Understanding Genetic Influence on Infectious Disease

During the COVID-19 pandemic, scientists observed that while some individuals experienced severe illness when infected with SARS-CoV-2, others were barely affected. These disparities left researchers and clinicians wondering what causes the wide variations in response to viral infections and what role genetics plays.

Jean-Laurent Casanova, M.D., Ph.D., Professor at Rockefeller University, is a leading expert in this crossover between genetics and infectious disease. Casanova has devoted his efforts to understanding the genetic determinants that influence our vulnerability to various viral and bacterial pathogens. His work in this field has demonstrated how certain genetic variations can predispose individuals to life-threatening infections, while others are resistant. This article discusses the insights shared by Casanova while highlighting some key research and discoveries in the field.

Genetics in Infectious Diseases
"We search for human genetic determinants of life-threatening disease in infected individuals,” Casanova shared. His laboratory, known as the Laboratory of Human Genetics of Infectious Diseases, is divided into five main areas, each targeting different aspects of infectious diseases. These include mycobacterial diseases, viral diseases of the brain and lungs, viral diseases of the skin, autoimmune phenocopies of infectious diseases, and computational genetics aimed at characterizing human genetic variants. Casanova’s work challenges the long-held belief that genetic errors that cause severe infections are rare and only found in patients with multiple infections.

Autoimmunity Against Immunity
Some of Casanova’s recent efforts were critical during the COVID-19 pandemic when he launched an international consortium to understand why certain individuals developed severe infections. The team identified genetic factors, including inborn errors of immunity and autoantibodies, which impair interferon responses necessary for viral defense^1,2.

“So many people in the general population have autoantibodies neutralizing the type I interferons," Casanova stated. This phenomenon is referred to as "autoimmunity against immunity,” and these autoantibodies, particularly those targeting type I and type II interferons (IFNs), can neutralize key immune signaling molecules, and in turn, impair the body's ability to control infections. Research has shown that individuals with autoantibodies neutralizing type I IFNs are prone to other severe viral infections such as Middle East respiratory syndrome (MERS)³ and influenza⁴, while those with autoantibodies against type II IFNs are vulnerable to mycobacterial diseases like tuberculosis⁵.

In the case of COVID-19, Casanova’s team identified that at least 10% of patients with life-threatening illnesses produced neutralizing autoantibodies against type I IFNs. This prevented the necessary antiviral effects of IFNs and an effective immune response against SARS-CoV-2. The group also determined that approximately 3.5% of severe COVID-19 cases can be attributed to genetic defects in the IFN pathway, particularly in genes related to TLR3- and IRF7-dependent type I IFN production. Additional research in patients with autoantibodies neutralizing type I IFNs included investigating the occurrence of severe COVID-19 pneumonia despite vaccination⁶. These patients had a normal antibody response to the vaccine, but also breakthrough infections which led to severe illness.

The Ouroboros of Autoimmunity
In a recent review, Casanova and colleagues likened this form of autoimmunity, where the immune system attacks elements crucial for protective immunity, to "ouroboros"—a snake eating its own tail⁷. This symbol represents the damaging cycle of autoimmunity, where the body’s defenses turn against itself and attack the immune response designed to protect it. One clear example of this autoimmunity is autoantibodies. As Casanova pointed out, this condition is more common than researchers had previously thought. In a sample of nearly 40,000 healthy individuals, the detection of autoantibodies neutralizing type I IFNs occurred in 0.3–1.0% of individuals under 65, with a strong rise in prevalence to 4–8% in individuals older than 70 years⁸. “That amounts to about 100 million people worldwide,” stated Casanova. “And these people are prone to severe viral illnesses.” He noted that this was one of the most surprising discoveries his group has made.

The review also details how autoantibodies can have a wide range of targets including neutrophils, complement systems, and cytokines like granulocyte-macrophage colony-stimulating factor (GM-CSF), type I and II interferons, IL-17, and IL-6. These autoantibodies can lead to conditions like neutropenia, severe bacterial infections, pulmonary alveolar proteinosis, and increased susceptibility to viral and fungal infections. The authors also suggest that these autoimmune conditions might be underrecognized and call for a broader investigation to understand their prevalence, genetic background, and potential links to other diseases.

Resistance to Infectious Diseases
While much of Casanova’s research has focused on genetic vulnerabilities to infections, he also acknowledged the importance of studying genetic resistance. “They are two sides to the same coin,” Casanova stated. “There's the genotype that makes you vulnerable that we've studied over the years. But there's another category; the genotypes that make you resistant.” Although Casanova’s lab does not focus on this area, he highlighted three interesting examples of genetic resistance: individuals with a Duffy antigen-negative blood type resistant to Plasmodium vivax, a cause of malaria; those lacking the CCR5 receptor due to a deletion mutation who are resistant to HIV; and people with FUT2 deficiency resistant to norovirus gastroenteritis.

Gibbs et al. explored these topics in their review of the human genetics of infectious disease⁹. In addition to these standout cases of genetic resistance, the authors discussed the rise of genome-wide association (GWA) studies and the advances leading to improving our understanding of pathophysiology. However, they noted that much of the heritability in infectious disease susceptibility remains unexplained. The authors suggest future research directions in the field should include refining phenotypic definitions, increasing cohort diversity, and using advanced methods like cellular GWA and phenome-wide association studies to further understand the genetic basis of infectious diseases.

Future Directions
With all the detailed genetic analysis needed for his research, it should come as no surprise that Casanova credits the introduction of next-generation sequencing (NGS) as a major contributor to his progress. "That was really the technical breakthrough that helped me the most in my career," he stated. This technology has enabled Casanova and his team to identify inborn errors of immunity and more closely investigate the molecular and cellular mechanisms of various deadly pathogens.

For their future work, Casanova explained that “the most important goal of the lab currently is to define the range of viral diseases that threaten people who carry autoantibodies against type I interferons.” He acknowledged that they’ve already discovered three types of viral pneumonia (COVID-19, MERS pneumonia, and influenza pneumonia), as well as several viral encephalitides (TBE, West Nile) including a few that have not been published yet. “There are many viral illnesses in humans,” Casanova stated. “So, we would like to try to better delineate the range of viral diseases to which these organs are vulnerable.”

References

1. Bastard P, Rosen LB, Zhang Q, et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science. 2020;370(6515):eabd4585. doi:https://doi.org/10.1126/science.abd4585
2. Zhang Q, Bastard P, Liu Z, et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science. 2020;370(6515):eabd4570. doi:https://doi.org/10.1126/science.abd4570
3. Alotaibi F, Alharbi NK, Rosen LB, et al. Type I interferon autoantibodies in hospitalized patients with Middle East respiratory syndrome and association with outcomes and treatment effect of interferon beta1b in MIRACLE clinical trial. Influenza Other Respi Viruses. 2023;17(3):e13116. doi:https://doi.org/10.1111/irv.13116
4. Zhang Q, Pizzorno A, Miorin L, et al. Autoantibodies against type I IFNs in patients with critical influenza pneumonia. J Exp Med. 2022;219(11):e20220514. doi:https://doi.org/10.1084/jem.20220514
5. Ogishi M, Yang R, Rosain J, et al. Inborn errors of human transcription factors governing IFN-γ antimycobacterial immunity. Current Opinion in Immunology. 2023;81:102296. doi:https://doi.org/10.1016/j.coi.2023.102296
6. Bastard P, Vazquez SE, Liu J, et al. Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs. Science Immunology. 8(90):eabp8966. doi:https://doi.org/10.1126/sciimmunol.abp8966
7. Casanova J, Peel J, Donadieu J, Neehus A, Puel A, Bastard P. The ouroboros of autoimmunity. Nature Immunology. 2024;25(5):743-754. doi:https://doi.org/10.1038/s41590-024-01815-y
8. Bastard P, Gervais A, Voyer L, et al. Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths. Science Immunology. 6(62):eabl4340. doi:https://doi.org/10.1126/sciimmunol.abl4340
9. Gibbs KD, Schott BH, Ko DC. The awesome power of human genetics of infectious disease. Annual Review of Genetics. 2022;56:41-62. doi:https://doi.org/10.1146/annurev-genet-080320-010449