Genetics and immunology of rare infections, a powerful tool for understanding common infections

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The air we breathe, the surfaces we touch, the social relationships we have... All these interactions with our environment expose us permanently to a very large variety of infectious agents. Faced with them, we are not all equal. Indeed, there is great variability between individuals in their response to the same pathogen. Some will have no symptoms at all, others will develop a mild form, while some – typically less than 1% of cases – will develop a very severe form.

In a review of the literature published in Cell, Jean-Laurent Casanova and Laurent Abel, co-directors of the Human Genetics of Infectious Diseases Laboratory at Institut Imagine and Rockefeller University, discuss the genetic and immunological origin of this inter-individual variability. In particular, they explain how the study of a handful of patients who have developed severe and rare infectious diseases can shed new light on the mechanisms at work in related but much more common infectious diseases [1].

“That is the whole purpose of this review, says Laurent Abel. We wanted to illustrate it with two concrete examples: tuberculosis and COVID-19”. These two diseases, one bacterial, the other viral, were not chosen by chance. In recent years, the laboratory's teams have been able to identify genetic and immunological causes for these two diseases by building on previous work on two infectious diseases that are as rare as they are severe: the Mendelian susceptibility syndrome to mycobacterial infections (MSMD) in the case of tuberculosis; and severe forms of influenza in the case of Covid-19.

"MSMD patients are at increased risk of developing infection with mycobacteria, bacteria that are very common and completely harmless to most individuals, but which in these patients can lead to severe and sometimes fatal forms".

As tuberculosis is also a mycobacterial infection (caused by Mycobacterium tuberculosis), the researchers studied the genetic basis of this disease, which only develops in 10% of people exposed to the bacteria. They have thus highlighted the involvement of a much more frequent variant of this same TYK2 gene in the occurrence of the disease, always in a recessive mode. "Approximately 1% of tuberculosis cases in Europe can be explained by homozygosity for this variant," he explains [2]. At the molecular level, the presence of this mutation blocks signalling pathways involving interleukin 23 (IL-23), the purpose of which is to produce IFN-γ, which has an anti-mycobacterial action.

Similarly, the study of rare severe pneumonia following influenza infection has led to a quantum leap in the understanding of Covid-19. Indeed, before the pandemic, researchers had already been able to identify defects in the IRF7, TLR3, IRF9, and STAT1 genes in this severe flu.

“Based on this knowledge obtained from the study of a few patients, our team was able to show that about 3% of severe forms of COVID-19, especially in subjects under 60 years of age, can be explained by genetic defects in several genes of the IFN-I pathway [3], the most frequent defect being that in the TLR7 gene, which alone explains about 1% of severe forms in humans (the TLR7 gene is located on the X chromosome) [4]”. The same mechanism affecting the IFN-I pathway was therefore altered in both cases. Continuing the analogy, the researchers were also able to identify a common immunological cause: the presence of autoantibodies directed against IFN-I and blocking their antiviral action. Further investigation enabled the researchers to attribute about a quarter of severe forms of Covid-19 to these anti-IFN-I autoantibodies [5,6]. This provides a basis for adapting the screening and management of these patients at risk.

Before all these studies, infectious diseases had very little information on the molecular and cellular mechanisms that explain common infections. With this new reading grid "from the rare to the frequent", Jean-Laurent Casanova and Laurent Abel propose a reversal of the traditional approach to the study of the causes of infectious diseases, based on the inaccurate postulate of a homogeneous population. On the contrary, they embrace inter-individual diversity and propose to start from rare clinical cases and to describe them precisely at the molecular and cellular level, at the genetic and immunological level, in order to uncover pathogenic mechanisms that may be common to related but more frequent diseases. A mechanistic approach that promises new discoveries that are as exciting as they are pragmatic, with the hope of identifying therapeutic targets that can be exploited for the benefit of the greatest number of people.

[1] J.L. Casanova & L. Abel, Cell, 2022.

[2] Boisson-Dupuis et al, Science Immunology, 2018 ; G. Kerner et al., PNAS, 116, 10430-10434, 2019.

[3] Inborn errors of type I IFN immunity in patients with life-threatening COVID-19, Q. Zhang et al., Science, 24 septembre 2020.

[4] X-linked recessive TLR7 deficiency in 1% of men under 60 years with life-threatening COVID-19, T. Asano et al, Science Immunology, 2021.

[5] Bastard, P et al. (2020). Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science 370, eabd4585

[6] Autoantibodies neutralizing type I IFNs are present in ~ 4% of uninfected individuals over 70 years and account for ~ 20% of COVID-19 deaths, P. Bastard et al., Science Immunology, 2021.