Androgen exposure impairs neutrophil maturation and function within the infected kidney.

Urinary tract infections (UTIs) in men are uncommon yet carry an increased risk for severe pyelonephritis and other complications. In models of Escherichia coli UTI, C3H/HeN mice develop high-titer pyelonephritis (most with renal abscesses) in a testosterone-dependent manner, but the mechanisms underlying this phenotype are unknown. Here, using female mouse models, we show that androgen exposure impairs neutrophil maturation in the upper and lower urinary tract, compounded by a reduction of neutrophil function within the infected kidney, enabling persistent high-titer infection and promoting abscess formation. Following intravesical inoculation with uropathogenic E. coli (UPEC), kidneys of androgen-exposed C3H mice showed delayed local pro-inflammatory cytokine responses while robustly recruiting neutrophils. These were enriched for an end-organ-specific population of aged but immature neutrophils (CD49d+, CD101-). Compared to their mature counterparts, these aged immature kidney neutrophils exhibited reduced function in vitro, including impaired degranulation and diminished phagocytic activity, while splenic, bone marrow, and bladder neutrophils did not display these alterations. Furthermore, aged immature neutrophils manifested little phagocytic activity within intratubular UPEC communities in vivo. Experiments with B6 conditional androgen receptor (AR)-deficient mice indicated rescue of the maturation defect when AR was deleted in myeloid cells. We conclude that the recognized enhancement of UTI severity by androgens is attributable, at least in part, to local impairment of neutrophil maturation in the urinary tract (largely via cell-intrinsic AR signaling) and a kidney-specific reduction in neutrophil antimicrobial capacity.IMPORTANCEAlthough urinary tract infections (UTIs) predominantly occur in women, male UTIs carry an increased risk of morbidity and mortality. Pyelonephritis in androgen-exposed mice features robust neutrophil recruitment and abscess formation, while bacterial load remains consistently high. Here, we demonstrate that during UTI, neutrophils infiltrating the urinary tract of androgen-exposed mice exhibit reduced maturation, and those that have infiltrated the kidney have reduced phagocytic and degranulation functions, limiting their ability to effectively control infection. This work helps to elucidate mechanisms by which androgens enhance UTI susceptibility and severity, illuminating why male patients may be predisposed to severe outcomes of pyelonephritis.

Immune defenses in the urinary tract.

Recent advances in preclinical modeling of urinary tract infections (UTIs) have enabled the identification of key facets of the host response that influence pathogen clearance and tissue damage. Here, we review new insights into the functions of neutrophils, macrophages, and antimicrobial peptides in innate control of uropathogens and in mammalian infection-related tissue injury and repair. We also discuss novel functions for renal epithelial cells in innate antimicrobial defense. In addition, epigenetic modifications during bacterial cystitis have been implicated in bladder remodeling, conveying susceptibility to recurrent UTI. In total, contemporary work in this arena has better defined host processes that shape UTI susceptibility and severity and might inform the development of novel preventive and therapeutic approaches for acute and recurrent UTI.

Uncharacterized and lineage-specific accessory genes within the Proteus mirabilis pan-genome landscape.

Proteus mirabilis is a Gram-negative bacterium recognized for its unique swarming motility and urease activity. A previous proteomic report on four strains hypothesized that, unlike other Gram-negative bacteria, P. mirabilis may not exhibit significant intraspecies variation in gene content. However, there has not been a comprehensive analysis of large numbers of P. mirabilis genomes from various sources to support or refute this hypothesis. We performed comparative genomic analysis on 2,060 Proteus genomes. We sequenced the genomes of 893 isolates recovered from clinical specimens from three large US academic medical centers, combined with 1,006 genomes from NCBI Assembly and 161 genomes assembled from Illumina reads in the public domain. We used average nucleotide identity (ANI) to delineate species and subspecies, core genome phylogenetic analysis to identify clusters of highly related P. mirabilis genomes, and pan-genome annotation to identify genes of interest not present in the model P. mirabilis strain HI4320. Within our cohort, Proteus is composed of 10 named species and 5 uncharacterized genomospecies. P. mirabilis can be subdivided into three subspecies; subspecies 1 represented 96.7% (1,822/1,883) of all genomes. The P. mirabilis pan-genome includes 15,399 genes outside of HI4320, and 34.3% (5,282/15,399) of these genes have no putative assigned function. Subspecies 1 is composed of several highly related clonal groups. Prophages and gene clusters encoding putatively extracellular-facing proteins are associated with clonal groups. Uncharacterized genes not present in the model strain P. mirabilis HI4320 but with homology to known virulence-associated operons can be identified within the pan-genome. IMPORTANCE Gram-negative bacteria use a variety of extracellular facing factors to interact with eukaryotic hosts. Due to intraspecies genetic variability, these factors may not be present in the model strain for a given organism, potentially providing incomplete understanding of host-microbial interactions. In contrast to previous reports on P. mirabilis, but similar to other Gram-negative bacteria, P. mirabilis has a mosaic genome with a linkage between phylogenetic position and accessory genome content. P. mirabilis encodes a variety of genes that may impact host-microbe dynamics beyond what is represented in the model strain HI4320. The diverse, whole-genome characterized strain bank from this work can be used in conjunction with reverse genetic and infection models to better understand the impact of accessory genome content on bacterial physiology and pathogenesis of infection.

Serologic responses to COVID-19 vaccination in children with history of multisystem inflammatory syndrome (MIS-C).

Understanding the serological responses to COVID-19 vaccination in children with history of MIS-C could inform vaccination recommendations. We prospectively enrolled seven children hospitalized with MIS-C and measured SARS-CoV-2 binding IgG antibodies to spike protein variants longitudinally pre- and post-Pfizer-BioNTech BNT162b2 primary series COVID-19 vaccination. We found that SARS-CoV-2 variant cross-reactive IgG antibodies variably waned following acute MIS-C, but were significantly boosted with vaccination and maintained for up to 3 months. We then compared post-vaccination binding, pseudovirus neutralizing, and functional antibody-dependent cell-mediated cytotoxicity (ADCC) titers to the reference strain (Wuhan-hu-1) and Omicron variant (B.1.1.529) among previously healthy children (n = 16) and children with history of MIS-C (n = 7) or COVID-19 (n = 8). Despite the breadth of binding antibodies elicited by vaccination in all three groups, pseudovirus neutralizing and ADCC titers were significantly reduced to the Omicron variant.

COVID-19 Vaccine Reactogenicity and Vaccine Attitudes Among Children and Parents/Guardians After Multisystem Inflammatory Syndrome in Children or COVID-19 Hospitalization: September 2021-May 2022.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a multiorgan hyperinflammatory condition following SARS-CoV-2 infection. Data on COVID-19 vaccine adverse events and vaccine attitudes in children with prior MIS-C are limited. We described characteristics associated with COVID-19 vaccination, vaccine adverse events and vaccine attitudes in children with a history of MIS-C or COVID-19 and their parents/guardians. METHODS: We enrolled children previously hospitalized for MIS-C or COVID-19 from 3 academic institutions. We abstracted charts and interviewed children and parents/guardians regarding vaccine adverse events and acceptability. RESULTS: Of 163 vaccine-eligible children enrolled with a history of MIS-C and 70 with history of COVID-19, 51 (31%) and 34 (49%), respectively, received mRNA COVID-19 vaccine a median of 10 (Interquartile Range 6-13) months after hospital discharge. Among 20 children with MIS-C and parents/guardians who provided interviews, local injection site reaction of brief duration (mean 1.8 days) was most commonly reported; no children required medical care within 2 weeks postvaccination. Vaccine survey results of interviewed, vaccinated children and their parents/guardians: of 20 children with MIS-C and 15 children with COVID-19, 17 (85%) and 13 (87%), respectively, listed doctors in the top 3 most trusted sources for vaccine information; 13 (65%) and 9 (60%) discussed vaccination with their doctor. CONCLUSIONS: COVID-19 vaccination was well tolerated in children with prior MIS-C or COVID-19 participating in our investigation. Parents/guardians regarded their children's doctors as a trusted source of information for COVID-19 vaccines, and most vaccinated children's parents/guardians had discussed COVID-19 vaccination for their child with their doctor.

Morphologic design of nanostructures for enhanced antimicrobial activity.

Despite significant progress in synthetic polymer chemistry and in control over tuning the structures and morphologies of nanoparticles, studies on morphologic design of nanomaterials for the purpose of optimizing antimicrobial activity have yielded mixed results. When designing antimicrobial materials, it is important to consider two distinctly different modes and mechanisms of activity-those that involve direct interactions with bacterial cells, and those that promote the entry of nanomaterials into infected host cells to gain access to intracellular pathogens. Antibacterial activity of nanoparticles may involve direct interactions with organisms and/or release of antibacterial cargo, and these activities depend on attractive interactions and contact areas between particles and bacterial or host cell surfaces, local curvature and dynamics of the particles, all of which are functions of nanoparticle shape. Bacteria may exist as spheres, rods, helices, or even in uncommon shapes (e.g., box- and star-shaped) and, furthermore, may transform into other morphologies along their lifespan. For bacteria that invade host cells, multivalent interactions are involved and are dependent upon bacterial size and shape. Therefore, mimicking bacterial shapes has been hypothesized to impact intracellular delivery of antimicrobial nanostructures. Indeed, designing complementarities between the shapes of microorganisms with nanoparticle platforms that are designed for antimicrobial delivery offers interesting new perspectives toward future nanomedicines. Some studies have reported improved antimicrobial activities with spherical shapes compared to non-spherical constructs, whereas other studies have reported higher activity for non-spherical structures (e.g., rod, discoid, cylinder, etc.). The shapes of nano- and microparticles have also been shown to impact their rates and extents of uptake by mammalian cells (macrophages, epithelial cells, and others). However, in most of these studies, nanoparticle morphology was not intentionally designed to mimic specific bacterial shape. Herein, the morphologic designs of nanoparticles that possess antimicrobial activities per se and those designed to deliver antimicrobial agent cargoes are reviewed. Furthermore, hypotheses beyond shape dependence and additional factors that help to explain apparent discrepancies among studies are highlighted.

The impact of biological sex on diseases of the urinary tract.

Biological sex, being female or male, broadly influences diverse immune phenotypes, including immune responses to diseases at mucosal surfaces. Sex hormones, sex chromosomes, sexual dimorphism, and gender differences all contribute to how an organism will respond to diseases of the urinary tract, such as bladder infection or cancer. Although the incidence of urinary tract infection is strongly sex biased, rates of infection change over a lifetime in women and men, suggesting that accompanying changes in the levels of sex hormones may play a role in the response to infection. Bladder cancer is also sex biased in that 75% of newly diagnosed patients are men. Bladder cancer development is shaped by contributions from both sex hormones and sex chromosomes, demonstrating that the influence of sex on disease can be complex. With a better understanding of how sex influences disease and immunity, we can envision sex-specific therapies to better treat diseases of the urinary tract and potentially diseases of other mucosal tissues.

Serologic and Cytokine Signatures in Children With Multisystem Inflammatory Syndrome and Coronavirus Disease 2019.

BACKGROUND: The serologic and cytokine responses of children hospitalized with multisystem inflammatory syndrome (MIS-C) vs coronavirus disease 2019 (COVID-19) are poorly understood. METHODS: We performed a prospective, multicenter, cross-sectional study of hospitalized children who met the Centers for Disease Control and Prevention case definition for MIS-C (n = 118), acute COVID-19 (n = 88), or contemporaneous healthy controls (n = 24). We measured severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike receptor-binding domain (RBD) immunoglobulin G (IgG) titers and cytokine concentrations in patients and performed multivariable analysis to determine cytokine signatures associated with MIS-C. We also measured nucleocapsid IgG and convalescent RBD IgG in subsets of patients. RESULTS: Children with MIS-C had significantly higher SARS-CoV-2 RBD IgG than children with acute COVID-19 (median, 2783 vs 146; P < .001), and titers correlated with nucleocapsid IgG. For patients with MIS-C, RBD IgG titers declined in convalescence (median, 2783 vs 1135; P = .010) in contrast to patients with COVID-19 (median, 146 vs 4795; P < .001). MIS-C was characterized by transient acute proinflammatory hypercytokinemia, including elevated levels of interleukin (IL) 6, IL-10, IL-17A, and interferon gamma (IFN-γ). Elevation of at least 3 of these cytokines was associated with significantly increased prevalence of prolonged hospitalization ≥8 days (prevalence ratio, 3.29 [95% CI, 1.17-9.23]). CONCLUSIONS: MIS-C was associated with high titers of SARS-CoV-2 RBD IgG antibodies and acute hypercytokinemia with IL-6, IL-10, IL-17A, and IFN-γ.

Distinguishing Multisystem Inflammatory Syndrome in Children From COVID-19, Kawasaki Disease and Toxic Shock Syndrome.

BACKGROUND: Distinguishing multisystem inflammatory syndrome in children (MIS-C) from coronavirus disease 2019 (COVID-19), Kawasaki disease (KD), and toxic shock syndrome (TSS) can be challenging. Because clinical management of these conditions can vary, timely and accurate diagnosis is essential. METHODS: Data were collected from patients <21 years of age hospitalized with MIS-C, COVID-19, KD, and TSS in 4 major health care institutions. Patient demographics and clinical and laboratory data were compared among the 4 conditions, and a diagnostic scoring tool was developed to assist in clinical diagnosis. RESULTS: A total of 233 patients with MIS-C, 102 with COVID-19, 101 with KD, and 76 with TSS were included in the analysis. Patients with MIS-C had the highest prevalence of decreased cardiac function (38.6%), myocarditis (34.3%), pericardial effusion (38.2%), mitral regurgitation (31.8%) and pleural effusion (34.8%) compared with patients with the other conditions. Patients with MIS-C had increased peak levels of C-reactive protein and decreased platelets and lymphocyte nadir counts compared with patients with COVID-19 and KD and elevated levels of troponin, brain natriuretic peptide and pro-brain natriuretic peptide compared with COVID-19. Diagnostic scores utilizing clinical findings effectively distinguished MIS-C from COVID-19, KD, and TSS, with internal validation showing area under the curve ranging from 0.87 to 0.97. CONCLUSIONS: Compared with COVID-19, KD, and TSS, patients with MIS-C had significantly higher prevalence of cardiac complications, elevated markers of inflammation and cardiac damage, thrombocytopenia, and lymphopenia. Diagnostic scores can be a useful tool for distinguishing MIS-C from COVID-19, KD, and TSS.

Morphologic Design of Silver-Bearing Sugar-Based Polymer Nanoparticles for Uroepithelial Cell Binding and Antimicrobial Delivery.

Platelet-like and cylindrical nanostructures from sugar-based polymers are designed to mimic the aspect ratio of bacteria and achieve uroepithelial cell binding and internalization, thereby improving their potential for local treatment of recurrent urinary tract infections. Polymer nanostructures, derived from amphiphilic block polymers composed of zwitterionic poly(d-glucose carbonate) and semicrystalline poly(l-lactide) segments, were constructed with morphologies that could be tuned to enhance uroepithelial cell binding. These nanoparticles exhibited negligible cytotoxicity, immunotoxicity, and cytokine adsorption, while also offering substantial silver cation loading capacity, extended release, and in vitro antimicrobial activity (as effective as free silver cations) against uropathogenic Escherichia coli. In comparison to spherical analogues, cylindrical and platelet-like nanostructures engaged in significantly higher association with uroepithelial cells, as measured by flow cytometry; despite their larger size, platelet-like nanostructures maintained the capacity for cell internalization. This work establishes initial evidence of degradable platelet-shaped nanostructures as versatile therapeutic carriers for treatment of epithelial infections.

A host receptor enables type 1 pilus-mediated pathogenesis of Escherichia coli pyelonephritis.

Type 1 pili have long been considered the major virulence factor enabling colonization of the urinary bladder by uropathogenic Escherichia coli (UPEC). The molecular pathogenesis of pyelonephritis is less well characterized, due to previous limitations in preclinical modeling of kidney infection. Here, we demonstrate in a recently developed mouse model that beyond bladder infection, type 1 pili also are critical for establishment of ascending pyelonephritis. Bacterial mutants lacking the type 1 pilus adhesin (FimH) were unable to establish kidney infection in male C3H/HeN mice. We developed an in vitro model of FimH-dependent UPEC binding to renal collecting duct cells, and performed a CRISPR screen in these cells, identifying desmoglein-2 as a primary renal epithelial receptor for FimH. The mannosylated extracellular domain of human DSG2 bound directly to the lectin domain of FimH in vitro, and introduction of a mutation in the FimH mannose-binding pocket abolished binding to DSG2. In infected C3H/HeN mice, type 1-piliated UPEC and Dsg2 were co-localized within collecting ducts, and administration of mannoside FIM1033, a potent small-molecule inhibitor of FimH, significantly attenuated bacterial loads in pyelonephritis. Our results broaden the biological importance of FimH, specify the first renal FimH receptor, and indicate that FimH-targeted therapeutics will also have application in pyelonephritis.

Sex Differences in Population Dynamics during Formation of Kidney Bacterial Communities by Uropathogenic Escherichia coli.

Uropathogenic Escherichia coli (UPEC), the primary etiologic agent of urinary tract infections (UTIs), encounters a restrictive population bottleneck within the female mammalian bladder. Its genetic diversity is restricted during establishment of cystitis because successful UPEC must invade superficial bladder epithelial cells prior to forming clonal intracellular bacterial communities (IBCs). In this study, we aimed to understand UPEC population dynamics during ascending pyelonephritis, namely, formation of kidney bacterial communities (KBCs) in the renal tubular lumen and nucleation of renal abscesses. We inoculated the bladders of both male and female C3H/HeN mice, a background which features vesicoureteral reflux; we have previously shown that in this model, males develop severe, high-titer pyelonephritis and renal abscesses much more frequently than females. Mice were infected with 40 isogenic, PCR-tagged ("barcoded") UPEC strains, and tags remaining in bladder and kidneys were ascertained at intervals following infection. In contrast to females, males maintained a majority of strains within both the bladder and kidneys throughout the course of infection, indicating only a modest host-imposed bottleneck on overall population diversity during successful renal infection. Moreover, the diverse population in the infected male kidneys obscured any restrictive bottleneck in the male bladder. Finally, using RNA in situ hybridization following mixed infections with isogenic UPEC bearing distinct markers, we found that despite their extracellular location (in the urinary space), KBCs are clonal in origin. This finding indicates that even with bulk reflux of infected bladder urine into the renal pelvis, successful ascension of UPEC to establish the tubular niche is an uncommon event.

Sex effects in pyelonephritis.

Urinary tract infections (UTIs) are generally considered a disease of women. However, UTIs affect females throughout the lifespan, and certain male populations (including infants and elderly men) are also susceptible. Epidemiologically, pyelonephritis is more common in women but carries increased morbidity when it does occur in men. Among children, high-grade vesicoureteral reflux is a primary risk factor for upper-tract UTI in both sexes. However, among young infants with UTI, girls are outnumbered by boys; risk factors include posterior urethral valves and lack of circumcision. Recent advances in mouse models of UTI reveal sex differences in innate responses to UTI, which vary somewhat depending on the system used. Moreover, male mice and androgenized female mice suffer worse outcomes in experimental pyelonephritis; evidence suggests that androgen exposure may suppress innate control of infection in the urinary tract, but additional androgen effects, as well as non-hormonal sex effects, may yet be specified. Among other intriguing directions, recent experiments raise the hypothesis that the postnatal testosterone surge that occurs in male infants may represent an additional factor driving the higher incidence of UTI in males under 6 months of age. Ongoing work in contemporary models will further illuminate sex- and sex-hormone-specific effects on UTI pathogenesis and immune responses.

HOME2 Study: Household Versus Personalized Decolonization in Households of Children With Methicillin-Resistant Staphylococcus aureus Skin and Soft Tissue Infection-A Randomized Clinical Trial.

BACKGROUND: A household approach to decolonization decreases skin and soft tissue infection (SSTI) incidence, though this is burdensome and costly. As prior SSTI increases risk for SSTI, we hypothesized that the effectiveness of decolonization measures to prevent SSTI when targeted to household members with prior year SSTI would be noninferior to decolonizing all household members. METHODS: Upon completion of our 12-month observational Household Observation of Methicillin-resistant Staphylococcus aureus in the Environment (HOME) study, 102 households were enrolled in HOME2, a 12-month, randomized noninferiority trial. Pediatric index patients with community-associated methicillin-resistant Staphylococcus aureus (MRSA) SSTI, their household contacts, and pets were enrolled. Households were randomized 1:1 to the personalized (decolonization performed only by household members who experienced SSTI during the HOME study) or household (decolonization performed by all household members) approaches. The 5-day regimen included hygiene education, twice-daily intranasal mupirocin, and daily bleach-water baths. At 5 follow-up visits in participants' homes, swabs to detect S. aureus were collected from participants, environmental surfaces, and pets; incident SSTIs were ascertained. RESULTS: Noninferiority of the personalized approach was established for the primary outcome 3-month cumulative SSTI: 23 of 212 (10.8%) participants reported SSTI in household approach households, while 23 of 236 (9.7%) participants reported SSTI in personalized approach households (difference in proportions, -1.1% [95% confidence interval, -6.7% to 4.5%]). In multivariable analyses, prior year SSTI and baseline MRSA colonization were associated with cumulative SSTI. CONCLUSIONS: The personalized approach was noninferior to the household approach in preventing SSTI. Future studies should interrogate longer durations of decolonization and/or decontamination of the household environment to reduce household MRSA burden. CLINICAL TRIALS REGISTRATION: NCT01814371.

Androgen-Influenced Polarization of Activin A-Producing Macrophages Accompanies Post-pyelonephritic Renal Scarring.

Ascending bacterial pyelonephritis, a form of urinary tract infection (UTI) that can result in hospitalization, sepsis, and other complications, occurs in ~250,000 US patients annually; uropathogenic Escherichia coli (UPEC) cause a large majority of these infections. Although UTIs are primarily a disease of women, acute pyelonephritis in males is associated with increased mortality and morbidity, including renal scarring, and end-stage renal disease. Preclinical models of UTI have only recently allowed investigation of sex and sex-hormone effects on pathogenesis. We previously demonstrated that renal scarring after experimental UPEC pyelonephritis is augmented by androgen exposure; testosterone exposure increases both the severity of pyelonephritis and the degree of renal scarring in both male and female mice. Activin A is an important driver of scarring in non-infectious renal injury, as well as a mediator of macrophage polarization. In this work, we investigated how androgen exposure influences immune cell recruitment to the UPEC-infected kidney and how cell-specific activin A production affects post-pyelonephritic scar formation. Compared with vehicle-treated females, androgenized mice exhibited reduced bacterial clearance from the kidney, despite robust myeloid cell recruitment that continued to increase as infection progressed. Infected kidneys from androgenized mice harbored more alternatively activated (M2) macrophages than vehicle-treated mice, reflecting an earlier shift from a pro-inflammatory (M1) phenotype. Androgen exposure also led to a sharp increase in activin A-producing myeloid cells in the infected kidney, as well as decreased levels of follistatin (which normally antagonizes activin action). As a result, infection in androgenized mice featured prolonged polarization of macrophages toward a pro-fibrotic M2a phenotype, accompanied by an increase in M2a-associated cytokines. These data indicate that androgen enhancement of UTI severity and resulting scar formation is related to augmented local activin A production and corresponding promotion of M2a macrophage polarization.

Incidence and treatment of hemophagocytic lymphohistiocytosis in hospitalized children with Ehrlichia infection.

We report a large cohort of pediatric patients with human monocytic ehrlichiosis (HME), enabling an estimated incidence of secondary hemophagocytic lymphohistiocytosis (HLH) in hospitalized children with HME. Among 49 children with PCR-confirmed Ehrlichia infection, 8 (16%) met current criteria for HLH. Those with HLH had more significant hematologic abnormalities and longer durations from symptom onset to admission and definitive anti-infective therapy. Among these eight, three received chemotherapy plus doxycycline, one of whom died; the other five were treated with doxycycline without chemotherapy, and all survived without HLH recurrence. Our findings demonstrate that antimicrobial therapy alone can successfully resolve Ehrlichia-associated HLH.

Environmental Methicillin-resistant Staphylococcus aureus Contamination, Persistent Colonization, and Subsequent Skin and Soft Tissue Infection.

Importance: The longitudinal association among persistent Staphylococcus aureus colonization, household environmental contamination, and recurrent skin and soft tissue infection (SSTI) is largely unexplored to date. Objectives: To identify factors associated with persistent S aureus colonization and recurrent SSTI in households with children with community-associated methicillin-resistant S aureus (MRSA) SSTI. Design, Setting, and Participants: This 12-month prospective cohort study included 150 children with community-associated MRSA SSTI, 542 household contacts, and 154 pets enrolled from January 3, 2012, through October 20, 2015. A total of 5 quarterly home visits were made to 150 households in the St Louis, Missouri, region. Statistical analysis was performed from September 18, 2018, to January 7, 2020. Exposures: Covariates used in S aureus strain persistence and interval SSTI models included S aureus colonization and contamination measures, personal hygiene and sharing habits, health history, activities external to the home, and household characteristics (eg, cleanliness, crowding, home ownership, and pets). Serial samples to detect S aureus were collected from household members at 3 anatomic sites, from pets at 2 anatomic sites, and from environmental surfaces at 21 sites. Main Outcomes and Measures: Molecular epidemiologic findings of S aureus isolates were assessed via repetitive-sequence polymerase chain reaction. Individual persistent colonization was defined as colonization by an identical strain for 2 consecutive samplings. Longitudinal, multivariable generalized mixed-effects logistic regression models were used to assess factors associated with persistent S aureus personal colonization, environmental contamination, and interval SSTI. Results: Among 692 household members in 150 households, 326 (47%) were male and 366 (53%) were female, with a median age of 14.82 years (range, 0.05-82.25 years). Of 540 participants completing all 5 samplings, 213 (39%) were persistently colonized with S aureus, most often in the nares and with the strain infecting the index patient at enrollment. Nine pets (8%) were persistently colonized with S aureus. Participants reporting interval intranasal mupirocin application were less likely to experience persistent colonization (odds ratio [OR], 0.44; 95% credible interval [CrI], 0.30-0.66), whereas increasing strain-specific environmental contamination pressure was associated with increased individual persistent colonization (OR, 1.17; 95% CrI, 1.06-1.30). Strains with higher colonization pressure (OR, 1.47; 95% CrI, 1.25-1.71) and MRSA strains (OR, 1.57; 95% CrI, 1.16-2.19) were more likely to persist. Seventy-six index patients (53%) and 101 household contacts (19%) reported interval SSTIs. Individuals persistently colonized with MRSA (OR, 1.56; 95% CrI, 1.17-2.11), those with a history of SSTI (OR, 2.55; 95% CrI, 1.88-3.47), and index patients (OR, 1.54; 95% CrI, 1.07-2.23) were more likely to report an interval SSTI. Conclusions and Relevance: The study findings suggest that recurrent SSTI is associated with persistent MRSA colonization of household members and contamination of environmental surfaces. Future studies may elucidate the effectiveness of specific combinations of personal decolonization and environmental decontamination efforts in eradicating persistent strains and mitigating recurrent SSTIs.