Student Theses and Dissertations
Monogenic Defects of the Type I Interferons Signaling Pathway in Humans: Molecular and Clinical Implications
Date of Award
Doctor of Philosophy (PhD)
The germ theory of disease, which dictates that microorganisms colloquially referred to as “germs” can invade humans or other hosts and cause disease, has remained the dominant conceptualization of infectious disease since the late nineteenth century. Since that time, growing appreciation for the extent of subclinical infections, that is, infections where the germ is detectable in its host without causing overt disease, and the Mendelian inheritance patterns of some infectious diseases have reinvigorated the study of the human genetic basis of infectious disease. This theory, so far demonstrated for a number of bacterial, fungal, and viral infections, holds that germs are a necessary but not sufficient condition for infectious disease with susceptibility determined by the genetics of individual members of the host species. In the first part of this thesis, I describe a child with inherited, complete interferon regulatory factor-9 (IRF9) deficiency who suffered from a life-threatening pulmonary influenza infection. This discovery adds to the growing body of evidence which indicates that susceptibility to severe primary infections, even from common pathogens such as influenza virus, is genetically determined. IRF9 is a critical regulator of innate anti-viral immunity in the type I and III interferon (IFN) signaling pathways, which share many signaling proteins. Consistent with this role, I show that the patient’s cells had drastically reduced responses to type I IFN which led to increased influenza virus replication. Profiling the transcriptome of the patient’s cells following stimulation with type I IFN revealed that the transcriptional response to IFN is not completely abolished in the patient’s cells. Indeed, the patient’s cells induced a small but partially overlapping set of antiviral mediators when compared to transcriptional responses from healthy control cells. Unfortunately, type III IFN signaling could not be directly assessed as fibroblasts, the cell line used throughout for viral and biochemical analyses, do not express the type III IFN receptor. These data demonstrate that IRF9 deficiency disturbs type I, and likely type III, IFN signaling, and that this deficiency underlies the patient’s severe influenza infection. In the second part of this thesis, I describe the first cases of inherited IFN IFNα/b receptor-1 (IFNAR1) deficiency in children who suffered severe complications following vaccination with attenuated viral vaccines but who were otherwise healthy. IFNAR1 is one of the two subunits that form the receptor for type I IFNs, and I show that type I IFN signaling is abolished in the patients’ cells. Consistent with a defect in type I IFN signaling, the patients’ cells exhibit a profound susceptibility to all viruses tested in vitro, in contrast with the patients’ specific and, compared to other primary immunodeficiencies, relatively mild phenotype. This susceptibility was dependent on the absence of a functional IFNAR1 receptor, which we established through complementation experiments. Taken together, these two studies interrogate the functions of the type I and III IFN pathways that are critical for human immunity to viral diseases and provide evidence for an underappreciated non-redundancy within these pathways.
Hernandez, Nicholas, "Monogenic Defects of the Type I Interferons Signaling Pathway in Humans: Molecular and Clinical Implications" (2020). Student Theses and Dissertations. 709.
A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy