This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Conditions leading to immune compromise in the host shift the balance between host and pathogen, making certain populations particularly susceptible to infectious diseases with accelerated rates of mortality and morbidity. The neonate is one such host. The protective intrauterine environment makes a robust immune defense unnecessary. However, the dramatic physiologic and environmental changes that occur at birth require adaptation in every fetal system, including immunity. Although even the full term infant requires months to fully develop the robust host defenses of older children, the preterm infant has additional challenges. These infants are vulnerable to infection due to impairment in both humoral and cellular immunity. Importantly, similar vulnerabilities are seen in some adult populations as well. Immune compromise occurs in such diverse settings as blood and solid organ malignancies, HIV/AIDS, and burn patients. Therefore, we believe that identification of the host factors in the premature neonate contributing to its susceptibility to infection will also inform the mechanisms of vulnerability in other immune compromised populations. We have generated and characterized monoclonal antibody fragments specific to the hyphae of C. albicans, a growth morphology associated with virulence.
Specific Aim 1 will further define the hyphal antigens that are recognized by these antibody fragments through cDNA library screening. We will also examine the role of these antigens in virulence of the organism by constructing mutants for these genes and examining their phenotype in a murine neonatal model of candidiasis.
Specific Aim 2 will express these antibody fragments in the context of bonafide human IgG and test these monoclonal antibodies for their ability to be protective against disseminated disease in the neonatal candidiasis model.
Specific Aim 3 will take advantage of a unique susceptibility of neonates to infection with another Candida species, C. parapsilosis, to better define the response of neutrophils to a fungal pathogen. Neutrophils are known to be key effector cells in anti-fungal host defense, and have recently been shown to have a robust transcriptional response to infectious agents. We will use microarray technology to characterize the differences in response to this fungus between premature neutrophils and those from adults, in order to better understand the deficiencies that lead to susceptibility. Relevance: People who have weakened immune systems are increasing in number, leading to increases in serious infections. Understanding the specific mechanisms in the microbe and in the immune system that lead to these infections will enable the design of strategies to improve the immune system and better protect these patients from life-threatening disease.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR018728-09
Application #
8360538
Study Section
Special Emphasis Panel (ZRR1-RI-6 (01))
Project Start
2011-08-01
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
9
Fiscal Year
2011
Total Cost
$175,706
Indirect Cost
Name
Women and Infants Hospital-Rhode Island
Department
Type
DUNS #
069851913
City
Providence
State
RI
Country
United States
Zip Code
02905
Patra, Aparna; Chen, Xiaodi; Sadowska, Grazyna B et al. (2017) Neutralizing anti-interleukin-1? antibodies reduce ischemia-related interleukin-1? transport across the blood-brain barrier in fetal sheep. Neuroscience 346:113-125
Taggart, Allison J; Lin, Chien-Ling; Shrestha, Barsha et al. (2017) Large-scale analysis of branchpoint usage across species and cell lines. Genome Res 27:639-649
Monahan, Zachary; Ryan, Veronica H; Janke, Abigail M et al. (2017) Phosphorylation of the FUS low-complexity domain disrupts phase separation, aggregation, and toxicity. EMBO J 36:2951-2967
Kao, Hung-Teh; Ryoo, Kanghyun; Lin, Albert et al. (2017) Synapsins regulate brain-derived neurotrophic factor-mediated synaptic potentiation and axon elongation by acting on membrane rafts. Eur J Neurosci 45:1085-1101
Kalkunte, Satyan; Huang, Zheping; Lippe, Eliana et al. (2017) Polychlorinated biphenyls target Notch/Dll and VEGF R2 in the mouse placenta and human trophoblast cell lines for their anti-angiogenic effects. Sci Rep 7:39885
Conicella, Alexander E; Zerze, Gül H; Mittal, Jeetain et al. (2016) ALS Mutations Disrupt Phase Separation Mediated by ?-Helical Structure in the TDP-43 Low-Complexity C-Terminal Domain. Structure 24:1537-49
Yilmaz, Atilgan; Kattamuri, Chandramohan; Ozdeslik, Rana N et al. (2016) MuSK is a BMP co-receptor that shapes BMP responses and calcium signaling in muscle cells. Sci Signal 9:ra87
Uzun, Alper; Schuster, Jessica; McGonnigal, Bethany et al. (2016) Targeted Sequencing and Meta-Analysis of Preterm Birth. PLoS One 11:e0155021
Zhang, Jiyong; Klufas, Daniel; Manalo, Karina et al. (2016) HMGB1 Translocation After Ischemia in the Ovine Fetal Brain. J Neuropathol Exp Neurol 75:527-38
Cheng, Shi-Bin; Nakashima, Akitoshi; Sharma, Surendra (2016) Understanding Pre-Eclampsia Using Alzheimer's Etiology: An Intriguing Viewpoint. Am J Reprod Immunol 75:372-81

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