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Team Pins Susceptibility to Innocuous Bacteria, Fungi on Mutations in Single Gene

NEW YORK (GenomeWeb) – A study published online today in Science Express suggests mutations in a single gene can chip away at individuals' immune responses, making them vulnerable to normally innocuous microbes dealt with by different immune pathways.

Researchers from Rockefeller and Hiroshima Universities used exome sequencing and genome-wide linkage analyses to narrow in on loss-of-function mutations affecting both copies of a gene called RORC in three families, each from a different ethnic background. The resulting inborn errors of immunity were linked to impaired Mycobacterium immunity in seven affected individuals and candidiasis in six of them.

These and other findings indicate that the RORC mutation alters activity of both cytokine interleukin-17A/F and interferon-gamma immune pathways, prompting susceptibility to candidiasis and other normally non-pathogenic bugs such as the Mycobacterium strain found in the live tuberculosis vaccine.

"By finding that RORC helps control the development of these two cytokines, interleukin-17 and interferon-[gamma], we have revealed a surprisingly dual role for RORC in human immunity to infection," corresponding author Jean-Laurent Casanova, a human genetics of infectious diseases researcher at Rockefeller, said in a statement.

In general, genetic glitches that make people particularly susceptible to Candida or Mycobacterium infections tend to occur in different branches of the immune system, the researchers noted.

For example, a condition called chronic mucocutaneous candidiasis (CMC) can occur due to changes affecting the cytokine interleukin-17A/F pathway, while so-called "Mendelian susceptibility to mycobacterial disease" (MSMD) stems from alterations affecting the interferon-gamma arm of the immune system.

In their current study, Casanova and colleagues focused on seven individuals from three consanguineous families who were prone to unexplained infections that did not seem to be caused by known CMC- or MSMD-related mutations.

The group included a Palestinian girl who suffered from an oral infection called thrush, but died from another infection following exposure to a weak strain of Mycobacterium used in a live tuberculosis vaccine.

Her siblings, too, showed unusually heightened sensitivity to Mycobacterium, as did children from families from Chile and Saudi Arabia. This sensitivity was coupled with CMC for all but one of the individuals.

Using exome sequencing and linkage analyses, the researchers uncovered homozygous missense or nonsense mutations shared by affected members of each family.

The bi-allelic mutations impacted RORC, a gene that produces ROR-gamma and ROR-gamma-T isoforms that contribute to the production of T cells that make the Candida-combating interleukin-17A/F cytokines.

Based on their findings in the families and in follow-up experiments on mouse models and human cell lines, the researchers concluded that these isoforms also have a role in interferon-gamma activity, with bi-allelic RORC mutations producing a pronounced dip in Mycobacterium immunity.

The mutations did not turn up in sequence variant databases, nor were they present in available exome sequences from thousands of unaffected controls. Unaffected members of the families carried one or no copies of the mutated RORC gene.

"Collectively, these data demonstrate that human RORC play a surprising dual role in host defense," the study's authors wrote.

"Human RORC is essential not only for the development of IL-17A/F-producing lymphocytes protecting the mucocutaneous barriers against Candida," they explained, "but also for the activation of IFB-[gamma]-producing T cells, and for systemic protection against Mycobacterium."

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