Hemolysin of uropathogenic Escherichia coli: A cloak or a dagger?

Abstract

Hemolysin from uropathogenic Escherichia coli (UPEC) is a hemolytic and cytotoxic protein active against a broad range of species and cell types. Expression of hemolysin correlates with severity of infection, as up to 78% of UPEC isolates from pyelonephritis cases express hemolysin. Despite decades of research on hemolysin activity, the mechanism of intoxication and the function of hemolysin in UPEC infection remain elusive. Early in vitro research established the role of hemolysin as a lytic protein at high doses. It is hypothesized that hemolysin is secreted at sublytic doses in vivo and recent research has focused on understanding the more subtle effects of hemolysin both in vitro and in elegant infection models in vivo, including inoculation by micropuncture of individual kidney nephrons. As the field continues to evolve, comparisons of hemolysin function in isolates from a range of UTI infections will be important for delineating the role of this toxin. This article is part of a Special Issue entitled: Pore-Forming Toxins edited by Mauro Dalla Serra and Franco Gambale.

Variation in hemolysin A expression between uropathogenic Escherichia coli isolates determines NLRP3‐dependent vs . ‐independent macrophage cell death and host colonization

“…An extensive literature has reported that UPEC HlyA contributes to bladder pathology but not urinary tract colonization in mice (23,40,41). In contrast, we find that HlyA does affect bacterial loads in the murine bladder at both 1 and 3 d pi (Fig.…”

“…Several studies have demonstrated that HlyA is cytotoxic to a wide range of host cells (26,(41)(42)(43)(44). However, to our knowledge, this is the first study to survey HlyA expression levels across strains from a closely related lineage (i.e., ST131) and to associate this variation with killing of innate immune cells (Fig.…”

Dysregulated hemolysin liberates bacterial outer membrane vesicles for cytosolic lipopolysaccharide sensing

“…coli harbors HlyA, while ∼50% of UPEC strains harbor and express HlyA, presenting a close correlation between increased clinic E . coli pathogenesis with HlyA expression [21,23,51]. In recent years, because it has been hypothesized that hemolysin is secreted at sublytic concentrations in vivo, there is increasing interest in understanding the more subtle effects of hemolysin on host cellular processes aside from outright lysis, including RhoA activation [52], Akt signaling [53], cell death pathway [22,54] and protease degradation [55].…”

“…Here, our study adds new findings to the scenario of hemolysin-mediated biological functions by identifying that abnormal expression of hemolysin in bacteria promotes host immune recognition of replicating pathogens via non-canonical inflammasomes and restricts bacterial colonization in vivo (Fig 6). Because hemolytic proteins exhibit multilayered or even antagonistic roles in modulating host responses to infections, it is not surprising that bacteria have evolved complicated mechanisms to fine-tune the synthesis, maturation, and transport of hemolysin [21,23,51]. Thus, studies of the spatiotemporal expression of hemolysin in vivo will be essential for understanding both host defense and bacterial survival.…”

“…Recently, hemolysin was found to participate in modulating cell death pathways at sublytic concentrations [21–23], representing more sophisticated toxin activity in contrast to outright pore-forming function. Uropathogenic Escherichia coli (UPEC) isolate CP9 activates caspase-3/7 and stimulates rapid cell apoptotic death in vitro; this phenotype was lost in a Δ hlyA mutant [24], indicating the involvement of hemolysin in the cell apoptosis pathway.…”