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.
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