robust humoral and T1 cellular immunity. Herein, we demonstrate that immunization with NE adjuvant induces a T17 response to diverse antigens in both outbred and inbred mice. CD86 deficiency had a limited effect on the induction of IL-17, however, double CD80/CD86, CD40, and IL-6 (interleukin 6) mutant mice failed to produce T17 immunity in response to NE adjuvant. Mice deficient in TLR2 and TLR4 (Toll-like receptors 2 and 4) had a diminished IL-17 response. Our data indicate that nasal mucosal immunization with NE adjuvant produces T1 and T17 immunity; that this process requires IL-6, CD40, and at least one of the CD80/CD86 molecules; and that the induction of TH17 is enhanced by the presence of TLR2 and TLR4 receptors. This unique approach to vaccination may have a significant role in protection against mucosal and intracellular pathogens.
Biomarkers for Serum Diagnosis of Infectious Diseases and Their Potential Application in Novel Sensor Platforms
201-222
10.1615/CritRevImmunol.v30.i2.70
Luiz R.
Goulart
Laboratory of Nanobiotechnology, Federal University of Uberlandia, Uberlandia, MG, Brazil
Carlos U.
Vieira
Laboratory of Nanobiotechnology, Federal University of Uberlandia, Uberlandia, MG, Brazil
Ana Paula P.
Freschi
Laboratory of Nanobiotechnology, Federal University of Uberlandia, Uberlandia, MG, Brazil
Fausto E.
Capparelli
Laboratory of Nanobiotechnology, Federal University of Uberlandia, Uberlandia, MG, Brazil
Patricia T.
Fujimura
Laboratory of Nanobiotechnology, Federal University of Uberlandia, Uberlandia, MG, Brazil
Juliana F.
Almeida
Laboratory of Nanobiotechnology, Federal University of Uberlandia, Uberlandia, MG, Brazil
Lucas F.
Ferreira
Laboratory of Polymeric Films and Nanotechnology, Federal University of Uberlandia, Uberlandia, MG, Brazil
Isabela M.B.
Goulart
Leprosy National Reference Center, Federal University of Uberlandia, Uberlandia, MG, Brazil
Ana Graci
Brito-Madurro
Laboratory of Polymeric Films and Nanotechnology, Federal University of Uberlandia, Uberlandia, MG, Brazil
Joao M.
Madurro
Leprosy National Reference Center, Federal University of Uberlandia, Uberlandia, MG, Brazil
recombinant peptides
particle gel agglutination assay
magnetic nanoparticle-ELISA
electrochemical sensors
infectious diseases
Nanotechnological tools and biomarkers for diagnosis and prognosis, as well as strategies for disease control and monitoring populations at higher risk, are continuous worldwide challenges for infectious diseases. Phage display and monoclonal antibody combinatorial libraries are important sources for biomarker discovery and for improved diagnostic strategies. Mimetic peptides were selected against polyclonal antibodies from patients with dengue fever, leprosy, and leishmaniasis as model diseases, and from immunized chickens with total antigens from all three pathogens. Selected single or combined multi-epitope peptide biomarkers were further associated with four different sensor platforms, classified as affinity biosensors, that may be suitable as general protocols for field diagnosis. We have also developed two methods for nanoparticle agglutination assays (a particle gel agglutination test and a magnetic microparticle [MMP]-enzyme-linked immunosorbent assay [ELISA]) and two electrochemical biosensors (impedimetric and amperometric) for DNA and antibody detection. For the agglutination tests, micro- and nanoparticles were coupled with flamentous bacteriophages displaying the selected mimotopes on their surfaces, which has favored the formation of the antigen-antibody or peptide-protein complexes, amplifying the optical detection in ELISA assays or after the chromatographic separation of the microagglutinates. We have also demonstrated a proof-of-concept for the electrochemical biosensors by using electrodes modifed with novel functionalized polymers. These electrochemical biosensors have proven to be fast, very sensitive, and specific for the detection of pathogen DNA and circulating antibodies of patients, which may become important in a wide range of diagnostic devices for many infectious agents.