Using the host immune response to hemorrhagic fever Viruses to understand pathogenesis and improve diagnostics

Hemorrhagic fever viruses cause severe infections characterized by a hyperactive immune response that often leads to multiorgan failure and death. Current diagnostic tests are based on detecting viral proteins and nucleic acids in the blood. These are late-stage events during infection, which makes it impossible to perform a diagnosis before they are present in the collected sample. In this thesis, I explore an alternative approach using the transcriptional changes of circulating immune cells during the early stages of infection to identify unique markers of viral infection. The main advantage of this method is that it can be used to identify highly pathogenic viruses before standard detection methods become effective. I initially used RNA sequencing data to compare the host patterns of expression of macaques infected with either Lassa virus or Marburg virus, two related hemorrhagic fever viruses. I identified a set of genes that quickly become upregulated after a viral infection and remain highly expressed throughout the entire disease course, irrespective of the specific virus that caused the infection. I was also able to identify a set of biomarker genes that follow unique patterns of expression depending on the type of infection. I used an independent dataset to validate the potential of these genes to be used as biomarkers of infection. Additionally, I compared these results to the patterns of expression of macaques infected with Ebola virus, looking at multiple experimental conditions, tissues and routes of infection. Finally, I validated the host patterns of expression using two independently generated datasets corresponding to infection by different strains of arenaviruses and filoviruses. Studying the host immune response has the potential to improve the diagnosis of viral hemorrhagic fevers and other diseases. It can also accelerate our efforts to understand the underlying molecular mechanisms that lead to pathogenesis and severe disease

Diagnosing Lassa Virus Infection by Tracking the Antiviral Response

<p>Hemorrhagic fever viruses can only be diagnosed by conventional methods when the infection has spread to the blood the patient (viremia, around 8 days after infection). We set out to determine if the transcriptional dynamics of the circulating immune cells (PBMCs) in non-human primates infected with the Lassa virus could be used as an ealier indicator of infection. We identified a strong signal of infection that appear almost 5 days earlier (3dpi) than the one detected by conventional methods.</p