Presently, antiviral strategies are mostly focused on targeting viral proteins. However, the high mutation rates of RNA viruses, such as SARS-CoV-2, make the development of effective antiviral drugs very challenging. Disrupting viral-host interactions such as by targeting pro-viral, non-essential human genes will more likely prove effective against new variants or future coronavirus outbreaks.

A promising area of clinical research has been growing in wearable diagnostics that has proven to be a powerful tool in healthy physiological as well as disease diagnostics. As the field grows and develops, a number of specializations are already emerging including diagnostics focused on: cardiac dysfunction, epilepsy, and most recently infectious disease detection.

Following the pandemic, there is a clear need for improved technology in the area of vaccines. A pressing challenge is to enable a rapid response to emerging threats, using an established platform technology.

UC researchers sought to define the host immune response, the “cytokine storm” , that has been implicated in fatal COVID-19 using an AI-based approach. Over 45,000 publicly available transcriptomic datasets of viral pandemics were analyzed to extract a 166-gene signature. The signature was surprisingly conserved in all viral pandemics, including COVID-19, inspiring the nomenclature ViP-signature. A subset of 20-genes classified disease severity in respiratory pandemics. The ViP signatures pinpointed airway epithelial and myeloid cells as the major contributors of an IL-15 cytokine storm, and epithelial and NK cell destruction as determinants of severity/fatality. They also helped formulate precise therapeutic goals to reduce disease symptoms and severity. Thus, the ViP signatures provide a quantitative and qualitative framework for titrating the immune response in viral pandemics and may serve as a powerful unbiased tool in our armamentarium to rapidly assess disease severity and vet candidate drugs. 

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.

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.

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.

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.

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.

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.  

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.

The gut is a complex environment; the gut mucosa maintains immune homeostasis under physiological circumstances by serving as a barrier that restricts access of trillions of microbes, diverse microbial products, food antigens and toxins to the largest immune system in the body. The gut barrier is comprised of a single layer of epithelial cells, bound by cell-cell junctions, and a layer of mucin that covers the epithelium. Loosening of the junctions induced either by exogenous or endogenous stressors, compromises the gut barrier and allows microbes and antigens to leak through and encounter the host immune system, thereby generating inflammation and systemic endotoxemia. An impaired gut barrier (e.g. a leaky gut) is a major contributor to the initiation and/or progression of various chronic diseases including, but not limited to, metabolic endotoxemia, type II diabetes, fatty liver disease, obesity, atherosclerosis and inflammatory bowel diseases. Despite the growing acceptance of the importance of the gut barrier in diseases, knowledge of the underlying mechanism(s) that reinforce the barrier when faced with stressors is incomplete, and viable and practical strategies for pharmacologic modulation of the gut barrier remain unrealized.

The Aedes aegypti mosquito is known to transmit dengue fever, yellow fever, chikungunya virus, and Zika virus which have a worldwide impact on people’s health. Moreover, both Chikungunya and Zika virus were recently introduced into the western hemisphere and are poised to sweep throughout the areas in the range of mosquitos with the potential of infecting people who live in these broad areas. Attempts to eradicate these diseases by eliminating the Aedes aegypti mosquito by conventional use of spraying insecticides has met with limited success. So, in the absence of effective mosquito abatement, vaccines may provide the best strategy of preventing disease. Currently, there are vaccines for Yellow Fever and Dengue Fever (undergoing further testing); no vaccines exist for either Chikungunya or Zika virus at present. In the absence of such vaccines, UC San Diego researchers have developed a novel approach to control the spread of mosquitos.

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P. falciparum surface proteins have been shown to block transmission of malaria. Producing them in algae results in proteins that are correctly folded and not glycosylated, so they are more similar to the native proteins than those produced in bacterial or mammalian systems. In order to produce them for use as vaccine candidates, they will need to be produced in an inexpensive expression system that does not require much, if any, post-production modification and algae chloroplasts provide a viable approach.  SAMPLE DATA   

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As part of a comprehensive campaign to screen for effective vaccine adjuvants, 180,000 compounds were tested in a cell-based HTS screen to assess ability to activate NF-kB. Several classes of scaffolds bearing appropriate substitutions were found to stimulate innate immune responses and some of these scaffolds were structurally different from all other known ligands. More interestingly, the structure of one class of scaffolds challenges current dogma regarding what is necessary for efficacy.

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Herpes simplex virus type 2 (HSV-2) infection is the most common cause of genital herpes, a sexually transmitted disease estimated to affect more than 500 million people worldwide. About one in six people in the United States aged between 14 and 49 years has genital herpes caused by HSV-2. In addition to causing painful recurring genital sores and emotional stress in those infected, the disease can be particularly severe in immunosuppressed patients and can cause death or brain damage in babies born to infected mothers. Antiviral drugs are being used widely to treat HSV-2, but they are ineffective at eradicating the disease. There is therefore an urgent need for a safe and effective HSV-2 vaccine.

Influenza has been the cause of yearly epidemics and global pandemics throughout history. Due to the high degree of sequence conservation between disease genes in humans and flies, Drosophila has been enlisted to serve as a powerful multicellular host model to identify novel interactions between viral proteins and host machinery. Among influenza's eleven viral genes, NS1 (nonstructural protein 1) is known to be indispensable for virulence. There are very few effective drugs to treat influenza infection and these drugs (e.g., Tamiflu) act on highly mutable extracellular proteins that function in the late phase of viral escape from the cell. Also, viral surface proteins which are the main targets for vaccines mutate rapidly to evade suppression. Knowledge of new host signaling responses to viral infection could lead to therapies targeted to these interactions. These treatments may be effective at suppressing the pathogenesis of many different strains of flu unlike vaccines which typically target only a few strains and require constant reformulation since the virus can evade host antibodies.

Group A streptococcus (GAS) is a ubiquitous human pathogen behind a spectrum of diseases. Worldwide, invasive S. pyogenes infections result in excess of half a million deaths each year. To date, there has been no effective GAS vaccine developed in part because there are more than 150 serotypes. A diagnostic for GAS has been developed utilizing the carbohydrate structure of the GAS called Group A carbohydrate (GAC) consisting of a rhamnose backbone and an immunodominant N-acetylglucosamine (GlcNAc) side chain. Initially, utilizing this same structure as a potential vaccine produced good outcomes in animals but safety concerns were raised since antibodies generated against the GlcNAc side chain could precipitate other conditions (e.g. rheumatic carditis and Sydenham's chorea).

Vaccines traditionally have and still consist of whole-inactivated or live-attenuated pathogens or toxins. The usage of these modified pathogens is however unattractive for several reasons. Live-attenuated pathogens can cause disease by reverting to a more virulent phenotype, especially in the non-developed immune system of newborns or immunodeficient patients, and whole-inactivated pathogens contain reactogenic components that can cause undesirable vaccine side effects. Therefore, there is growing interest and ongoing research to develop a new generation of vaccines containing recombinant protein subunits, synthetic peptides, and plasmid DNA. While these new modalities promise to be less toxic, many are poorly immunogenic when administered without an immune-stimulating adjuvant. As adjuvants are a crucial component of the new generation of vaccines, there is a great need for safer and more potent adjuvants.

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While successful vaccines have been developed against acute infections, persistent infections have remained refractory to both natural immunity and vaccination protocols. The standard strategy of selecting immunogens on their ability to generate a strong T-cell response has proven ineffective. In reality, one observes immunogens that generate a surfeit of T-cells but are completely ineffective as vaccines. On the other hand, one can immunize with DNA and get protection using a gene against which no immunity is generated during natural infection. Therefore, to vaccinate against persistent infections, a vaccine may have to be better than natural immunity. An effective approach may be evolved by learning from and targeting the "Achilles heel" of natural immunity.