Immunology and Pathogens Initiative

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•  Accomplishments
•  Faculty
•  Scholarly Publications
•  Featured Story

The Immunology and Pathogens 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 Children's Hospital Los Angeles. Our mission is to translate innovative, scientific research into novel diagnostics, therapeutics, and preventative strategies for pathogens affecting our patients at Children's Hospital Los Angeles.

The program focuses on microbial pathogenesis using the tools of cellular and molecular biology, bioinformatics animal models and epidemiology. We strive to understand the mechanisms by which bacteria, viruses and fungi colonize, invade, evade immune response and damage their host. We also seek to define the role of innate, adaptive and intrinsic immune responses in response to these pathogens. Our studies serve as the basis for design of antimicrobials, vaccines and public health interventions.
 
 

Accomplishments

The investigators in the Immunology and Pathogens Initiative have continued to develop complementing basic, translational and clinical research activities in collaboration amongst themselves and with investigators at numerous other institutions.

  1. 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).
  2. 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).
  3. 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).
  4. 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.
  5. 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).

Faculty

Grace Aldrovandi, MD

Sheng-He Huang, PhD

Ambrose Jong, PhD

Kevin Nash, PhD

Prasadarao Nemani, PhD

Scholarly Publications

Aldrovandi GM, Chu C, Shearer WT, Li D, Walter J, Thompson B, McIntosh K, Foca M, Meyer WA 3rd, Ha BF, Rich KC, Moye J Jr. Antiretroviral exposure and lymphocyte mtDNA content among uninfected infants of HIV-1-infected women. Pediatrics. 2009 Dec;124(6):e1189-97. Epub 2009 Nov 23. PMID: 19933732; PMCID: PMC2904486.

Aldrovandi GM, Kuhn L. What infants and breasts can teach us about natural protection from HIV infection J Infect Dis. 2010 Nov 1;202(Suppl 3):S366-70. PMID: 20887226; PMCID: PMC2951298.

Armenian SH, Nash KA, Kapoor N, Franklin JL, Gaynon PS, Ross LA, Hoffman JA. Prospective monitoring for invasive aspergillosis using galactomannan and polymerase chain reaction in high risk pediatric patients. J Pediatr Hematol Oncol. 2009 Dec;31(12):920-6. PMID: 19855303.

Arpadi S, Fawzy A, Aldrovandi GM, Kankasa C, Sinkala M, Mwiya M, Thea DM, Kuhn L. Growth faltering due to breastfeeding cessation in uninfected children born to HIV-infected mothers in Zambia. Am J Clin Nutr. 2009 Aug;90(2):344-53. Epub 2009 Jun 24. PMID: 19553300; PMCID: PMC2709311.

Bharadwaj S, Naidu TA, Betageri GV, Prasadarao NV, Naidu AS. Inflammatory responses improve with milk ribonuclease-enriched lactoferrin supplementation in postmenopausal women. Inflamm Res. 2010 Nov;59(11):971-8. Epub 2010 May 15. PMID: 20473630.

Chi BH, Ellis GM, Chintu N, Cantrell RA, Sinkala M, Aldrovandi GM, Warrier R, Mbewe F, Nakamura K, Stringer EM, Frenkel LM, Stringer JS. Intrapartum tenofovir and emtricitabine reduces low-concentration drug resistance selected by single-dose nevirapine for perinatal HIV prevention AIDS Res Hum Retroviruses. 2009 Nov;25(11):1099-106. PMID: 19886836 PMCID: PMC2828257.

Chi F, Jong TD, Wang L, Ouyang Y, Wu CH, Li W, Huang SH. Vimentin-mediated signalling is required for IbeA+ E. coli K1 invasion of human brain microvascular endothelial cells. Biochem J. 2010 Mar 15;427(1):79-90. PMID: 20088823.

Chi F, Wang Y, Gallaher TK, Wu CH , Jong A, Huang SH. Identification of IbeR as a stationary-phase regulator in meningitic Escherichia coli K1 that carries a loss-of-function mutation in rpoS. J Biomed Biotechnol. 2009;2009:520283. Epub 2009 Mar 12. PMID: 19300523; PMCID: PMC2655632.

Fox MP, Brooks DR, Kuhn L, Aldrovandi G, Sinkala M, Kankasa C Hornsburgh R, Thea DM Role of breastfeeding cessation in mediating the relationship between maternal HIV disease stage and increased child mortality among HIV-exposed uninfected children. Int. J. Epidemiol. 2009 Apr;38(2):569-76. Epub 2008 Nov 30. PMID: 19047077; PMCID: PMC2734073.

Gray RR, Salemi M, Lowe A, Nakamura KJ, Decker WD, Sinkala M, Kankasa C, Mulligan CJ, Thea DM, Kuhn L, Aldrovandi G, Goodenow MM. Multiple independent lineages of HIV-1 persist in breast milk and plasma. AIDS. 2011 Jan 14;25(2):143-52. PMID: 21173592.

Heath L, Conway S, Jones L, Semrau K, Nakamura K, Walter J, Decker WD, Hong J, Chen T, Heil M, Sinkala M, Kankasa C, Thea DM, Kuhn L, Mullins JI, Aldrovandi GM. Restriction of HIV-1 genotypes in breast milk does not account for the population transmission genetic bottleneck that occurs following transmission PLoS One. 2010 Apr 20;5(4):e10213. PMID: 20422033

Huang SH, He L, Zhou YH, Wu CH, Jong A. Lactobacillus rhamnosus GG suppresses meningitic E. coli K1 penetration across human intestinal epithelial cells in vitro and protects neonatal rats against .experimental hematogenous meningitis. Int J Microbiol. 2009;2009:647862. Epub 2008 Nov 24. PMID: 20016677; PMCID: PMC2775688.

Huang SH, Jong A. Evolving role of laminin receptors in microbial pathogenesis and therapeutics of CNS infection. Future Microbiol. 2009 Oct;4(8):959-62.  PMID: 19824788.

Hui CY, Guo Y, He QS, Peng L, Wu SC, Cao H, Huang SH. Escherichia coli outer membrane protease OmpT confers resistance to urinary cationic peptides. Microbiol Immunol. 2010 Aug;54(8):452-9. PMID: 20646209.

Jacobson DL, Lindsey JC, Gordon CM, Moye J, Hardin DS, Mulligan K, Aldrovandi GM; Pediatric Aids Clinical Trial Group P1045 Team. Total body and spine bone mineral density across Tanner stage in perinatally HIV-infected and uninfected children and youth in PACTG 1045. AIDS. 2010 Mar 13;24(5):687-96. PMID: 20168204.

Kuhn L, Aldrovandi GM. Clean water helps but is not enough: challenges for safe replacement feeding of infants exposed to HIV. J Infect Dis. 2009 Oct 15;200(8):1183-5. PMID: 19758096; PMCID: PMC2904506.

Kuhn L, Aldrovandi GM, Sinkala M, Kankasa C, Kasonde P, Thea DM. Potential impact of new WHO criteria for antiretroviral treatment for prevention of mother-to-child HIV transmission AIDS. 2010 Jun 1;24(9):1374-7. PMID: 20568677 PMCID: PMC2946203.

Kuhn L, Aldrovandi GM, Sinkala M, Kankasa C, Semrau K, Kasonde P, Mwiya M, Tsai WY, Thea, DM; Zambia Exclusive Breastfeeding Study (ZEBS). Differential effects of early weaning for HIV-free survival of children born to HIV-infected mothers by severity of maternal disease. PLoS One. 2009 Jun 26;4(6):e6059. PMID: 19557167 PMCID: PMC2698120.

Kuhn L, Semrau K, Ramachandran S, Sinkala M, Scott N, Kasonde P, Mwiya M, Kankasa C, Decker D, Thea DM, Aldrovandi GM. Mortality and virologic outcomes after access to antiretroviral therapy among a cohort of HIV-infected women who received single-dose nevirapine in Lusaka, Zambia. J Acquir Immune Defic Syndr. 2009 Sep 1;52(1):132-6. PMID: 19506483; PMCID: PMC2782481.

Kuhn L, Sinkala M, Thea DM, Kankasa C, Aldrovandi GM. HIV prevention is not enough: child survival in the context of prevention of mother to child HIV transmission. J Int AIDS Soc. 2009 Dec 11;12(1):36. PMID: 20015345; PMCID: PMC2796993.

Kuhn L, Sinkala M, Semrau K, Kankasa C, Kasonde P, Mwiya M, Hu CC, Tsai WY, Thea DM, Aldrovandi GM. Elevations in mortality associated with weaning persist into the second year of life among uninfected children born to HIV-infected mothers. Clin Infect Dis. 2010 Feb 1;50(3):437–444. PMID: 20047479; PMCID: PMC2805776.

Mittal R, Gonzalez-Gomez I, Goth KA, Prasadarao NV. Inhibition of inducible nitric oxide controls pathogen load and brain damage by enhancing phagocytosis of Escherichia coli K1 in neonatal meningitis. Am J Pathol. 2010 Mar;176(3):1292-305. Epub 2010 Jan 21. PMID: 20093483; PMCID: PMC2832150.

Mittal R, Gonzalez-Gomez I, Panigrahy A, Goth K, Bonnet R, Prasadarao NV. IL-10 administration reduces PGE-2 levels and promotes CR3-mediated clearance of Escherichia coli K1 by phagocytes in meningitis. J Exp Med. 2010 Jun 7;207(6):1307-19. Epub 2010 May 24. PMID: 20498022; PMCID: PMC2882833.

Mittal R, Gonzalez-Gomez I, Prasadarao NV. Escherichia coli K1 promotes the ligation of CD47 with thrombospondin-1 to prevent the maturation of dendritic cells in the pathogenesis of neonatal meningitis. J Immunol. 2010 Sep 1;185(5):2998-3006. Epub 2010 Jul 30. PMID: 20675593.

Mittal R, Prasadarao NV. Nitric oxide/cGMP signalling induces Escherichia coli K1 receptor expression and modulates the permeability in human brain endothelial cell monolayers during invasion. Cell Microbiol. 2010 Jan;12(1):67-83. Epub 2009 Sep 2. PMID: 19732056; PMCID: PMC2804784.

Mulligan K, Harris RD, Monte D, Stoszek S, Emmanuel P, Hardin DS, Kapogiannis BG, Worrell C, Meyer WA 3rd, Sleasman J, Wilson CM, Aldrovandi GM; Adolescent Trials Network 021 Protocol Team. Obesity and dyslipidemia in behaviorally HIV-infected young women: Adolescent Trials Network study 021 Clin Infect Dis. 2010 Jan 1;50(1):106-14. PMID: 19947855; PMCID: PMC2939739.

Murnane PM, Arpadi S, Sinkala M, Kankasa C, Mwiya M, Kasonde P, Thea DM, Aldrovandi GM, Kuhn L. Lactation-associated postpartum weight changes among HIV-infected women in Zambia Int J Epidemiol. 2010 Oct;39(5):1299-310. Epub 2010 May 19. PMID: 20484334; PMCID: PMC2972438.

Nakamura K, Gach JS, Jones L, Semarau K, Walter J, Bibollet-Ruche F, Decker JM, Heath L, Decker WD, Sinkala M, Kankasa C, Thea D, Mullins J, Kuhn L, Zwick MB, Aldrovandi GM. 4E10-resistant HIV-1 isolated from four subjects with rare membrane-proximal external region polymorphisms. PLoS One. 2010 Mar 23;5(3):e9786. PMID: 20352106. PMCID: PMC2843716.

Qiao MH, Qi H, Tan WY, Huang SH. Qualitative analysis of the hepatitis B virus infection model with impulsive vaccination. J Biomed Biotechnol. In press (JBB/574543), 2010.

Walter J, Ghosh M, Kuhn L, Kankasa C, Semrau K, Sinkala M, Thea DM, Aldrovandi GM. High concentrations of interleukin 15 in breast milk are associated with protection against postnatal HIV transmission. J Infect Dis. 2009 Nov 15;200(10):1498-502. PMID: 19835475 PMCID: PMC2811259.

Walter J, Kuhn L, Semrau K, Decker D, Sinkala M, Kankasa C, Thea DM, Bultrys M, Ou CY, Aldrovandi GM. Detection of low levels of human immunodeficiency virus (HIV) may be critical for early diagnosis of pediatric HIV infection by use of dried blood spots. J Clin Microbiol. 2009 Sep;47(9):2989-91. Epub 2009 Jul 22. PMID: 19625479. PMCID: PMC2738105.

Wang A, Alimova IN, Luo P, Jong A, Triche TJ, Wu L. Loss of CAK phosphorylation of RAR{αlpha} mediates transcriptional control of retinoid-induced cancer cell differentiation. FASEB J. 2010 Mar;24(3):833-43. PMID: 19917671; PMCID: PMC2830139.

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