Tuberculosis (TB) remains one of the worlds most important infectious diseases. The causative agent, Mycobacterium tuberculosis, is the leading cause of death of any infectious agent. Each year, approximately 8 million people develop active pulmonary TB and 2 million die from this disease. The World Health Organization has declared TB a global health emergency, the first disease so designated. Moreover, multi-drug resistant strains of M. tuberculosis have been classified by the Centers for Disease Control and Prevention as potential weapons of bioterrorism.In the United States, the incidence of TB has been falling over the past half-century, but remains high in HIV-infected persons, the elderly, homeless and under-served populations, and immigrants from endemic areas. Moreover, the emergence of multidrug-resistant strains complicates TB control efforts and posts a health threat to the general public, especially immunocompromised individuals. In HIV patients, an infection strain that has developed resistance to available drugs results in a 50% death rate within 60 days.The current TB vaccine, M. bovis BCG, is a live attenuated form of the bovine TB pathogen developed in the 1900s. The vaccine is of modest efficacy but has been used in combination with drug therapy as a means to control the disease. (more...)

Attenuated, or weakened, viruses have played a significant role in the development of vaccines, such as the current vaccine for tuberculosis. Viruses undergo genetic change through mutation and recombination of their genetic material, the result of which may be either an increase in pathogenicity or the initiation of an immune response within the host organism. For example, point mutations have been used in the development of attenuated viruses for respiratory vaccines to allow for greater phenotypic stability of the viral vaccine. Current vaccines are typically systemic in nature and are not targeted to a specific tissue within the body. The development of a tissue-specific vaccine could hold significant promise in the development of new treatments for cancers or for the generation of targeted immunity.   Viruses also play an important role in the developing field of gene therapy. Viruses have been used to introduce and target replacement gene sequences to specific tissues to replace defective ones. Viruses are uniquely suited to this as they naturally infect host cells and integrate their genetic material with that of the host cell. (more...)

This work identifies a physiological role for the Influenza A virus RNAi suppressor protein NS1 in the inhibition of specific host miRNA function. Influenza A virus causes seasonal infections and periodic pandemics in humans and is a major public health concern. The viral pathogenesis requires expression of its multifunctional non-structural protein 1 (NS1), which inhibits the interferon response and binds dsRNA in vitro. NS1 also suppresses experimentally induced RNAi, but a physiological role for this activity is unknown. Here we show that NS1 interferes with the biogenesis of specific cellular miRNAs by direct binding to the structured miRNA precursors in infected human cells. Expression of NS1 is associated with depletion of specific precursor miRNA that have important cellular and/or immune functions, our findings indicate a role for viral suppression of RNAi in the influenza virus pathogenesis and specific methods for the treatment or inhibition of influenza infection. The mission of UCR’s Office of Technology Commercialization (OTC) is to insure that research results are made available for public use and benefit. For this purpose, OTC is currently marketing this technology to industry. Any inquiry regarding this technology can be directed to Michael Arciero at michael.arciero@ucr.edu.    Purple-and-green conjugates of peptides and double-stranded RNA target cell-surface receptors (purple) and deliver double-stranded RNA to the Dicer enzyme (orange), which cuts the RNA to the right size for RNA interference.  (more...)

HBV infection can lead to chronic infections that result in 0.6 million deaths per year worldwide by causing liver failure and cancer. Clearance of HBV infection is age dependent, with the majority of adult-acquired infections leading to spontaneous clearance, whereas infection in young children often leads to chronic infections. To study these early events of infection and immune activation that lead to HBV clearance or persistence, in vivo models are needed to screen and validate lead drug candidates. HBV cannot infect mice, however, researchers at UCSF have generated transgenic mouse models that mimic critical features of primary HBV infection observed in humans. (more...)

The Human Immunodeficiency Virus (HIV) has evolved a number of mechanisms of evading the human immune system.  One way is through a high level of mutation, which makes it difficult to develop a vaccine that stimulates protective immunity against all of the different HIV variants.  Therefore, scientists are searching for a general surrogate marker that could be used to target any HIV-infected cell regardless of its mutational status, enabling eradication of the virus. In this regard, scientists at UCSF have recently begun to take a closer look at Human Endogenous Retroviruses (HERVs) that are present in all human cells.  HERVs are a family of retroviruses found in the human genome and are thought to have originated from an ancient retrovirus that become permanently integrated with the DNA of its host's germ cells.  HERV viruses are inactive in normal cells but one type of HERV, HERV-K, is activated in HIV-infected cells.  The HERV-K proteins are presented on the surface of HIV-infected cells.  Because HERV-K is expressed in all HIV-infected cells, it is thought HERV-K antigens presented on the surface could be a good candidate to generally target any HIV+ cell. (more...)

Tuberculosis (TB) infection remains highly prevalent worldwide. The WHO estimates 1.7 million deaths from TB annually. Africa and Southeast Asia have the highest burden of TB mortality. The persistence of TB infection has promoted the emergence of multi- and extensively drug-resistant (M/XDR) strains, which pose an imminent threat to industrialized nations. The vaccine currently used for TB, BCG, has been widely administered but lacks optimal protection. In fact, a large, carefully conducted meta-analysis by Colditz et al. (1994) estimates the potency of BCG protection to be approximately 50%. Therefore, new vaccines or booster strategies are necessary to combat TB infection. Improvements in the potency of TB vaccination will represent a significant advancement in global health and a step towards eradication of TB. (more...)

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Tuberculosis (TB) remains one of the world's most important infectious diseases. The causative agent, Mycobacterium tuberculosis, is the leading cause of death of any infectious agent. Each year, approximately 8 million people develop active pulmonary TB and two million die from this disease. The World Health Organization (WHO) has declared TB a global health emergency, the first disease so designated. Compounding the problem, strains of M. tuberculosis resistant to the major antibiotics used to treat tuberculosis are rapidly emerging worldwide. This has given new urgency to the need to develop an effective prophylaxis for TB. Vaccination is particularly important for developing nations and at-risk populations.Four billion people in the world have been vaccinated with the currently used vaccine, bacille Calmette-Guerin or BCG, and approximately 100 million additional individuals are vaccinated with BCG each year. Since BCG provides only partial immunity to tuberculosis, these people could benefit from a booster vaccine that enhances their level of protection against tuberculosis.  (more...)

A system using nanotechnology to synthetically replicate the body's immune function for uses in body fluid filtration, stimulation of immune system, therapeutics and diagnostics. (more...)

Hepatitis C virus (HCV) afflicts about 170 million people worldwide and yet the mechanisms responsible for the entry and trafficking of HCV into cells are poorly understood. HCV induces an acute illness and often leads to chronic hepatitis and in some cases may lead to hepatocellular carcinoma and/or cirrhosis. There currently is no treatment that the majority of patients with HCV respond to, and those that are given interferon plus ribaviron often display serious adverse side effects. (more...)

Tularemia is a disease caused by the bacterium Francisella tularensis, one of the most infectious pathogenic bacteria known to affect both animals and humans. Although natural infections of F. tularensis have become less of a threat, the ease with which this bacterium can be manufactured and disseminated, its high infectivity, and high mortality when transmitted by the respiratory route remain a major concern. For that reason, the CDC has classified F. tularensis as a Category A bioterrorism agent. This biological agent has long been considered a potential biological weapon, and there are indications suggesting its use during World War II. It is believed that if used as a biological weapon, an aerosol release would have the greatest adverse effect resulting in a highly fatal pneumonia. To protect against potential use of this agent as a bioterrorist weapon, a safe, well-characterized, stable, and effective vaccine against F. tularensis is needed. (more...)

The only currently available TB vaccine, an attenuated Mycobacterium bovis strain Bacille Calmette-Guerin (BCG), is of variable efficacy. A large carefully conducted meta-analysis has estimated the potency of BCG to be approximately 50%. UCLA researchers developed and reported in the last several years a recombinant BCG expressing the Mycobacterium tuberculosis 30 kDa major secretory protein (r30). This vaccine, named rBCG30, induces greater protection than BCG against aerosol challenge with a highly virulent strain of M. tuberculosis. (more...)

Dendritic cells (DC) are a group of professional antigen presenting cells (APC) that provide a central stimulus for the generation of cell-mediated responses against foreign antigens. Dendritic cells are ubiquitously distributed throughout the body, where they pick up antigens, process them, and migrate to T-cell enriched areas of lymphoid tissue to activate corresponding antigen-specific T-cell clones.1 A major limitation in the human response to foreign challenges, including infections and tumors, is the limited number of DC and their suppression in individuals suffering from these conditions. As a result, patients often fail to respond to vaccines that might otherwise be effective.Previous in vitro data indicated that granulocyte-macrophage-colony stimulating factor (GM-CSF) and interleukin-4 (IL-4), when used in combination, induce precursor cells, such as CD34+ stem cells and monocytes, to mature into dendritic cells. These cells were classified as DC by their expression of cell surface markers characteristic of DC cells (CD83, CD40, CD86, CD11c, etc.), by their ability to take-up and process antigens, and by their ability to stimulate the proliferation of T cells in an antigen-specific manner. The strategy of using GM-CSF AND IL-4 to enhance the number and/or function of antigen presenting cells (including dendritic cells) in the blood, tissues and lymphoid organs of patients may be employed as a mechanism to improve the immune responses of individuals with a suppressed immunity. Therefore, this method has implications in treating conditions such as cancer, infections, AIDS, malnutrition and shock. Cytokine therapy using GM-CSF and IL-4 may further be implemented into immunization and vaccination strategies for infections that respond poorly to conventional vaccine approaches. Examples of these indications include AIDS, pneumonia, and tuberculosis.This cytokine combination therapy produced promising tumor responses in Phase I testing and is currently being tested in Phase II studies in patients with prostate cancer. Additional preclinical testing is ongoing to optimize combination therapy with vaccines, to better evaluate the form and function of the dendritic cells generated, and to evaluate the use of combination cytokine therapy as a mechanism for harvesting DC for use in the production of cell-based vaccines. (more...)

BACKGROUND: Vaccine targets for prostate cancer have generally been identified either by tissue specific expression in prostate cancer or by assessing immune responses in cancer patients. However, UCSF investigators have taken a novel approach to identify the targets of an immune response in patients who are either responding or not responding to an immune-based treatment (anti-CTLA4 antibody) in a clinical trial at UCSF. CTLA4 blockade with antibody treatment can augment endogenous anti-tumor immunity in animal models and is being developed as an immunotherapy for cancer patients. Defining the antigen-specific responses induced by this treatment can lead to immunological identification of therapeutic targets that may be relevant in prostate cancer patients. These studies provide a unique opportunity to determine the antigen-specific responses that are relevant for immune-mediated clinical responses in prostate cancer, can provide opportunities to predict which patients may respond to therapy, and can provide novel approaches to prostate cancer treatment and vaccination. DESCRIPTION: UCSF investigators found that immune-mediated clinical responses to CTLA4 blockade is seen in the absence of a specific vaccination, suggesting that endogenous antigen-specific immune responses can be potentiated through this treatment. By focusing on immune responses unique to those patients that responded to immunotherapy, the UCSF investigators were able to identify candidate antigens that correlated with clinical outcome in prostate cancer patients. In addition, a patient’s immune response to the prostate cancer-associated antigens can be used as a diagnostic assay to determine the likelihood that an individual having prostate cancer will exhibit a clinically beneficial response to an immunomodulatory treatment. Furthermore, targeting these antigens with antibodies and/or vaccination may lead to novel therapies for prostate cancer. One antigen in particular has shown promise because it is expressed at a higher intensity in prostate cancer patients and in prostate cancer cell lines compared to other previously described antigens. Kaplan-Meier survival curves for tumor challenge were plotted for C57BL/6 and FVB mice (5 control and 5 test mice per mouse model) that were immunized with a mouse homolog of the particular antigen. The mice were challenged with Tramp cells or Myc-Cap prostate cancer cells respectively. Immunization with the novel antigen induced anti-tumor responses in both models of prostate cancer. (more...)

UCSF investigators have developed the methods to significantly enhance the viral yield of infected cell cultures. These methods rely on the inhibition of interferon-stimulated genes, especially double-stranded RNA (dsRNA) dependent kinase (PKR). This method can be used in a wide variety of common cell lines and to produce a wide variety of viruses, including polio, measles, mumps, rubella, hepatitis A, and influenza. (more...)

In the pharmaceutical industry, synthetic chemists often alkylate starting compounds to generate compounds that have more desirable properties. However, the current reagents used in this modification process can be expensive or harmful to the chemist. (more...)

Mycobacteria are a significant cause of morbidity and mortality, particularly among immunocompromised or elderly individuals and in countries with limited medical resources. Ninety-five percent of human infections are caused by seven species: Mycobacterium tuberculosis, M. avium (also known as the mycobacterium avium complex or M. avium-intracellulare), M. leprae, M. kansasii, M. fortuitum, M. chelonae, and M. absecessus. The most common mycobacterial infections in the United States are pulmonary infections by M. tuberculosis or M. avium. Such mycobacterial infections have been of increasing concern over the past decade, particularly in light of the increasing incidence of multi-drug resistant strains.   Mycobacterium tuberculosis is the causative agent of the disease tuberculosis in humans. Estimates indicate that one-third of the world's population, including 10 million in the U.S., are infected with M. tuberculosis, with 8 million new cases and 3 million deaths reported world wide each year. Although incidence of tuberculosis steadily decreased since the early 1900s, this trend changed in 1984 with increased immigration from endemic countries and increased infection among homeless individuals, drug and alcohol abusers, prisoners, and HIV-infected individuals. The increasing occurrence of drug-resistant strains requires continued research into new and more effective treatments. SUMMARY OF THE INVENTION Novel mycobacterial sulfation pathway proteins and polypeptides related thereto, as well as nucleic acid compositions encoding the same, are provided. The subject polypeptide and nucleic acid compositions find use in a variety of applications, including research, diagnostic, and therapeutic agent screening applications. Also provided are methods of inhibiting growth and/or virulence of a pathogenic mycobacterium, and methods of treating disease conditions associated with a pathogenic mycobacterium, particularly by administering an inhibitor of a mycobacterial sulfation pathway protein. The present invention further provides genetically modified mycobacteria having a defect in a sulfation pathway enzyme gene; and immunogenic compositions that include such genetically modified mycobacteria. ABSTRACT Novel mycobacterial sulfation pathway enzymes and polypeptides related thereto, as well as nucleic acid compositions encoding the same, are provided. The subject polypeptide and nucleic acid compositions find use in a variety of applications, including research, diagnostic, and therapeutic agent screening applications. Also provided are methods of inhibiting growth and/or virulence of a pathogenic mycobacterium, and methods of treating disease conditions associated with a pathogenic mycobacterium, particularly by administering an inhibitor of a mycobacterial sulfation pathway enzyme. Normal.dotm 0 0 1 85 489 UC Berkeley 4 1 600 12.0 0 false 18 pt 18 pt 0 0 false false false /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman"; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;} (more...)

On-bead Screening Process of Neuraminidase Inhibitors (more...)

Peptide fusion with or encapsulation of nucleic acid by the truncated capsid protein of the hepatitis E virus (HEV) can cause specific antigenic responses in the host. (more...)

Cancer is the result of cumulative multiple genetic mutations, which result in the activation of oncogenes and/or the inactivation of tumor suppressor genes. It is the differential expression of these critical genes and their downstream effectors that enables cells to override growth controls and undergo carcinogenesis. While a variety of methods are currently employed to isolate genes associated with particular differential phenotypes, these techniques identify tissue-enriched mRNAs rather than tissue-specific proteins. Thus, there remains a need for a differential screening technique that provides actual confirmation of the presence of a protein product, not just the capacity to synthesize a protein. In addition, there is a need for proteins with antigenic determinants that may be recognized by the immune system. (more...)

The tick-borne organism responsible for Lyme disease, Borrelia burgodorferi, produces a lipoprotein that serves as an antigen for the existing Lyme disease vaccine. However, this vaccine has limited efficacy, mainly due to downregulation of the lipoprotein while B. burgodorferi is present in a mammalian host. A further problem in treating Lyme disease is the current difficulty in diagnosing infections. Thus, there is a pressing need for B. burgodorferi antigens that would more efficiently single out B. burgodorferi within mammalian hosts. University of California researchers have isolated and characterized three outer membrane-spanning proteins from B. burgodorferi which have the potential to serve as targets for immunoprotective and/or diagnostic antibodies, offering a promising alternative to the lipoprotein. The researchers also confirmed that one of the UC proteins elicits immunoprotective responses in laboratory mice, thus showing that these proteins are likely to lead to greatly improved vaccines and diagnostic reagents (e.g. for serodiagnostic kits) against Lyme disease. Because of the localized concentration of the disease in certain geographic regions, use of diagnostic and therapeutic agents derived from this invention would be particularly attractive given the existence of readily identifiable populations of at-risk humans and animals. With thousands of Lyme disease cases being reported annually in the United States, there is a substantial market for improved vaccines and diagnostic agents. (more...)