Microbial Pathogens
Director: Wilbert Mason, MD, MPH
Emerging Initiative
Kevin A. Nash, PhD, has spent the past decade trying to unravel the difficult problem of drug resistance: the ability of some disease-causing microorganisms, such as bacteria, to survive and even multiply in the presence of drugs designed to kill them.
Lately, he’s been tackling the problem from another angle, asking which processes make microorganisms less susceptible to antibiotics. It’s a subtle but important difference, especially when facing down one of the most important single causes of preventable death worldwide—tuberculosis (TB).
Dr. Nash’s laboratory has been active in discovering multiple processes in mycobacteria (a large family of hardy bacteria resistant to many commonly used antibiotics), including the causative agent of TB. Recently, the team was instrumental in the characterization of a novel drug resistance gene and now is working to understand how that gene is being regulated.
Such strategies are crucial because each year there are about eight to nine million new cases of symptomatic TB, which lead to two to three million deaths—more than all forms of cancer combined. Dwarfing these numbers: the estimated two billion people infected with TB bacteria and possibly 50 million with drug-resistant organisms.
Dr. Nash also is concerned about a collection of diseases caused by rapidly growing mycobacteria (RGM), which are very difficult to treat. He has discovered that some RGM have “cryptic” or hidden drug resistance, which can actually be triggered by chemotherapy. His investigations are motivated by the fact that TB is preventable. To pursue that goal, he has received funding from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health.
Research Focus
The Microbial Pathogen Initiative is comprised of a group of researchers engaged in basic, translational and clinical investigations on the pathogenesis, immunology and clinical diagnosis and management of microbial pathogens in pediatrics. The scientific focus is complementing and simultaneous studies on the genomics and proteonomics on infectious pathogens in the patient populations found at Childrens Hospital Los Angeles. Our mission is to translate innovative, scientific research into novel diagnostics, therapeutics, and preventative strategies for pathogens affecting our patients at Childrens Hospital Los Angeles.
Accomplishments
The investigators in the Microbial Pathogens Initiative have continued to develop complementing basic, translational and clinical research activities in collaboration amongst themselves and with investigators at numerous other institutions.
- S. Pneumoniae Infection in Children
Dr. Hoffman and her colleagues at six institutions in the USA reported on the epidemiology, clinical presentation and microbiology of Streptococcus pneumoniae infections in neonates. Among their findings was that the incidence of meningitis was significantly higher in neonates than non-neonates. While the disease is uncommon, the morbidity and mortality is significantly high (Hoffman et al, 2003).
- Molecular Pathogenesis of Meningitis
Dr. Nemani and his colleagues continued their studies of how bacterial pathogens exploit host signaling pathways to invade and penetrate the blood-brain barrier. In this article they show that the stimulation of phospholipase (PLC)-gamma1 by meningitis-causing E. coli is required for invasion of microvascular endothelial cells (Sukumaran et al, 2003).
- HIV Recombination in T Cells
Dr. Aldrovandi and her colleagues used a novel method to measure the dynamics of HIV-1 recombination in target cells such as CD4 lymphocytes and macrophages. Recombination events were detected as shifts in fluorescence, which allowed quantification of infection, co-infection and recombination. They showed that a single round of HIV-1 replication generated recombination and cross-over events an order of magnitude greater than previously recognized. These results have significant implications for our understanding of the rapid evolution as well as the management of HIV-1 infection (Levy et al, 2004).
- Macrolide Resistance in Mycobacterium
Dr. Nash reported on the mechanism of intrinsic resistance to macrolides that is commonly observed in a variety of species of mycobacteria. He showed that resistance is inducible and results from the induction of a novel erm gene, which encodes for a ribosome methylase. These observations may provide insight into the intrinsic macrolide resistance of M. tuberculosis and to drug design strategies to overcome that resistance.
- Dr. Inderlied and colleagues show in a forthcoming publication that patients with disseminated M. avium infection are colonized in the gastrointestinal and respiratory tract with strains of M. avium that differ in virulence properties such as endothelial cell invasion and macrophage invasion and replication. These observations may lead to a better understanding of the colonization versus infection process and new targets for prophylaxis and treatment (Nash et al, 2004).
Membership
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Investigator
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Title
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Research Interest
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Aldrovandi, Grace, PhD
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Assoc. Professor, Pediatrics |
Pathogenic mechanisms of HIV infection; material transmission of HIV
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| Hoffman, Jill, MD |
Asst. Professor, Pediatrics
|
Infections in immunocoprovised and transplant patients S.pneumoniae infections in children
|
| Huang, Sheng He, MD |
Asst. Professor, Pediatrics
|
Pathogenic mechanisms of bacterial meningitis: mechanism of endothelial cell invasion
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| Inderlied, Clark, PhD |
Professor, Pathology |
Atnimicrobial drug discovery: target identification in mycobaceria and structure-activity relationships |
| La Via, Wiliam, MD |
Asst. Professor, Pediatrics |
Pathogenic mechanisms of bacterial gastroenteritis: mechanisms of attachment and translocation |
| Mason, Wilbert, MD, MPH |
Professor, Pediatrics |
Kawasaki disease: epidemiology and management; antimicrobial therapy: jucicious use; safety and quality in pediatric practice |
| Nash, Kevin, PhD |
Asst. Professor, Pathology |
Antimicrobial resistance: Macrolide resistance in mycobacterium |
| Neely, Michael, MD |
Asst. Professor, Pediatrics |
Pathogenic mechanisms of bacterial meningitis: exploitation of host signaling pathways |
| Nemani, Prasadarao V., PhD |
Assoc. Professor, Pediatrics |
Pathogenic mechanisms of bacterial meningitis: exploitation of host signaling pathways
|
| Pietzak, Michelle, MD |
Asst. Professor, Pediatrics |
Pathogenic mechanisms of bacterial meningitis: exploitation of host signaling pathways |
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Ross, Larry A., MD
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Professor, Pediatrics |
Infection control in pediatric practice |
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