Molecular determinants of disease severity in urinary tract infection

Abstract

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.

Immunomodulation therapy offers new molecular strategies to treat UTI

“…Mechanisms of APN pathogenesis and innate immune activation have been extensively studied and reviewed 4 – 6 , 29 . Briefly, pathogen-specific recognition mechanisms activate a rapid innate immune response in infected tissues, leading to inflammation and the mobilization of an antibacterial defence 65 .…”

“…Mechanisms of innate immune activation and essential effector functions in APN have been mapped using cellular infection technology, animal models and clinical studies 4 , 10 , 11 , 14 , 16 , 18 , 19 , 32 , 75 – 80 . Key regulators of UTI severity have been evaluated using gene knockout technology and their relevance to human disease has been verified in clinical studies 10 , 11 , 29 , 78 .…”

“…Innate immunity provides a rapid and selective first line of defence 1 – 4 , preventing pathogens from gaining access to host tissues while sustaining symbiosis with the commensal flora. This impressive level of precision is maintained by specific pathogen recognition mechanisms coupled with the immediate activation of the innate immune system 4 – 8 (Fig. 1 ).…”

The C5a/C5aR1 Axis Contributes to the Pathogenesis of Acute Cystitis Through Enhancement of Adhesion and Colonization of Uropathogenic E. coli

“…UTI is a wide spectrum of diseases including bladder infection (cystitis), kidney infection (pyelonephritis), and systemic infection with multiorgan failure (in severe case) ( Ambite et al., 2021 ). UTI usually starts in the bladder and can spread to the kidney ( Nielubowicz and Mobley, 2010 ; Klein and Hultgren, 2020 ).…”

“…Uroepithelial cells are usually the first to respond to microbial challenge and then orchestrate the subsequent host response by release of cytokines, other mediators of inflammation, and complement proteins and stimulate the influx of neutrophils ( Spencer et al., 2014 ; Jones-Freeman et al., 2021 ). However, most human UPEC strains are resistant to complement-mediated killing ( Li et al., 2009 ; Bjanes and Nizet, 2021 ), and several lines of study have suggested that these bacteria mediate excessive inflammatory responses that cause uroepithelial destruction ( Wullt et al., 2003 ; Ambite et al., 2021 ; Paludan et al., 2021 ), impair innate immune cell function, and lead to chronic and recurrent UTI ( Hannan et al., 2010 ; Choudhry et al., 2016 ).…”