Host immune response to malaria infection

Project: Research project

Project Details

Description

PROJECT SUMMARY/ABSTRACT
This application addresses Broad Challenge area (04) Clinical research and Specific
Challenge topic, (AI-102) the human immune response to infection and
immunization-profiling via modern immunological and systems biology.
Malaria remains a major source of morbidity and mortality in many countries. Fundamental
questions such as the mechanisms of immunity, the role of the immune system in cerebral
disease and the mechanism of loss of malaria immunity in HIV infected adults remain
poorly understood. The clinical relevance of these issues is extremely high. Patients that
develop cerebral malaria have a 15% mortality rate despite potent antimalarials. HIV has
resulted in hundreds of thousands of additional symptomatic infections in adults who
previously were immune. Understanding mechanisms of cerebral malaria and protection
mediated by the immune system will guide interventions to improve survival rates and
lessen HIV related malaria. The lack of understanding of the immune systems role in these
clinical scenarios is in part due to a lack of comprehensive analysis of the immune
response in natural cohorts. We propose to carry out immune profiling through new
methods of whole genome transcription in malaria infected patients to provide an
unbiased view of immune response in malaria infection. This analysis will be carried
out in two phenotypically highly characterized cohorts 1) children with cerebral malaria 2)
adults with HIV/malaria co-infection. There is prior evidence to suggest that a deregulated,
pro-inflammatory immune response is the mechanism that gives rise to cerebral malaria.
Specific Aim I will address this hypothesis through whole genome transcriptional profiling in
a cerebral malaria disease cohort. Through an ongoing study of cerebral malaria,
peripheral blood aliquots are available to analyze host transcriptional responses.
Comparison of whole genome transcriptional responses to other datasets including mild
malaria and systemic inflammatory syndrome will be carried out. We will develop a
prediction model for survivors vs. non survivors of cerebral malaria with the goal of
developing biomarkers that can be used in patient care. Our second specific aim is based
on the clinical observation that HIV infected adults lose their natural immunity to malaria
disease. Typically immune adults are frequently infected but have no physical symptoms
or laboratory abnormalities. HIV infected patients have an increase in the risk of
asymptomatic parasitemia, symptomatic malaria and more severe disease;this increase
is inversely proportional to CD4+ T cell count. The basis of this loss of immunity is
unknown. Through the analysis of a second cohort, we will characterize the immune
response to malaria in HIV negative and HIV positive adults. Using biostatistical and
computational analysis we will identify the genes and biological pathways that have
altered expression based on CD4+T cell counts. These studies may provide insight into
components of protective immunity in malaria. Conversely we will further understand
how HIV impacts patients'immune response to malaria which may inform studies of HIV
and other pathogens. All datasets will be compared to previously published relevant
transcriptional host response profiling using systems biology and computational biology
approaches to develop broader models of immune response to pathogens.
This study brings together two components that are critical for high impact, high quality
clinical research. The first is the clinical expertise in the disease and the experience and
cohorts to carry out high quality field research in malaria and HIV. The second is the
experience and creativity of the analysis team which include epidemiologists,
biostatisticians and computational biologists. This proposal has brought together an
outstanding team with these skills to provide high impact results to inform pathogenesis
models and vaccine/drug development in malaria.
StatusFinished
Effective start/end date9/29/109/28/12

Funding

  • National Institute of Allergy and Infectious Diseases: $499,999.00

ASJC

  • Microbiology (medical)
  • Infectious Diseases
  • Molecular Medicine
  • Parasitology
  • Immunology

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