Unraveling the Genetic Predisposition on Respiratory Infections: From Single Nucleotide Polymorphisms to Inborn Errors of Immunity

Background: The complex interplay between the human genome and microbial pathogens has captured scientific interest, leading to profound insights into the genetic basis of host’s susceptibility to infections. Objective: Here, we explore the spectrum of genetic susceptibility in infectious diseases, ranging from common single nucleotide polymorphisms (SNPs) to rare monogenic inborn errors of immunity (IEIs). Defects in intrinsic and innate immunity lead to susceptibility to a narrow spectrum of pathogens, including respiratory viruses, pyogenic bacteria, mycobacteria, and fungi. Sources: A comprehensive review of the literature on human genetic susceptibility to infections was conducted using a search strategy that included all article types and keywords related to genetic susceptibility, SNPs, IEIs, intrinsic and innate immunity, infections, and specific pathogens. Content: The study synthesizes the intricate relationships between genetic variants and infectious susceptibility to common microbial agents. It delineates the prevalent role of common SNPs in modulating immune responses and investigates rare IEIs, focusing on those affecting intrinsic and innate immunity in a monogenic fashion. Cross-pathogen analyses reveal distinct patterns in genetic susceptibility, providing a comprehensive understanding of host–pathogen interactions and methodically analyzing respiratory viruses, pyogenic bacteria, mycobacteria, and fungi. Implication: This review aims to highlight the continuum from common polymorphisms to rare monogenic disorders in susceptibility to narrow-spectrum infections, focusing on respiratory pathogens. The ever-deepening comprehension of the molecular interplay governing immune responses to respiratory pathogens could lay the groundwork for personalized diagnostic and therapeutic strategies tailored to individual genetic profiles, offering insights with potential implications for infectious diseases.