Molecular pathways involved in human genetic susceptibility to infections: from the bedside to the bench

Background. The widespread use of high-throughput genomic technologies has speeded up the discovery of genetic defects impairing non-redundant or tissue-specific key pathways involved in the pathogenesis of the so-called intrinsic and innate inborn errors of immunity (IEIs). These disorders manifest as susceptibility to a narrow spectrum of pathogens expressing in terms of severe, critical, or even potentially life-threatening infections, generally occurring in otherwise healthy individuals irrespective of age, number of episodes, familial infectious history, microorganism’ pathogenicity and epidemiology. Objectives. We provide key elements to properly investigate underlying IEIs in patients with infectious susceptibility restricted to a selective spectrum of pathogens, describing the clinical red flags worthy of an immunologic and genetic evaluation. Content. We address the main signs suggestive for IEI-related infectious susceptibility relying on a “bedside to the bench” approach, starting from clinical scenarios, going through the key determinants of host defense against the specific spectrum of pathogens involved, finishing with the proper molecular tests adopted by reason of a specific clinical- and basic laboratory-guided suspicion. Implications. An early intrinsic and innate IEI diagnosis can result in prompt patient-tailored management, reducing the burden of infections- and immune-dysregulation-related comorbidities.