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Rockefeller Researchers Link Genetic Mutations to Infectious Disease Susceptibility

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NEW YORK (GenomeWeb) – Dedicated to identifying single-gene mutations that compromise the immunity of otherwise healthy patients, Rockefeller University professor and Howard Hughes Medical Institute investigator Jean-Laurent Casanova believes that sporadic infectious diseases should be defined as monogenic disorders.

Casanova has been examining the link between infectious disease and human genetics since he was a senior pediatrics resident in in 1993. Publishing research on the link between mutations in the IRN-γ gene and mycobacterial infections in the New England Journal of Science in 1996, Casanova and his colleagues discovered the first cases of monogenic pediatric predisposition to tuberculosis. Since then, Casanova has continued identifying and characterizing specific genetic defects linked to single infectious diseases.

At a presentation last week at Rockefeller University, Casanova discussed his current research on human genetic determinism in pediatric diseases, including viral, bacterial, and fungal infections. He explained that for a vast majority of known microbes, only a small proportion of infected patients suffer from life-threatening diseases.

Casanova highlighted that essentially two types of infections exist: rare, chronic diseases that segregate in Mendelian behavior, and common diseases that are typically sporadic in the ER and ICU.

While he notes that idea of genetic-based infections has been around for multiple decades, Casanova wants to prove the idea correct by identifying mutations in specific genes that cause susceptibility to most infectious diseases. His team at Rockefeller views the infectious agent as a trigger for a patient's genetic response, and therefore attempts to discover the root cause of severe cases of infectious disease.

"In a given family, there might be two or more genetically at-risk individuals, but only one develops the life-threatening condition," Casanova explained during the talk. "In genetics, that's called incomplete penetration, and we found in some families that certain genetic lesions were shown to be causal."

In order to identify links between sporadic infectious diseases and genetic disorders, Casanova's team starts by using exome or genome sequencing, and then analyzes genetic variation in patients and their families.

In an interview with GenomeWeb, Casanova explained that his team "select[s] certain variants based on a presumed model of inheritance, hypothetical penetrance, observed prevalence of the disease, basis of segregation of variants and their frequency, and on the nature of the variant ... and gene, particularly in terms of its expression and function."

Casanova's team tests these genetic models and selection variations, and eventually establishes causality between genotype and phenotype. Once the team discovers links between variations and the infectious disease, it examines the mechanism and attempts to understand the disease's' molecular and cellular basis.

During the talk, Casanova highlighted some of his previous and ongoing research on a variety of pathogens linked to inborn errors of immunity, including influenza and tuberculosis.

Casanova explained that he and his colleagues have found at least two genetic etiologies linked to influenza. One involves children, otherwise healthy until the ages of six or seven, who suddenly contract influenza and spend long periods of time in the ICU. In a study published in Science in April 2015, Casanova's team performed exome sequencing on such individuals and found that a loss-of-function (LOF) mutation in IRF7 disrupted autonomous control of the influenza virus in patient's pulmonary tissue.

In addition, Casanova said his team has found evidence that mutations in the IRF9 gene also cause severe pulmonary infection, work that will be published later this year.

During the lecture, Casanova talked about how his team recently discovered genetic mutations that caused influenza in patients. In a study published in Frontiers in Immunology in December 2017, Casanova's team used genomic de novo sequencing to find gain-of-function (GOF) mutations in the STAT1 gene. Casanova noted that the mutation is "more common than cystic fibrosis and hemochromatosis [and] strikes more than 1 in 600 New Yorkers," discovering the inborn errors were phenotypically linked to tuberculosis.

Casanova therefore realized that missense mutations in STAT1, which cause a drop in IFN-γ production, could induce genetic susceptibility to not only fungal but also mycobacterial infection, including tuberculosis. According to Casanova, the genetic disorders in the study were monogenetic and most common in individuals with European descent. His team is currently researching the exact mechanisms behind the gene activation.

Casanova also explained how certain mutations hinder a person's neurons and oligodendrocytes from controlling viruses and producing interferon. In a study published in Neurology in November 2014, his team found that disruptions in the TLR3 pathway predispose patients to herpes simplex virus (HSV) infections. They saw that patients who had a loss-of-function mutation for TLR3 deficiency almost immediately developed childhood-onset herpes simplex encephalitis once infected with HSV.

While he discussed well-known infectious diseases in the lecture, Casanova later noted in an interview that his team has studied about 25 diseases so far since 1993. Casanova's ongoing goal is to redefine how certain immunological circuits play a role for immunity against one or a few specific infections.

"We're not saying that all patients with a given infection are genetic, but that for all infectious diseases, there are some patient cases that are indeed genetic," Casanova explained. "The proportion of how many are genetic ... still needs to be clearly defined."

In terms of public health, Casanova noted in the lecture that the "way natural selection operates, in 500 to 550 years, the microbes we know will be resistant to all medications we have, and the likelihood that they become resistant faster than our capacity to develop new drugs is pretty high." Casanova emphasized that clinicians and researchers currently have a shrinking window of opportunity to examine the root of infectious diseases.

During the interview, Casanova said he envisions at least two diagnostic applications for the genetic-basis of infectious disease. Once clinicians discover that a patient has a genetic mutation underlying susceptibility to an infectious disease, they should conduct genetic testing all of that individual's relatives to see if they also carry the mutation. Casanova noted while that doctors are applying this method to a certain degree, detection could increase in the future as researchers find more links between mutations and susceptibility to infectious disease.

In addition, Casanova believes that there should be genetic diagnostic tests for the general population. He noted that there is no genetic cause of infection that is common enough to warrant screening at the population level.

"However, the general prediction is that within a year or two, [a diagnostic test] will be needed, because there will be several reliably common genetic disorders underlying severe infectious disease, based on our unpublished data" Casanova explained.

While his team does not have specific plans to start a company around these findings, Casanova said that he would be happy to partner with outside groups who wish to develop diagnostics tests for common diseases that target specific genes.

Casanova noted during the lecture that once clinicians diagnose individuals with certain genetic mutations linked to infectious disease susceptibility, they could treat those patients by compensating for the lack of protein or other molecule production. If researchers understand and find cases where the infectious disease is indeed genetic, they then can treat the issue by "restoring the missing piece in the child, adolescent, or adult."

When asked whether the mutations he and his team are studying could be addressed with gene editing techniques such as CRISPR, Casanova agreed that these approaches could be radical solutions. However, he emphasized that researchers need to identify the genetic cause of infection before fixing the gene itself.

"From there, we can look at options, whether it's providing specific molecules or gene editing, as they are all potential solutions in the future," Casanova added.

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