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Live Attenuated Vaccine Against Group A Streptococcus Infection

Streptococcus pyogenes (group A Streptococcus [GAS]) is a leading health and economic burden worldwide, with an estimated 700 million infections occurring annually. Among these are 18.1 million severe cases that result in over 500,000 deaths. Despite active research, a protective vaccine remains elusive, leaving antimicrobial agents as the sole pharmacological intervention against GAS. To date, penicillin remains a primary drug of choice for combating GAS infections. However, despite no apparent emergence of resistant isolates, the rate of treatment failures with penicillin has increased to nearly 40% in certain regions of the world. Due to the high prevalence of GAS infection and the decreasing efficacy of the available repertoire of countermeasures, it is critical to investigate alternative approaches against GAS infection. An emerging strategy for combating pathogenic bacteria involves targeting virulence. To avoid immune clearance, GAS expresses a wide variety of secreted and cell-associated virulence factors to facilitate survival during infection. Despite decades of inquiry into the role and regulation of GAS virulence factors, the function and potential importance of many proteins involved in pathogenicity remain unknown.

Novel Methods To Eliminate Dormant HIV Reservoirs

Human immunodeficiency virus type-1 (HIV-1) is a pathogenic retrovirus and the causative agent of acquired immunodeficiency syndrome (AIDS) and AIDS-related disorders. There were 1.7 million new infections globally in 2018, and ~38 million people are currently living with HIV-1. Although the introduction of antiretroviral therapy (ART) has prevented millions of AIDS-related deaths worldwide, patients must continue to receive ART for the remainder of their lives. HIV-1 reservoirs persist even while subjects are on ART, leading to a rapid increase in viral replication when therapy is discontinued. Therefore, eradication of persistent HIV-1 reservoirs remains the main barrier to achieving a cure for HIV-1/AIDS. The prevailing view of persistence suggests that the virus remains in a latent state in memory CD4+ T cells regardless of plasma viral loads, allowing the virus to establish a life-long infection in the host. Since the latent virus is refractory to existing antiretroviral therapies, curative strategies are now focusing on agents that reactivate viral replication and render it susceptible to conventional therapy. Any strategy aimed at controlling and eradicating viral reservoirs in HIV-1-infected individuals must target such latent reservoirs. The mammalian genome encodes thousands of long noncoding RNAs (lncRNAs, >200 nucleotides), including intergenic lncRNAs (lincRNAs), which are increasingly recognized to play major roles in gene regulation. The pathophysiological functions and mechanisms of lncRNAs in gene regulation have started to emerge. Work over the last few years has begun to uncover the role of lncRNAs in modulating HIV-1 gene expression.

Computational Cytometer Based On Magnetically-Modulated Coherent Imaging And Deep Learning

UCLA researchers in the Department of Electrical & Computer Engineering have designed and built a computational cytometer capable of detecting rare cells at low concentration in whole blood samples. This technique and instrumentation can be used for cancer metastasis detection, immune response characterization and many other biomedical applications.

Vaccine Adjuvant That Bypasses the Cold Chain

Dr. David Lo and his colleagues at UCR have developed a new vaccine adjuvant that is composed of engineered cross-linked polymeric flagellin.  This new adjuvant stabilizes vaccines so that it may bypass the cold chain and may potentially increase vaccination rates in remote areas without a reliable source of electricity.  Another aspect of this flagellin adjuvant is that it may induce a T helper independent immune response.  This immune response may be desirable in patients with T cell immunodeficiency disorders. Fig. 1 is a schematic that shows disulfide bonds between neighboring flagellin filaments. The covalently stabilized flagellar filament provides additional immune efficacy through the stabilization of its polymeric filament structure and this contributes to the long-term storage of a vaccine absent the cold chain Fig. 2 shows the long term temperature stability of the adjuvant in solution. Less than 50% of the engineered adjuvant was degraded after being heated to 42°C for 7 days.  

Crosslinkable Polymer Coating Prevents Bacterial Infection on Implant Surface

UCLA researchers in the Department of Orthopedic Surgery have developed a polymer implant coating that mitigates bacterial infections on the implant surface.

TRM:CRAMP Knockout Mice In The C57bl/6 Background

The mouse Camp gene is an ortholog of the human gene CAMP, which encodes the precursor of cathelicidin antimicrobial peptide LL-37 (or CRAMP in mouse). Expressed mucosal epithelial cells, circulating neutrophils, and myeloid bone marrow cells, Camp is an essential part of the first line of defense against infection. In addition to antimicrobial activity, cathelicidin antimicrobial peptide plays a role in NK cell-mediated tumor growth suppression, and when secreted by neutrophils acts, as an attractant for monocytes, promoting wound healing or angiogenesis. Mouse CRAMP is implicated in adaptive immune response regulation and can interfere with TLR function via interactions with hyaluronan. Mice deficient in CRAMP are more susceptible to experimentally induced necrotic skin infection with Group A Streptococcus, urinary tract infection with uropathogenic E. coli, Pseudomonas aeruginosa infection, and meningococcal Neisseria meningitidis infection.

Antibody and Vaccine Therapy for C. diff. Infection

Clostridium difficile (C. diff.) infection is estimated to cause nearly 0.5 million illnesses in the US. C. diff. can cause severe gastrointestinal effects, including life-threatening inflammation, is contagious, and is an urgent antibiotic-resistant threat, according to the Centers for Disease Control and Prevention. UCI researchers have determined the crystal structure for the virulent C. diff. toxin, TcdB, and characterized sites to target for neutralization along with immunogens that can be used in vaccine strategies to prevent and treat C. diff. infection.

Predicting Cefixime Susceptiblity Using Molecular Genotyping

UCLA researchers in the David Geffen School of Medicine have developed a novel method to detect the susceptibility of Neisseria gonorrhoeae to the antibiotic cefixime.

Pharmacological Mitigation of Late-Stage Toxemia

Anthrax disease, caused by Bacillus anthracis, is a highly lethal infection with patient fatality rate between 45-85% during fulminant, toxemia-related late-stages of infection. Systemic release of anthrax edema toxin during late-stage infection induces vascular collapse through endothelial barrier disruption, culminating in fatal hypovolemic shock, a hallmark of systemic anthrax infection. Existing therapeutic strategies to mitigate the effects of anthrax infections only target early-stage infection vis-à-vis bacterial clearance (antibiotics) and toxin-host cell interactions (anti-toxin antibodies), but are ineffective in preventing toxemic-shock which is induced even after pathogen clearance. In fact, patients with fulminant infection require aggressive, continuous fluid drainage and assisted breathing, and no effective therapeutic interventions exist currently for this critical stage of infection. Pathogen induced cell-cell barrier disruption (anthrax, cholera, traveler’s diarrhea, gastroenteritis, pertussis, pneumonia) account for significant socio-economic impacts each year. Stand-alone antitoxin therapies such as those mentioned here can fulfill the unmet medical need for measures that significantly improve the survival rate of patients with severe infections, and lower the risk for development of antibiotic resistance.   High fatality rate of anthrax infections, despite intense antibiotic and supportive therapies, are primarily due to the continuing activities of anthrax exotoxins (ET and LT) released in the patient's circulatory system. Edema toxin or ET, a highly active adenylate cyclase that induces uncontrolled, pathological elevation in cellular levels of the second messenger cAMP is a major virulence protein of Bacillus anthracis and mediates significant lethality during fulminant stages of infection. ET induces rapid disruption of the endothelial barrier, resulting in irreversible tissue damage and lethality due massive fluid loss resulting in cardiovascular collapse and hypovolemic shock. It is therefore imperative that new therapeutic measures be developed that effectively blocks the intracellular function of ET (i.e. cellular proteins/pathways co-opted to induce barrier instability), to reduce fatalities associated with anthrax toxemia.

Novel Non-Antibody-Based Chimeric Antigen Receptor Against HIV That Also Protects Cells From Infection

UCLA researchers in the Department of Medicine have developed a novel chimeric antigen receptor (CAR) that targets T cells against HIV while protecting T cells from HIV infection.

New Molecular Tweezers Against Neurological Disorders And Viral Infections

UCLA researchers in the Department of Neurology with an international team of scientists have developed several new molecular tweezer derivatives with novel synthesis methods that significantly improved the therapeutic efficacy and pharmacokinetic characteristics of the drug candidates.

Vaccines Against Herpes Simplex Virus Infection

Herpes simplex virus (HSV) infections affect billions of patients worldwide and can manifest its symptoms as painful blisters or ulcers at oral, ocular or genital locations. Symptomatic patients can currently only alleviate their pains with antiviral medication. These technologies propose a shift in focus toward novel protective epitopes as the foundation for new vaccines.

Viral Expression Vector Targeting HIV-1

UCLA researchers from the Department of Microbiology, Immunology, & Molecular Genetics have developed a viral expression vector that combines two reagents effective against HIV-1 infection.

Novel Synthesis of Streptogramin A Antibiotics

A modular, scalable, chemical synthesis platform that produces new Streptogramin A class antibiotic candidates.

Safe Potent Single Platform Vaccine Against Tier 1 Select Agents and Other Pathogens

UCLA researchers in the Department of Medicine have developed a novel vaccine platform against Tier 1 Select Agents to prevent infectious diseases such as tularemia, anthrax, plague, and melioidosis.

Nanoparticles For Specific Detection And Killing of Pathogenic Bacteria

UCLA researchers in the Department of Chemistry and Biochemistry and Department of Medicine have developed novel functionalized mesoporous silica nanoparticles that can specifically identify pathogenic bacteria and deliver on-target drug treatments.

Systems And Methods For Therapeutic Agent Delivery

UCLA researchers at the Department of Physics have developed a system that is capable of delivering a therapeutic agent to a specifically targeted tissue using ultrasound.

Disulfide Bioconjugation

UCLA researchers in the Department of Chemistry and Biochemistry have proposed a one-step radical mechanism for disulfide bioconjugation that overcomes many concerns associated with the free cysteine residues that result from current bioconjugation techniques.

Endogenous Human Protein Nanoparticle-Based Immune-Focusing Antiviral Vaccine

UCLA researchers in the Department of Biological Chemistry have developed a novel nanoparticle based antiviral vaccine capable of targeting many viruses.

Development Of Surface Enhanced Graphene Oxide For Ubiquitous Antibacterial Coatings

UCLA researchers in the Department of Medicine have developed a novel graphene oxide (GO) based material with significantly enhanced antibacterial effects with maximized surface display of carbon radicals.

Metabolic Requirements for Alternative Macrophage Activation

UCLA researchers in the Department of Molecular and Medical Pharmacology have discovered that Coenzyme A is a targetable requirement for anti-inflammatory macrophage differentiation.

Composition Of Matter And Method For Leptospirosis Vaccine

Leptospirosis is one of the most widespread diseases estimated to infect up to 7-10 million people per year worldwide (2014) that can be transmitted from animals to humans. The most common transmission is via the urine of rodents or domestic animals that contaminates water or soil. Unfortunately, it can cause severe infection and currently there is not an efficient vaccine present to combat this disease. The disease is caused by Leptospira, a genus of the spirochaete bacteria of which there are ~13 pathogenic species that effect humans. The signs and symptoms of the disease are quite variable and can range from mild headaches, muscle pains, and fevers to the more severe form which causes bleeding from the lungs.

Disposable and Semi-Disposable Medical Consumables for Infection Control

In the United States lives are lost every year due to the spread of infections in hospitals and healthcare facilities. Thus, healthcare workers must take all precautions to prevent the spread of infectious diseases, especially in surgical spaces. One key step in this process is to control environmental surfaces because certain types of microbial bacteria or fungi are capable of surviving on environmental surfaces for months at a time. A potential solution would be to use consumables that are disposable, or semi-disposable, and offer a platform of products for the purposes of infection control.  

Development of a Novel cAMP–Inhibitor that Restores Epithelial and/or Endothelial Barrier Integrity in Human Cells Infected by Pathogenic Bacteria

Pathogenic bacteria have evolved elaborate and clever ways to enter our cells and breach the protection offered by our innate immune system. To initiate disease, many bacterial toxins target a specific cell, usually by binding to a receptor and thereby gaining access to the cytoplasm to promote pathogenesis. Interestingly, a set of toxins produced by diverse bacterial species act by distinct mechanisms to dramatically increase the intracellular concentration of cAMP. This striking evolutionary convergence suggests that overproduction of this second messenger represents a successful strategy to promote growth and dissemination of infectious agents, as well as disease symptoms. The organisms that produce these toxins that disrupt cAMP include:  Bacillus anthracis (B.a. and Anthrax edema toxin- ET, LT), Bordetella pertussis (CyaA), and Vibrio cholerae (Ctx) will be the focus of this study.     Current therapies to alleviate symptoms of cholera and anthrax are less than adequate and demonstrate that there is an urgent need for updated strategies and therapies for the treatment of these pathogenic diseases.

Label-Free Digital Bright Field Analysis of DNA Amplification

UCLA researchers in the department of Bioengineering have developed a novel method for quantitative analysis of DNA amplification products.

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