Genetic susceptibility to infections due to particular pathogens

Genetic susceptibility to infections due to particular pathogens (also referred to as Mendelian susceptibility to specific infections) encompasses a group of rare primary immunodeficiency disorders in which affected individuals carry inherited genetic variants that confer selective vulnerability to specific infectious organisms, while their immune response to other pathogens remains largely intact. Unlike broader primary immunodeficiencies that cause widespread susceptibility to many types of infections, these conditions are characterized by a narrow predisposition — for example, Mendelian susceptibility to mycobacterial disease (MSMD), predisposition to invasive pneumococcal disease, herpes simplex encephalitis, chronic mucocutaneous candidiasis, or severe viral infections such as those caused by Epstein-Barr virus or influenza. The immune system is the primary body system affected, with defects occurring in specific immune signaling pathways such as the IL-12/IFN-gamma axis, TLR3 signaling, IRAK-4/MyD88 pathway, or NK cell function, among others. Clinical features vary depending on the specific genetic defect and the associated pathogen. Patients may present with unusually severe, recurrent, or disseminated infections caused by organisms that are typically well-controlled in immunocompetent individuals. For instance, individuals with MSMD may develop severe disease following BCG vaccination or environmental mycobacterial exposure, while those with TLR3 pathway defects may develop herpes simplex encephalitis. Onset is often in infancy or childhood, though some forms may not manifest until later in life depending on pathogen exposure. Treatment strategies are pathogen- and defect-specific and may include prolonged antimicrobial therapy, prophylactic antibiotics or antivirals, cytokine replacement therapy (such as interferon-gamma for MSMD), immunoglobulin supplementation, and in some severe cases, hematopoietic stem cell transplantation. Genetic testing and identification of the causative variant are essential for guiding management and genetic counseling.

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