Molecular determinants of disease severity in urinary tract infection

• Published in: Nature reviews. Urology Vol. 18; no. 8; pp. 468 - 486
• Main Authors: Ambite, Ines, Butler, Daniel, Wan, Murphy Lam Yim, Rosenblad, Therese, Tran, Thi Hien, Chao, Sing Ming, Svanborg, Catharina
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2021; Nature Publishing Group
• Subjects: 631/208; 631/250/255; 631/326; 631/80; 692/4017; Antibodies, Viral - immunology; Basic Medicine; COVID-19; COVID-19 - epidemiology; COVID-19 - immunology; Disease prevention; Genetic aspects; Genotype; Health aspects; Host-bacteria relationships; Humans; Identification and classification; Immune system; Immunity, Innate; Immunologi inom det medicinska området; Immunology in the medical area; Medical and Health Sciences; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Medicinska och farmaceutiska grundvetenskaper; Pandemics; Pathogens; Review; Review Article; Risk factors; SARS-CoV-2 - immunology; Severity of Illness Index; Urinary tract diseases; Urinary tract infections; Urinary Tract Infections - diagnosis; Urinary Tract Infections - epidemiology; Urinary Tract Infections - immunology; Urogenital system; Urology; Virulence (Microbiology); Sweden
• ISSN: 1759-4812; 1759-4820
• DOI: 10.1038/s41585-021-00477-x

The most common and lethal bacterial pathogens have co-evolved with the host. Pathogens are the aggressors, and the host immune system is responsible for the defence. However, immune responses can also become destructive, and excessive innate immune activation is a major cause of infection-associated morbidity, exemplified by symptomatic urinary tract infections (UTIs), which are caused, in part, by excessive innate immune activation. Severe kidney infections (acute pyelonephritis) are a major cause of morbidity and mortality, and painful infections of the urinary bladder (acute cystitis) can become debilitating in susceptible patients. Disease severity is controlled at specific innate immune checkpoints, and a detailed understanding of their functions is crucial for strategies to counter microbial aggression with novel treatment and prevention measures. One approach is the use of bacterial molecules that reprogramme the innate immune system, accelerating or inhibiting disease processes. A very different outcome is asymptomatic bacteriuria, defined by low host immune responsiveness to bacteria with attenuated virulence. This observation provides the rationale for immunomodulation as a new therapeutic tool to deliberately modify host susceptibility, control the host response and avoid severe disease. The power of innate immunity as an arbitrator of health and disease is also highly relevant for emerging pathogens, including the current COVID-19 pandemic. In this Review the authors describe advances in our understanding of the molecular determinants of urinary tract infection pathogenesis, focusing on specific host susceptibility factors and their consequences. Key points Host resistance to infection is maintained by tight control of the immune response. If uncontrolled, excessive immune activation can lead to severe disease and inefficient microbial clearance. Urinary tract infections (UTIs) are a major cause of acute disease morbidity and mortality, as well as chronic sequelae. Uropathogens trigger innate immune responses in the kidneys (acute pyelonephritis) or the urinary bladder (acute cystitis). Disease severity is regulated at specific innate immune checkpoints, which control transcription and critical antimicrobial effector functions. Distinct susceptibility genes distinguish the two forms of symptomatic UTI through different mechanisms of immune hyperactivation. Bacteria with reduced virulence are carried asymptomatically and enhance their fitness by actively inhibiting the host response. This level of molecular resolution in UTI offers an exciting potential for improved diagnosis and novel immunomodulatory therapies.