Jean-Laurent Casanova, M.D., Ph.D.
Investigator, Howard Hughes Medical Institute
Senior Attending Physician
Casanova studies how human genes determine the clinical manifestations and outcome of primary infections by viruses, bacteria, fungi, and parasites. He searches for single-gene mutations that selectively compromise the immunity of otherwise healthy children and adults who are exquisitely vulnerable to specific infectious diseases, including the novel coronavirus (SARS-CoV-2). He thus characterizes the molecular, cellular, and immunological mechanisms of life-threatening infectious diseases.
Casanova’s laboratory aims to understand why some children and adults develop a life-threatening or lethal illness in the course of primary infection, while most people exposed to the same microbe remain unharmed. The team has a particular interest in so-called inborn errors of immunity, the genetic variations that affect a person’s ability to fight off an infectious agent. Work in the lab has revealed that variations of this type can confer selective vulnerability to severe illness during primary infection. These inborn errors of immunity to infection can be rare or common, and can affect children or adults. This work provides theoretical and experimental support for a human genetic theory of severe infectious diseases.
With Laurent Abel, at the Imagine Institute of the Necker Hospital for Sick Children in Paris, Casanova’s work identifying and characterizing single-gene defects underlying specific infectious illnesses has broadened the field’s dominant paradigm, which for decades held that single-gene inborn errors of immunity were invariably rare and would only be found in patients with numerous infections, while common variants in multiple genes would influence risk for any specific type of infectious disease. Abel leads the mathematical “dry lab” at Necker and Rockefeller, whereas Casanova heads the experimental “wet lab” in both locations.
Casanova’s team has uncovered hidden genetic vulnerabilities to a variety of pathogens. For example, they discovered that mutations in IRF7 can predispose to severe influenza pneumonitis. Likewise, they have found that errors in CIB1 immunity confer unusual vulnerability to certain papillomavirus-driven skin warts and cancer; that disruptions in different neuron-intrinsic immunity genes predispose patients to viral infections of the forebrain or the brainstem; and that mutations in IL18BP contribute to fulminant viral hepatitis.
Building on their identification of a large group of errors in IFN-γ immunity responsible for severe clinical disease caused by poorly virulent mycobacteria, Casanova and Abel discovered the first cases of rare and common monogenic forms of bona fide tuberculosis.
These discoveries have revealed that many immunological circuits that were previously thought to play a broad role in host defense are largely redundant and essential for immunity against one or a few specific infections only. They also revealed that immunity to infection is not provided solely by the cells of the “immune system”, i.e. leukocytes and related cells: it requires many more cell types throughout the entire body. They contribute to defining the function of host defense genes in the natural ecosystem in which human populations live and are subjected to natural selection.
Since the outbreak of the coronavirus pandemic, Casanova has been sequencing the genomes of previously healthy young patients with life-threatening COVID-19, searching for genetic variations that may explain their insufficient immunity to SARS-CoV-2. Revealing monogenic holes in the host defense of otherwise healthy humans also has profound clinical implications, offering many families worldwide the possibility of molecular diagnosis and genetic counseling, as well as treatments aimed at restoring a deficient immune response. Patients with genetically impaired IFN-γ production, for example, are prone to tuberculosis and benefit from IFN-γ.