Graduate Program Affiliations
- BISI-Molecular & Cellular Biology (MOCB)
Research Interests
1. ROLE OF PANDEMIC VIRAL INFECTIONS IN PULMONARY AND CARDIAC INJURY
Pandemic Influenza. While the molecular and epidemiological effects of influenza infection in pulmonary tissue are well-documented, the effects of infection in other organs remains unclear. Several clinical and experimental studies have shown influenza virus to be cardiotropic, with virus disseminating from the lungs to cardiac tissue early after severe infection. The scientific premise for these studies comes from the extensive clinical evidence of aberrant cardiac pathologies (myocarditis, ischemia, cardiac dysfunction, and other major adverse cardiac events) associated with influenza infections, with these being more pronounce during pandemics. Our overall hypothesis is that acute viral infection leads to localized inflammatory and metabolic changes that promote the development of major adverse cardiac events that persist through convalescence. In our studies we propose to link the effector proteins of influenza viruses to the aberrant cardiac changes observed during in vivo infection, the role of cell death pathways in it, and characterize the long-lasting effects of such and the role pre-existing cardiac disease in such with the purpose of developing new therapies to prevent respiratory virus-induced cardiac complications. Most importantly, in the development of novel therapeutic or vaccine candidates it is essential to understand the full spectrum of the pathogenesis of an organism such as influenza viruses, an area currently understudied.
SARS-CoV-2 infection. The global pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had great effects in the overall health of infected and convalescent patients. While immediate medical attention had been dedicated to respiratory illness and lung infection, more and more clinical evidence is revealing a wide range of systemic manifestations by the virus, of which one includes cardiac injury (e.g., heart attack or arrhythmia). Recent reports have indicated a potential direct role for SARS-CoV-2 in causing myocarditis, fatal arrhythmias and other major adverse cardiac events as viral particles are present in the cardiac tissue of patients that succumbed to infection. Moreover, recently discovered variants have shown greater infectivity and exacerbation to cardiac complications. We aim to define the cellular and molecular mechanisms that modulate SARS-CoV-2 cardiac pathogenesis.
2. UNDERSTANDING THE HOST-PATHOGEN INTERACTIONS DURING NASOPHARYNGEAL COLONIZATION AND PULMONARY INFECTIONS TO DEVELOP NOVEL THERAPIES AND VACCINES
Using bacteriophage endolysins as parallel therapeutic and immunizing approaches against pneumococci. An emerging way to address the growing antimicrobial resistance problem is the use of bacteriophages and bacteriophage endolysins. Endolysins are enzymes that can degrade the bacterial peptidoglycan, killing and dispersing biofilm bacteria and its matrix. In preliminary studies, we have purified the endolysins Pal and Cpl-1 from Spn bacteriophages Dp-1 and Cp-1, respectively, as well as a chimeric derivative of Cpl-1 that displays >100-fold increase in antimicrobial activity. We have also shown the ability of these endolysins to lyse planktonic Spn, and importantly we also observed that Cpl-1 and Pal were able to both kill biofilm Spn, as well as disperse the biofilm matrix. In addition, we have shown that upon Spn nasopharyngeal colonization, activation of programmed necrosis, i.e., necroptosis, leads to development of antigen-specific antibodies. Herein, we have proposed to address three overall hypotheses: a) that endolysins are efficient pneumococcal anti-biofilm agents, b) that endolysins can be an effective way to prevent Spn colonization in a serotype (strain) independent manner, and c) that intranasal treatment with endolysins promotes protective immunity, to prevent re-colonization and severe disease. We will use a combination of in vitro and in vivo studies with static and dynamic biofilms, cell culture, mice, biochemistry (to engineer more efficient endolysins), transgenic mice (to define the role of programmed cell death in protective immunity), molecular and immunological techniques and next generation technologies (proteomics) to develop novel endolysin treatments against pneumococcal disease and test their effectiveness in development of long-term serotype independent protective immunity.
Defining the role of cell death as a modulator of inflammation and immunity. Influenza infection promotes an extremely severe form of secondary bacterial pneumonia, characterized by necrotic lung damage and significantly increased mortality. We aim to identify the molecular mechanisms behind this synergism not only in the pulmonary setting but in extrapulmonary organs. Moreover, we aim to exploit cell death as a way to drive immunotherapies against infectious agents and other diseases.
Protein-based vaccines. One of the major problems of the great burden of Streptococcus pneumoniae (Spn) infections is the acquisition of antimicrobial resistance and the global spread of resistant clones. These problems get enhanced by the major disadvantages of the current capsular polysaccharide-based vaccines, such as cost, serotype specificity, and the resulting incomplete coverage. This occurs mainly because of disease being caused by serotypes not present in the vaccine (maximum of 23 of the >97 capsule types, only 13 in the conjugate vaccine) and replacement carriage. Our rationale for this project is that development of a subunit-based vaccine utilizing novel conserved antigenic proteins in conjunction with novel polyphosphazene (PPZ) adjuvants, proven to induce adaptive immunity will deepen the current toolkit to prevent pneumococcal disease without serotype limitations.
3. ANTIMICROBIAL RESISTANCE.
Using commensals to reduce and or counter antimicrobial resistance (AR). Our current studies aim to use commensal bacteria and their products to decrease AR infections through 3 aims: 1) Systematic testing of human commensals for antimicrobial functions on AR ESKAPE pathogens. 2) Bioinformatics mining for bacterial biosynthetic gene clusters (BGCs) encoding antimicrobials. 3) Determine the identity of antimicrobial/antibiofilm substances using HPLC, proteomics and NMR.
Development bacteriophage therapies against Streptococcus pneumoniae. One of the biggest limitations of the conjugate vaccines and naturally obtained phages is that they are both serotype- and strain-specific, mostly due to targeting the variable components of the S. pneumoniae polysaccharide capsule and teichoic acids, respectively. Our goal is to target conserved outer membrane proteins (OMPs) of Strep for entry of engineered phages to infect and replicate and in doing so, kill the Strep pathogen.
4. MICROBIOME IN ASTHMA INDUCED BY ENVIRONMENTAL PARTICLE EXPOSURE.
Microbial dysbiosis in the gut and the lung is increasingly being associated with the incidence and severity of asthma, however causality studies are lacking. We have adapted a mouse model that focuses on the onset of allergic asthma early in life after an in-utero exposure to environmental particles to study how microbiome may lead to the asthma onset. In this model, we have shown that maternal exposures to allergen or particulate matter, e.g. concentrated urban air particles (CAP), diesel exhaust particles (DEP) and titanium dioxide particles (TiO2), trigger increased asthma risk in several generations of the offspring. Humans are widely exposed to these particulates, especially in urban and industrial settings, where the incidence of asthma is also higher. We found that the increased ‘preparedness’ for asthma in these neonates is associated with DNA methylation changes in key immune cells – dendritic cells that are essential in asthma origin. Important unanswered questions are why these epigenetic changes occur, and whether there is a causative link to the aberrant microbiome seen in asthma. We hypothesize that in utero exposures to particles alter the microbiome of the pregnant mice and their offspring, which then signals to the immune cells in a way that predisposes the offspring to allergy. We postulate two, potentially interconnected, mechanisms in asthma onset: epigenetics and the microbiome. Both the epigenetic alterations in immune cells and the dysbiosis in the gut and lung have been linked to asthma in humans and mouse models but causality studies are lacking. Our research addresses this gap in knowledge in a study designed to test basic mechanisms of relatively common environmental exposures.
Education
- Postdoctoral Fellow, Infectious Diseases and Immunology, University of Alabama at Birmingham
- Ph.D., Immunology and Microbiology, University of Texas Health San Antonio
- B.Sc., Microbiology, University of Puerto Rico at Arecibo
