The kidney is an organ particularly susceptible to damage caused by infections and autoimmune conditions. Renal inflammation confers protection against microbial infections. However, if unchecked, unresolved inflammation may lead to kidney damage. Although proinflammatory cytokine IL-17 is required for immunity against extracellular pathogens, dysregulated IL-17 response is also linked to autoimmunity. In this review, we will discuss the current knowledge of IL-17 activity in the kidney in context to renal immunity and autoimmunity and raise the intriguing question to what extent neutralization of IL-17 is beneficial or harmful to renal inflammation.
The kidneys are frequent targets of infectious agents as well as pathogenic immune response in systemic and organ-specific autoimmunity. According to the National Institutes of Health, ∼14% of the people (∼20 million) in the United States suffer from some form of chronic kidney diseases (https://www.niddk.nih.gov/). In addition, pyelonephritis is a frequent complication of urinary tract infection (UTI) by Escherichia coli, the most frequent infection in humans (1). Yet our understanding of the fundamental immune processes in the kidney lags behind that of other visceral organs, such as the gut or liver. The kidney is an immunologically distinct organ, owing to its poor regenerative capacity, toxins (uremia), hypoxia, and arterial blood pressure, which have profound impacts on the ongoing immune response in the kidney (2, 3). Additionally, lack of reliable animal models of kidney diseases and technical difficulties in procuring adequate human renal biopsy samples make it challenging to interrogate pathways linked to host defense and autoimmune diseases in the kidney. Conversely, kidney failure disturbs immunity, causes intestinal barrier dysfunction and dysbiosis, and drives systemic inflammation or immunodeficiency. Therefore, kidney disease is a major health problem, and understanding the mechanisms leading to renal disease is an important endeavor with a great potential health impact. Renal inflammation and immune system activation play a key role in acute or chronic kidney diseases. The objective of this review is to outline some of the evidence connecting immune and inflammatory mechanisms in renal antimicrobial immunity and autoimmune kidney diseases (Fig. 1).
In the past decade, IL-17A (IL-17), a proinflammatory cytokine, has received considerable attention for its pathogenic role in autoimmune diseases. Although protective in infectious settings, overproduction of IL-17 promotes inflammation and autoimmunity (4). IL-17 recruits and stimulates different cells to drive chronic inflammation. Regulating IL-17 levels or action by using IL-17 or IL-17R blocking Abs has shown remarkable efficacy in attenuating experimental autoimmune diseases. In this review, we will overview IL-17 induction and function in relation to host defense and autoimmune diseases in the kidney.
Biology of IL-17
IL-17 (IL-17A, also termed CTLA-8) was originally cloned in 1993 (5). The IL-17 family consists of six cytokines: IL-17A (IL-17), IL-17B, IL-17C, IL-17D, IL-17E (IL-25), and IL-17F (6, 7). The IL-17R family includes five receptor subunits, IL-17RA, IL-17RB, IL-17RC, IL-17RD, and IL-17RE (7). IL-17 and IL-17F exist either as a homodimer or as a heterodimer and signal through dimeric IL-17RA and IL-17RC receptor complex (7). Although IL-17R is ubiquitously expressed, nonhematopoietic cells are generally the principal responders to IL-17. Upon ligand binding, adaptor protein Act1 is recruited to the receptor subunits and activates multiple cell signaling pathways via different TNF receptor–associated factor (TRAF) proteins. Activation of TRAF6 leads to triggering of multiple transcription factors, including NF-κB, C/EBPβ, C/EBPδ, and MAPK (7). IL-17R–Act1 complex also links with MEKK3 and MEK5 in a TRAF4-dependent manner, resulting in ERK5 activation (7). Although TRAF6 and TRAF4-mediated IL-17 signaling results in transcription of classical IL-17 responsive inflammatory genes, IL-17 signaling via Act1-TRAF2-TRAF5 complex controls mRNA stability of IL-17 target genes.
IL-17 induces inflammatory gene expression either by driving de novo gene transcription or by stabilizing target mRNA transcripts. IL-17 activates NF-κB and induces the expression of NF-κB–dependent cytokines. Subsequent studies identified a characteristic “IL-17 gene signature,” including cytokines (IL-6, IL-1, G-CSF, GM-CSF and TNF-α), chemokines (CXCL1, CXCL2, CXCL5, CCL2, CCL7 and CCL20), antimicrobial peptides (β-defensins, S100 proteins, and lipocalin2), and matrix metalloproteinases (MMPs) (MMPs 1, 3, 9, and 13) (8, 9). Moreover, tissue-specific gene targets are also identified in different organs. For example, IL-17 upregulates renal-protective genes encoding the kallikrein–kinin system (KKS) in Candida albicans–infected kidney, which prevent kidney damage during acute or chronic kidney injury (10, 11). IL-17 also activates MAPK pathways, including ERK, p38, and JNK (12). Additionally, C/EBP transcription factors act as transcriptional regulators of IL-17 signaling in target cells (13).
IL-17 came into prominence in 2005 with the discovery of a new population of CD4+ Th cells characterized by the expression of IL-17 (14–17). This subset became known as Th17 cells. During priming of naive CD4+ T cells, APCs secrete IL-1, IL-6, and IL-23. This favors Th17 differentiation via STAT3 and RORγt and secretion of IL-17, IL-17F, GM-CSF, and IL-22. Furthermore, a number of innate immune subsets make IL-17, such as γδ+ T cells, NK T cells, and TCRβ+ natural Th17 cells and type 3 innate lymphoid cells (ILC3) (18).
Renal immunity against pathogens
Kidneys in a healthy state are sterile. However, renal infections are common and occur via hematogenous routes or from ascending spread from the bladder or urethra. The very early response to invading pathogens is provided by the unidirectional flow and acidic pH of urine and epithelial barriers and local production of antimicrobial factors that trap pathogens or interfere with their ability to attach to tissue (2, 19–22). This is followed by a robust innate immune response in the kidney, which provides the first line of host defense. The innate response is initiated by several classes of pattern recognition receptors, such as membrane-bound TLRs and nucleotide-binding oligomerization domain (NOD)–like receptors, together with inflammasomes. Following pathogen clearance, both innate effector cells and kidney-resident cells release tissue repair enzymes and anti-inflammatory proteins, which are necessary to maintain immune homeostasis and repair injured tissue. Innate response also set the stage for adaptive immunity, required for long-term protective immunity in the kidney.
IL-17–mediated renal immunity against bacterial infections.
The most common bacteria responsible for kidney infection is E. coli, which accounts for close to 80% of cases of kidney (pyelonephritis), urinary tract, and bladder infections (cystitis) (23). Other bacteria include methicillin-resistant Staphylococcus aureus (MRSA), Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterococcus faecalis (23).
Uropathogenic E. coli.
UTI caused by uropathogenic E. coli (UPEC) is one of the most common infection in humans, affecting 150 million people each year worldwide (23). Bacteria present in fecal matter infect the peri-urethral area and bladder. If left unchecked, the bacteria ascend the ureters to the kidney and establish acute pyelonephritis. In most severe cases, UPEC infection may lead to permanent renal scarring and septicemia (1).
Sivick et al. (24) systematically interrogated the impact of IL-17 in innate and adaptive immunity against UPEC in a mouse model of trans-urethral infection. In this system, IL-17 has been shown to play no role in adaptive immune response in the bladder. In contrast, IL-17 produced by γδ+ T cells drives bacterial clearance in the infected bladder at an early time point. The protective effect of IL-17 was attributed to its ability to induce cytokines and chemokines necessary to facilitate the influx of neutrophils and other innate effectors in the bladder. In line with this observation, mice deficient in γδ+ T cells showed increased susceptibility to UTI (25). However, this study did not measure renal IL-17 levels or investigate the contribution of IL-17 in defense against UPEC in the kidneys. A separate report showed that expression of IL-17 is increased in the kidney following UPEC infection at 24 and 48 h postinfection. This increase in IL-17 level is regulated by surfactant proteins A and D in the infected kidney (26). Consequently, surfactant proteins A and D knockout mice showed increased bacterial load in the kidney following UPEC infection. Future in-depth studies should focus on addressing the renal activities of IL-17 in the kidneys following UTI infection.
MRSA infection is a major clinical challenge and in most cases is difficult to treat. Although MRSA resides in the skin and nasal tract, infection of kidney may occur through blood stream infection and from ascending spread from urinary tract (27). If uncontrolled, MRSA infection in the kidney may lead to the development of more serious conditions, including septic shock. The first evidence documenting a 15-fold increase in the kidney burden of MRSA following IL-17 neutralization suggests that IL-17 plays a vital role in protecting against disseminated infection (22). Interestingly, neutralization of IL-22, another cytokine produced by Th17 cells, has no impact on renal bacterial load. Kidneys of mice subjected to IL-17 neutralization showed reduced number of T cells and neutrophils. However, renal expression of antimicrobial peptides and cytokines were unchanged (28). Indeed, protective efficacy of NDV3 vaccine against invasive MRSA infection requires the induction of IL-17 response (29). O-Acetylation of peptidoglycan of MRSA limits Th17 cell priming and permits MRSA reinfection in the absence of functional Th17 memory (30). Moreover, vaccination with recombinant N terminus of the candidal Als3p adhesin resulted in ∼5-fold reduction in kidney bacterial burden and improved survival in mice. The vaccination primed Th1, Th17, and Th1/Th17 cells in the draining lymph nodes, which in turn stimulated neutrophil influx and proinflammatory cytokine levels in the kidney (31). A new report showed that vaccination with nontoxic mutant TSST-1 drives IL-17–dependent protection against S. aureus infection (32). In vaccinated animals, IL-17 producing cells were increased in the spleen and the vaccine-induced protection against S. aureus was abolished in the IL-17 knockout mice (32).
IL-17–mediated renal immunity against fungal infections.
Invasive fungal infections are a major cause of mortality in hospitalized patients (33). The opportunistic pathogens such as Candida, Aspergillus, Mucor, Cryptococcus, and Histoplasma are particularly known to infect the kidneys in predisposed individuals with serious complications. At the same time, there is a high incidence of invasive fungal infections in patients with renal disease and kidney transplant recipients under effects of immunosuppression and environmental exposure (34). There are two mechanisms by which these fungal species infect the kidney; infections can begin in the lower urinary tract and ascend to the kidneys, and infection can also occur via hematogenous dissemination to the kidneys.
C. albicans is the causative agent of candidiasis at the mucosal sites, including oral cavity, skin, and vagina (35). However, the most severe Candida-induced disease resulting in high mortality rate (∼40%) is disseminated candidiasis (33, 36, 37). The kidney is the most common organ involved in disseminated candidiasis. This was demonstrated in a review of 45 autopsies of patients with disseminated candidiasis. Almost 89% (40 out 45) had overt histological evidence of renal involvement (38). Similarly, the majority of the fungus is recovered from the kidneys of systemically infected mice. During disseminated candidiasis, C. albicans hyphae invade and damage kidney leading to renal insufficiency (10). Considerable data implicate IL-17 in immunity to disseminated candidiasis (39–42). Data from our group and others have shown that IL-17 is produced locally in the kidney within 24 to 48 h in response to fungal infection (10, 43). Accordingly, mice lacking IL-17RA or IL-17 exhibited increased fungal load in the kidney and succumb to infection earlier than control animals (39–42).
Although IL-17 has been detected in the fungal infected kidney, the exact cellular source of IL-17 was unknown. By taking advantage of sensitive IL-17 fate tracking mice, we demonstrated that innate γδ+ T cells are the primary cellular source of IL-17 in the C. albicans–infected kidneys, with minor contribution from innate αβ+ T cells (44). In uninfected mice, a small baseline population of IL-17–producing γδ+ T cells was also observed, which proliferated in response to systemic fungal infection. These data indicate that both kidney resident and infiltrating γδ+ T cells may contribute to renal IL-17 production in the fungal infected kidney.
IL-17 is classically known as a regulator of neutrophils and antimicrobial peptides. Neutrophil influx was reduced in the kidneys of IL-17RA−/− mice during disseminated candidiasis (39). Furthermore, mobilization of the neutrophils in the blood during systemic challenge with C. albicans was also impaired. Interestingly, two reports indicated that IL-17–driven signaling in disseminated candidiasis does not occur in the kidney but instead targets bone marrow to stimulate NK cell production of GM-CSF: a cytokine responsible for driving candidacidal activity of neutrophils in the kidney (41, 45). In sharp contrast, we showed that IL-17R expression on nonhematopoietic cells is required for host defense against disseminated candidiasis, and there is no contribution for hematopoietic cells (44). IL-17 acts on renal tubular epithelial cells to induce the expression of nephron-protective KKS (10). Activation of KKS is critical to prevent kidney damage and restore renal function by inhibiting apoptotic cell death of kidney-resident cells during hyphal invasion. Accordingly, treatment of mice with specific KKS agonist, currently in clinical trial for numerous inflammatory diseases (https://www.clinicaltrials.gov), prevents renal damage and improved survival following disseminated candidiasis (10, 44). Interestingly, vaccination with candidal Als3p adhesin with aluminum hydroxide adjuvant lowers renal fungal burden by a log in a Th17 and neutrophil-dependent manner (31). In contrast, mice deficient in IL-17C show improved survival due to reduced renal inflammation and damage in the fungal infected kidney (46). Supporting this line, others have proposed that the Th17-induced activation of neutrophils may also result in an overwhelming inflammatory tissue response that impairs antifungal immune resistance and leads to defective pathogen clearance (47). Although renal infections by non–C. albicans species are increasing at an alarming rate, very little is known about the role of IL-17–dependent renal immunity against these fungal species. A recent analysis of C. tropicalis systemic infection in mice revealed that IL-17R/Act1 signaling is dispensable for antifungal immunity, whereas CARD9 and TNF-α signaling in neutrophils are essential (48).
IL-17 in autoimmune kidney diseases
IL-17 is a pleiotropic cytokine that plays important role in tissue inflammation. This is primarily mediated by inducing the expression of proinflammatory cytokines, chemokines, and MMPs. As kidney is often affected by dysregulated systemic or organ-specific immunity, in this article, we will only highlight the pathogenic role for IL-17 in autoimmune kidney diseases.
Mouse models of experimental autoimmune glomerulonephritis.
Since the discovery of Th17 cells in 2005, IL-17 has been implicated in many autoinflammatory diseases. Interestingly, the link between IL-17 and renal inflammation was first demonstrated long before the discovery of Th17 cells. Van Kooten et al. (49) showed that IL-17 drives the expression of cytokines and chemokines from tubular epithelial cells under in vitro condition. We demonstrated that IL-17–mediated expression of inflammatory mediators’ from tubular epithelial cells is critical for migration of neutrophils. Similarly, mice deficient in IL-17R signaling showed diminished neutrophil influx, but not monocytes and macrophages, in a mouse model of anti–glomerular basement membrane glomerulonephritis (50). Data from our laboratory and others have shown that both kidney infiltrating CD4+ and γδ+ T cells produce IL-17 in response to kidney injury (43, 50). Indeed, a series of studies involving mouse models of various forms of autoimmune glomerulonephritis have provided evidence for functional importance of IL-17 in disease pathogenesis. For example, studies in mouse models of crescentic glomerulonephritis and nephrotoxic nephritis showed that IL-23/Th17 axis and IL-17 are absolutely required for renal dysfunction and pathogenesis (51, 52). Interestingly, ameliorated renal pathology observed in the IL-23p19−/− and IL-17−/− mice are independent of Th1 response, thus arguing against the longstanding notion that glomerulonephritis is a Th1-mediated disease. IL-17, along with TNF-α (a cytokine with which IL-17 exhibits profound synergy), drives the expression of chemokine signals such CCL20 from renal tubular epithelial cells, required for the infiltration of CCR6+ Th17 and T regulatory cells in the kidney (43). Subsequently, by taking advantage of p40−/− (mice deficient in both IL-12 and IL-23), p35−/− (mice deficient in IL-12 only), and p19−/− (mice deficient in IL-23 only), the relative contribution of IL-12 and IL-23 was interrogated in a mouse model Goodpasture disease. Knockout of IL-23, but not IL-12, led to the diminished proliferation and activation of alpha 3 type IV collagen-specific T and B cells and reduced cytokine and Ab production by immune cells (52). As a result, disease severity was significantly diminished in mice deficient in IL-23 signaling. Using a mouse model of T cell–planted Ag on the glomerular basement membrane, it was shown that both Th1 and Th17 cells can mediate renal injury (53). However, the immunopathological features, time kinetic, and prevalence of certain inflammatory mediators were different in recipient mice receiving either Th1 or Th17 cells. Th17 cells induced the expression of chemokines necessary for neutrophil infiltration and causing early kidney pathology. These results support a report showing that IL-17 promotes early but attenuates established disease in crescentic glomerulonephritis in mice (54). In contrast, Th1 cell recipients showed more of a macrophage dominated renal injury at later time points. Following glomerulonephritis, renal infiltration of Th17 cells peaks at day 10 after glomerular injury, followed by a decline in the number in course of disease. In contrast, Th1 cells and T regulatory cells infiltrate the kidney at later stages. The mechanisms for differential infiltration of various subsets of CD4+ T cells are poorly understood. However, careful analyses of multiple IL-17 reporter mice revealed that Th17 cells are very stable and do not show signs of transdifferentiation to IFN-γ+ or T regulatory cells in the nephritic kidneys (55). Recently, the migration of Th17 cell from the intestine to nephritic kidney has been elegantly demonstrated in a photoconvertible Kaede mice (56), indicating that intestinal microbiome may impact Th17-dominated kidney diseases. Mice deficient in T-bet and consequently in Th1 cells showed diminished nephritis despite enhanced Th17 response, suggesting that Th1 cells are required for Th17 cell–driven nephritis (57). Finally, a crucial role for IL-17 as a mediator of renal tissue damage was also demonstrated in a murine model of antineutrophilic cytoplasmic Ab (ANCA)–associated vasculitis. In this study, IL-17 knockout mice were protected from kidney injury due to impairment of both the innate and the adaptive arms of the immune response (58). Similar to IL-17, other IL-17 family members have been implicated in autoimmune kidney diseases. Mice deficient in IL-17F and IL-17C signaling showed ameliorated renal pathology in mouse model of experimental crescentic and ANCA-associated glomerulonephritis, respectively (59, 60). In two independent studies, polymorphism in the IL-17 pathway genes has been linked to the risk of chronic kidney disease. An association was identified between allele rs4819554 A, part of the IL-17RA promoter, and risk of developing end stage renal disease and increased expression of IL-17RA and Th17 cell frequency (61, 62).
IL-17RA is used by all the IL-17 family members for signaling (4). Although IL-17RA is ubiquitously expressed, the majority of the studies showed that IL-17R signaling is mostly restricted to cells of nonhematopoietic origin. Accordingly, we found that IL-17RA−/− mice were protected from autoimmune glomerulonephritis, as evident by reduced glomerular crescent formation, tubulointerstitial inflammation, and neutrophil influx in the kidney (50). Interestingly, systemic and humoral immunity was not affected in the absence of IL-17R signaling, suggesting that IL-17RA might be a promising therapeutic target with minimal adverse effects (50). In contrast, another study showed that IL-17RA deficiency protected mice from crescent formation but not from glomerular necrosis or renal interstitial injury. Investigation of bone marrow chimeras to identify the IL-17 target cell types in glomerulonephritis revealed similar contributions of IL-17 signaling in hematopoietic and nonhematopoietic cells in the pathogenesis of glomerular pathology (63). However, the role of humoral immunity remains controversial and the exact mechanisms still need to be elucidated.
Lupus nephritis is a severe clinical manifestation of systemic lupus erythematous and affects up to 60% of patients (64). Although experimental evidence suggests a pathogenic role for IL-17 in mouse models of experimental glomerulonephritis, the contribution of IL-17 in lupus nephritis is an active area of debate. IL-17–producing double-negative T cells (CD3+CD4−CD8−) were detected in the nephritic kidneys of MRL/lpr mouse and lupus patients (65, 66). Using MHC class II tetramers, Kattah et al. (67) identified IL-17–producing CD4+ T cells specific for spliceosomal protein U1-70 in MRL/lpr mice. Subsequent studies demonstrated that omission of the IL-23R protected B6/lpr mice from lupus nephritis and that transfer of IL-23–treated lymph node cells from B6/lpr mice induced lupus nephritis in Rag1−/− mice (68). Studies by our group and others have also implicated Th17 cells and IL-17 in the development of proliferative glomerulonephritis in MRL/lpr mice (69, 70). IL-17 cytokines and their signaling via the adaptor protein Act1 contributes to lethal pathology in an FcγR2b-deficient mouse model of lupus nephritis (71). Moreover, studies in autoimmune prone BXD2 mice showed that IL-17 and Th17 cells orchestrate autoreactive germinal center formation and, consequently, lupus-like disease development (72). In the pristine-induced model of lupus nephritis, lack of IL-17A or IL-17F ameliorated disease severity (70, 73). We showed that cross-talk between complement component C5a and Th17 cells is required to inhibit Th17-suppressive type I IFN signals and pathogenesis of pristine-induced lupus nephritis (74–76). However, nagging discrepancies exist against these interpretations. In a recent study, IL-17 deficiency or neutralization of IL-17 demonstrated minimal impact on the development of proliferative glomerulonephritis in MRL/lpr mice or NZB/NZW mice, respectively (77). The frequency of kidney infiltrating IL-17–producing double-negative T cells and CD4+ T cells was scant compared with the number of IFN-γ+ cells, indicating a predominance of the Th1 immune response in these models of lupus nephritis. The reasons for the apparent disagreement between these findings are currently unclear. However, difference in genetic backgrounds and microbiome population may account for the discordance observed between these findings and require careful evaluation in the near future.
Multiple studies showed that patients with lupus exhibit elevated serum levels of IL-17, increased numbers of circulating IL-17–producing T cells, and increased IL-17 production by lymphocytes compared with age- and sex-matched healthy volunteers (65, 78). In some, but not all, cases, IL-17 serum levels correlated with lupus disease activity (78, 79). The number of Th17 cells in the peripheral blood of lupus patients increased during flares and decreased following successful treatment (79). Another study demonstrated that IL-17 plasma levels correlated positively with proteinuria and levels of dsDNA Abs in patients with lupus nephritis, suggesting that IL-17 could serve as a biomarker of disease activity (80). Interestingly, we observed a negative correlation between the frequency of Th17 cells and type I IFN level in a subset of lupus patients (76). IL-17–expressing double-negative T cells were found in kidney biopsy samples of patients with lupus nephritis (65). In sharp contrast, a separate study found no significant association between serum IL-17 levels and nephritis in patients with lupus (81). Thus, the functional role of IL-17 or IL-17–producing innate and adaptive immune cells in renal involvement in lupus patients remains to be fully elucidated.
Patients with IgA nephropathy showed increased serum level of IL-17 in comparison with healthy individuals (82). In vitro stimulation of human mesangial cells with IgA1 has been shown to induce IL-17 production (83). IL-17 might participate in the development of nephropathy by inducing the production and glycosylation of IgA1 in B cells (84). IL-17 can also stimulate the release of cytokines from PBMCs in patients with IgA nephropathy (85). Moreover, imbalance of Treg to Th17 ratio in IgA nephropathy patients has been suggested to play a role in disease pathogenesis and progression (86). With regard to the Th17 response in other human renal inflammatory diseases, such as ANCA-associated glomerulonephritis, Goodpasture syndrome, or acute interstitial nephritis, there are no data available, emphasizing the pressing need for future research efforts in this field.
IL-17 and IL-17–producing cells are vital to a wide range of immunologic functions in the kidney. The generation of IL-17 occurs promptly after the initial insults, which may be either infections or chronic kidney injury. The early IL-17 response shapes the inflammatory milieu and orchestrates many downstream processes in innate as well as adaptive immune responses in the kidney. The net consequence can be promotion or inhibition of local renal immune reactions. What factor dictates which one or the other overcomes remains to be precisely defined in the kidney. IL-17 causes autoimmune diseases but is also implicated in mediating protection against antimicrobial infections. Thus, it is imperative to understand how IL-17, which protects kidney from infections, is rendered harmful in the presence of autoinflammatory conditions. Abs to IL-17 and IL-17RA are currently approved for the treatment of psoriasis (87, 88). Several other clinical trials (∼90 trials) are currently ongoing that target various IL-17 pathway molecules in autoimmune diseases (https://www.clinicaltrials.gov). Therefore, answering these questions is crucial to developing anti–IL-17–based therapies for autoimmune kidney diseases. Because IL-17 is a key determinant of local renal immunity processes, such interventions should be cautiously designed.
We thank Biswas laboratory members for helpful suggestions and discussions.
This work was supported by the Division of Rheumatology and Clinical Immunology, University of Pittsburgh Medical Center, and the National Institutes of Health (Grant DK104680 to P.S.B.).
Abbreviations used in this article:
antineutrophilic cytoplasmic Ab
methicillin-resistant Staphylococcus aureus
TNF receptor–associated factor
uropathogenic E. coli
urinary tract infection.
The authors have no financial conflicts of interest.