PURPOSEFUL GAS-INDUCED RESORPTION OF SUBMACULAR FLUID IN MACULA-OFF RETINAL DETACHMENTS (PERSIMMON STUDY).

PURPOSE: To examine the visual outcomes in patients with macula-off rhegmatogenous retinal detachments with intentional submacular fluid retention after pars plana vitrectomy (PPV) or PPV/scleral buckle surgery (PPV/SB). METHODS: Patients with macula-off retinal detachments were included if they had a PPV or PPV/SB without drainage retinotomy or perfluorocarbon liquid to flatten the retina. RESULTS: The mean age of the patients was 65.0 years. The mean presenting vision was 20.0 Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Six months after repair, the vision improved to 62.9; 75.4% of patients had 20/40 or better at best achieved visual acuity. Pseudophakic eyes had better vision compared with phakic eyes ( P = 0.049). Patients younger than 80 years had better best achieved vision ( P = 0.0118) compared with patients 80 years or older. Patients with initial vision better than or equal to 20/100 had better best achieved vision ( P = 0.016) compared with those with initial vision worse than 20/100. CONCLUSION: Leaving submacular fluid after macula-off retinal detachments surgery was not detrimental for visual outcomes or anatomic success for retinal detachments repair and may lead to better visual outcomes for patients, specifically for those patients younger than 80 years, who are pseudophakic, and have presenting vision 20/100 or better.

Diflunisal and Analogue Pharmacophores Mediating Suppression of Virulence Phenotypes in Staphylococcus aureus.

Invasive methicillin-resistant Staphylococcus aureus (MRSA) infections are leading causes of morbidity and mortality that are complicated by increasing resistance to conventional antibiotics. Thus, minimizing virulence and enhancing antibiotic efficacy against MRSA is a public health imperative. We originally demonstrated that diflunisal (DIF; [2-hydroxy-5-(2,4-difluorophenyl) benzoic acid]) inhibits S. aureus virulence factor expression. To investigate pharmacophores that are active in this function, we evaluated a library of structural analogues for their efficacy to modulate virulence phenotypes in a panel of clinically relevant S. aureus isolates in vitro. Overall, the positions of the phenyl, hydroxyl, and carboxylic moieties and the presence or type of halogen (F vs. Cl) influenced the efficacy of compounds in suppressing hemolysis, proteolysis, and biofilm virulence phenotypes. Analogues lacking halogens inhibited proteolysis to an extent similar to DIF but were ineffective at reducing hemolysis or biofilm production. In contrast, most analogues lacking the hydroxyl or carboxylic acid groups did not suppress proteolysis but did mitigate hemolysis and biofilm production to an extent similar to DIF. Interestingly, chirality and the substitution of fluorine with chlorine resulted in a differential reduction in virulence phenotypes. Together, this pattern of data suggests virulence-suppressing pharmacophores of DIF and structural analogues integrate halogen, hydroxyl, and carboxylic acid moiety stereochemistry. The anti-virulence effects of DIF were achieved using concentrations that are safe in humans, do not impair platelet antimicrobial functions, do not affect S. aureus growth, and do not alter the efficacy of conventional antibiotics. These results offer proof of concept for using novel anti-virulence strategies as adjuvants to antibiotic therapy to address the challenge of MRSA infection.

Diflunisal Attenuates Virulence Factor Gene Regulation and Phenotypes in Staphylococcus aureus.

Virulence factor expression is integral to pathogenicity of Staphylococcus aureus. We previously demonstrated that aspirin, through its major metabolite, salicylic acid (SAL), modulates S. aureus virulence phenotypes in vitro and in vivo. We compared salicylate metabolites and a structural analogue for their ability to modulate S. aureus virulence factor expression and phenotypes: (i) acetylsalicylic acid (ASA, aspirin); (ii) ASA metabolites, salicylic acid (SAL), gentisic acid (GTA) and salicyluric acid (SUA); or (iii) diflunisal (DIF), a SAL structural analogue. None of these compounds altered the growth rate of any strain tested. ASA and its metabolites SAL, GTA and SUA moderately impaired hemolysis and proteolysis phenotypes in multiple S. aureus strain backgrounds and their respective deletion mutants. Only DIF significantly inhibited these virulence phenotypes in all strains. The kinetic profiles of ASA, SAL or DIF on expression of hla (alpha hemolysin), sspA (V8 protease) and their regulators (sigB, sarA, agr (RNAIII)) were assessed in two prototypic strain backgrounds: SH1000 (methicillin-sensitive S. aureus; MSSA) and LAC-USA300 (methicillin-resistant S. aureus; MRSA). DIF induced sigB expression which is coincident with the significant inhibition of RNAIII expression in both strains and precedes significant reductions in hla and sspA expression. The inhibited expression of these genes within 2 h resulted in the durable suppression of hemolysis and proteolysis phenotypes. These results indicate that DIF modulates the expression of key virulence factors in S. aureus via a coordinated impact on their relevant regulons and target effector genes. This strategy may hold opportunities to develop novel antivirulence strategies to address the ongoing challenge of antibiotic-resistant S. aureus.

PATTERNS OF SUBRETINAL AND/OR INTRARETINAL FLUID RECURRENCE IN PATIENTS WHO RECEIVED AS-NEEDED RANIBIZUMAB THERAPY IN THE HARBOR TRIAL.

PURPOSE: To evaluate subretinal fluid (SRF) and/or intraretinal fluid recurrence in patients with neovascular age-related macular degeneration who received as-needed (PRN) ranibizumab in a HARBOR (NCT00891735) post hoc analysis. METHODS: Analyses included patients with SRF and/or intraretinal fluid at baseline and fluid recurrence after a ≥3-month absence (N = 222). Baseline fluid location(s) were compared with location of recurrence after a ≥3-month absence. RESULTS: At baseline, fluid was equally distributed across all locations. On recurrence, the location was most frequently central (69%). Eyes with central fluid at baseline typically had recurrence in the same location (72% vs. 47%-53% with fluid in other locations). The type of recurrent fluid was typically the same as at baseline (SRF, 64%; intraretinal fluid, 75%). Overall, 37% (39/105) of eyes exhibited fluid recurrence in a new location, most frequently central (53%). There was a significant gain in best-corrected visual acuity (mean [95% confidence interval], +2.2 [0.4-4.0] letters) between the months of SRF resolution and recurrence. CONCLUSION: Although the location of SRF and/or intraretinal fluid was equally distributed at baseline, recurrent fluid was typically centrally located. The authors identified a subgroup of eyes exhibiting fluid recurrence in a different location than at baseline, potentially indicating new choroidal neovascularization.

Long term results of patients with neovascular age-related macular degeneration switched from other anti-VEGF agents to intravitreal Aflibercept.

BACKGROUND: This study explores the long term anatomic and functional results of patients who were switched to intravitreal aflibercept injections (IAI) after being initially managed with other anti-VEGF agents for neovascular age-related macular degeneration (nAMD). METHODS: Patients with nAMD were included if they started with another anti-VEGF agent and were switched to IAI. Subjects had at least 3 years of consistent therapy with IAI and at least 1 injection quarterly. RESULTS: Eighty-eight patients had at least 3 years of treatment while 58 of those patients, had at least 4 years of IAI. Average treatment time with other anti-VEGF agents was 32 months prior to switching. Baseline best corrected vision (VA) was 59.4 letters (20/70 + 2). At time of switch, VA increased significantly to 66.7 letters (20/50 + 2). At 3 months after switch, VA increased significantly to 69.0 (20/40-) letters. After 3 years of consistent IAI, vision was 67.5 letters (20/40-2), and for those patients that completed 4 years of therapy, the average VA was 66.0 letters (20/50 + 2), with a gain of 6.6 letters over baseline vision. 32.1% of patients gained 3 or more lines of vision. Initial central macular thickness (CMT) was 369 µm, which improved to 347 µm at time of switch, and further improved at 3 months to 301 µm and was maintained over time. CONCLUSION: Patients switched to IAI can maintain vision over the long term. Patients treated on average for 5.7 years, had a visual gain of 8.1 letters after 3 years and 6.6 letters after 4 years of IAI therapy. CMT significantly improved following the switch and was maintained.

Results of patients with neovascular age-related macular degeneration managed by a treat-extend-stop protocol without recurrence.

PURPOSE: To assess vision, injection quantity, initial lesion size, and final anatomic status in patients with nAMD completing the treat-extend-stop (TES) protocol. METHODS: Patients with nAMD received ≥ 3 monthly anti-VEGF injections followed by 1-2 week injection interval extensions, with intra/subretinal fluid resolution on SD-OCT, to 12 weeks. With quiescent disease, and 2 quarterly injections, patients were monitored alone beginning at 4 weeks extending by 1-2 week intervals until quarterly monitoring. RESULTS: Eighty-eight of 143 eyes with nAMD completed the TES protocol without disease recurrence. Sixteen (18.2%) developed sub-foveal geographic atrophy (GA), 25 (28.4%) developed fibrovascular scarring (FV) and 47 (53.4%) developed regressed choroidal neovascularization (rCNV) with 16.9 ± 13.3 average injections between the 3 groups which was not statistically significant. Average treatment time was 30.3 ± 26.1 months and subsequent follow-up was 23.2 ± 19.8 months. Average lesion size for FV was 18.77 ± 10.8mm2 vs. GA at 12.00 ± 9.99mm2 vs. regressed CNV at 7.12 ± 6.5mm2 (p < 0.05). Pre, post, and final vision for GA was 39.6 letters (20/160) vs. 32.7 letters (20/200 + 2, p = 0.4725) vs. 25.0 letters (20/320, p = 0.0865); FV was 22.4 letters (20/400 + 2) vs. 11.6 letters (20/640, p = 0.0351) vs. 11.0 letters (20/640 + 1, p = 0.0226), and rCNV was 56.4 letters (20/80 + 1) vs. 69.5 letters (20/40, p < 0.001) vs. 67.3 letters (20/40-2, p = 0.0016). In the rCNV group, 17/46 eyes gained ≥ 3 lines and 30/46 eyes achieved ≥ 20/40 vision. Non-central GA expanded 0.226 ± 0.126 mm vs. 0.225 ± 0.098 mm during and after treatment completion over 24 months (p = 0.99). CONCLUSIONS: Central GA or FV portends worse visual outcomes vs. rCNV after cessation of therapy. Anti-VEGF therapy may not affect the rate of GA expansion. Final anatomic character and location are key determinants of final vision.

Central Serous Chorioretinopathy in Elderly Patients Mimicking Occult Neovascular Age-Related Macular Degeneration.

PURPOSE: To describe elderly patients with central serous chorioretinopathy (CSCR) mimicking occult neovascular age-related macular degeneration (nAMD). MATERIALS AND METHODS: The records of 522 patients with initial diagnoses of nAMD over one year were reviewed to determine characteristics meeting diagnostic criteria for CSCR with three or more months of follow-up. Patients were evaluated by clinical examination, fluorescein angiography (FA) and optical coherence tomography (OCT). At the time of initial evaluation, patients were either monitored, treated with anti-VEGF therapy or with combination anti-VEGF and photodynamic therapy (PDT). When no response to anti-vascular endothelial growth factor (anti-VEGF) treatment was observed, the diagnosis of CSCR was favored and patients were observed with close follow-up. The Student's t-test was used for statistical analysis; a p-value < 0.05 was considered statistically significant. RESULTS: Eleven elderly patients met diagnostic criteria for CSCR among 522 patients initially diagnosed with nAMD. Average age was 75.9 years, and average follow-up was 16.9 months. Average presenting visual acuity was 20/50+2 (67.9 ± 5.9 ETDRS letters), and choroidal thickness was 232.0 ± 69.4 µm. After observation or treatment, the average vision improved to 20/40+ (70.5 ± 7.8 ETDRS letters, p=0.289). When intravitreal bevacizumab was given, no changes were observed for patients' neurosensory retinal detachments (NSRD). When NSRD changes were observed, they likewise did not correlate to the timing of anti-VEGF treatment. For patients who were monitored alone, one patient lost one line of vision, one gained one line, one gained two lines, and one gained three lines. One patient subsequently developed a choroidal neovascular membrane (CNVM) during initial follow-up with visual improvement after anti-VEGF treatment. Four patients developed CNVM overall with long term follow-up. CONCLUSION: CSCR in elderly patients can mimic occult CNVM, especially on FA. In this group, many patients were monitored without treatment, which typically resulted in stable or improved vision. Careful monitoring is required because of possible development of CNVM.

Purtscher-like retinopathy following total knee arthroplasty: A report of 2 cases.

PURPOSE: To describe two cases of Purtscher-like retinopathy after total knee arthroplasty. OBSERVATIONS: Two patients were referred for blurred vision after knee surgery. They received a complete vision examination including slit lamp exam, dilated fundus exam, fluorescein angiogram and optical coherence tomography. Two patients developed Purtscher-like retinopathy after knee surgery. The first was a 58-year-old male who underwent bilateral total knee arthroplasty. The second patient developed an infected joint and subsequently received a total knee arthroplasty revision surgery. Both patients experienced decreased vision and were found to have characteristic findings of Purtscher-like retinopathy including vessel attenuation, cotton wool spots and nerve fiber layer infarcts following their respective operations in the absence of other injury. CONCLUSIONS AND IMPORTANCE: Purtscher-like retinopathy can occur immediately following total knee arthroplasty. Factors including fatty acid liberation, endothelial damage, aberrant coagulation cascade activation, leukocyte aggregation, embolic vascular occlusion and microinfarction likely contributed to these findings. When patients undergo knee arthroplasty and complain of visual scotomas, the diagnosis of Purtscher-like retinopathy should be considered with careful ophthalmic examination and work-up.

Rapid displacement of subretinal hemorrhage from a choroidal neovascular membrane with intravitreal C3F8 gas and face-down positioning.

PURPOSE: To describe a case of rapid displacement of subretinal hemorrhage (SRH) from a choroidal neovascular membrane (CNV) with intravitreal injection of C3F8 gas. OBSERVATIONS: A 66-year-old patient presented in clinic with count fingers (CF) vision from a fibrovascular scar in the right eye (OD) and 20/30 vision in the left eye (OS) with butterfly dystrophy. His left eye developed a CNV and was managed with monthly intravitreal anti-VEGF agents for 29 months. Five days after a ranibizumab treatment, the patient developed a moderate subfoveal hemorrhage. The vision decreased from 20/30 to 20/50. He elected to monitor the disease process. Eleven days later the vision decreased to 20/200, and he consented to intravitreal injection of 0.3 cc of 100% C3F8 with face-down positioning. The patient received an anterior chamber paracentesis to manage the intraocular pressure. The patient had near complete displacement of subretinal hemorrhage and fluid in less than 2 hours. He then had repeat OCT and fundus photos to document the rapid displacement. His vision returned to 20/30-2 twelve days later, at which point the subretinal fluid and blood had been completely displaced from the macula. CONCLUSIONS AND IMPORTANCE: The patient had rapid displacement of subretinal hemorrhage and fluid with intravitreal C3F8. New blood filling the space of pre-existing neurosensory fluid from the active CNV likely enhanced displacement. Timely intervention before stable clot formation was helpful for ease of displacement of the subretinal hemorrhage.

Consistent Long-Term Therapy of Neovascular Age-Related Macular Degeneration Managed by 50 or More Anti-VEGF Injections Using a Treat-Extend-Stop Protocol.

PURPOSE: To examine the clinical results for patients with neovascular age-related macular degeneration (nAMD) who were managed with a treat-extend-stop (TES) protocol and received 50 or more injections of anti-vascular endothelial growth factor (VEGF) agents. DESIGN: Retrospective case study. PARTICIPANTS: Data for patients from a private retina practice meeting the following criteria were included: diagnosis of nAMD and having received 50 or more intravitreal injections of anti-VEGF agents. METHODS: The patients' baseline visual acuity (VA; obtained using Snellen charts and converted to Early Treatment Diabetic Retinopathy Study [ETDRS] letters), age, length of follow-up, anti-VEGF agents used, and interval between treatments were obtained. These data were examined through the 51st injection and at the last follow-up examination. Patients were excluded if they lost significant vision because of a diagnosis unrelated to AMD during therapy. MAIN OUTCOME MEASURES: Visual acuity and complications. RESULTS: Seventy-one eyes of 67 patients were identified who met inclusion criteria. The mean age of patients was 83.0 years. Women made up 58.2% of the study population, whereas men constituted 41.8%. The mean initial VA was 55.6 ETDRS letters. The mean duration of follow-up at the 51st visit for an injection was 6.5 years, and the mean duration of follow-up at the last visit was 8 years. The mean number of injections at final follow-up was 63.7. The mean interval between treatments at the 51st follow-up was 5.4 weeks, and the mean follow-up at the last examination was 6.4 weeks. Mean VA at the 51st injection was 65.3 letters, and the mean change from baseline was 9.7 letters (P < 0.001, Student paired t test). The mean vision gained at last follow-up was 8.7 letters from baseline (P < 0.001), or 64.3 letters. CONCLUSIONS: In this study, patients gained a mean of 2 ETDRS lines after 50 injections. This study had a mean follow-up of 8 years, and 35.2% of eyes had a 3-line or more gain in VA at the last follow-up examination. Patients who require consistent long-term anti-VEGF therapy, managed with a TES protocol, are likely able to maintain or improve their vision.

Recurrence Rate of Choroidal Neovascularization in Neovascular Age-Related Macular Degeneration Managed with a Treat-Extend-Stop Protocol.

PURPOSE: To examine visual outcomes and recurrence rates in patients with choroidal neovascularization (CNV) resulting from neovascular age-related macular degeneration (nAMD) with successful cessation of therapy using a treat-extend-stop (TES) protocol. DESIGN: Cohort study. PARTICIPANTS: Three hundred eighty-five eyes of 321 patients with nAMD identified in clinical practice and treated with a TES protocol between 2008 and 2016. METHODS: Retrospective review of patients initially managed with 3 anti-vascular endothelial growth factor (VEGF) injections at 4-week intervals; treatment was extended if the macula remained "dry" based on spectral-domain OCT, using a TES protocol. Treatment was stopped if warranted and was reinitiated if there was a new or recurrent CNV. MAIN OUTCOME MEASURES: Percentage of eyes meeting criteria for treatment cessation and percentage experiencing recurrence after treatment cessation, average time to recurrence, and visual function at each of these time points, including recovery of vision after reinstitution of therapy. RESULTS: A total of 37.3% of eyes met criteria for treatment cessation, with an average follow-up of 27 months. Overall recurrence rate was 29.4% at a mean time interval of 14 months for patients who stopped anti-VEGF therapy. In those patients whose CNV recurred, 54.8% recurred in the first year and 26.2% recurred in the second year after treatment was stopped. Average initial vision was 20/70 and improved to 20/50 (P < 0.001) after patients met criteria for cessation of therapy. A mean loss of vision occurred with recurrence (20/60; P < 0.003). However, once therapy was reinitiated, visual acuity recovered to the level at TES completion and wasn't statistically different than at final treatment (20/50; P < 0.34). Overall, 54.8% of eyes that demonstrated a recurrence of CNV had final vision of 20/40 or better compared with 45% of patients at the time of recurrence and 60% before recurrence. CONCLUSIONS: After completing the TES protocol, 29.4% of patients showed recurrence of CNV. Patients who lost vision with recurrence recovered to the level of vision at treatment cessation with reinstitution of therapy. Patients managed with a TES protocol may stop therapy successfully and maintain improved vision even if the CNV recurs.

Bevacizumab (Avastin) and Thermal Laser Combination Therapy for Peripapillary Choroidal Neovascular Membranes.

Objective. This is a retrospective interventional case series describing the results of 5 eyes from 5 patients with symptomatic peripapillary choroidal neovascularization (CNVM) receiving initial bevacizumab treatment followed by thermal laser and bevacizumab combination therapy. Methods. Patients received intravitreal bevacizumab injections until the lesions were well-defined. Thermal laser ablation was then administered and followed by an additional bevacizumab injection after one week. Visual outcomes, OCT changes, and rates of recurrence were recorded and analyzed. Results. Median visual outcomes improved from 20/50 to 20/30 (p = 0.0232). Median central macular thickness decreased from 347 µm to 152 µm (p = 0.0253). The mean visual improvement was 3 lines. An average of 3.8 bevacizumab injections per patient were given overall. Patients were followed for an average of 24 months, during which all eyes were absent for recurrence. Conclusion. Symptomatic peripapillary CNVM may be successfully managed with bevacizumab followed by a combination of thermal laser and bevacizumab without the need for frequent retreatment. The area requiring treatment may be better defined using bevacizumab, limiting the ablation of the healthy retina and improving treatment margins. With this treatment regimen, the patients experience improved visual outcomes and have a low rate of recurrence.

Innate Immune Memory Contributes to Host Defense against Recurrent Skin and Skin Structure Infections Caused by Methicillin-Resistant Staphylococcus aureus.

Staphylococcus aureus is the leading cause of skin and skin structure infections (SSSI). The high frequency of recurring SSSI due to S. aureus, including methicillin-resistant S. aureus (MRSA) strains, despite high titers of specific antibodies and circulating T cells, implies that traditional adaptive immunity imparts incomplete protection. We hypothesized that innate immune memory contributes to the protective host defense against recurring MRSA infection. To test this hypothesis, SSSI was induced in wild-type and rag1-/- mice in the BALB/c and C57BL/6 backgrounds. Prior infection (priming) of wild-type and rag1-/- mice of either background afforded protection against repeat infection, as evidenced by reduced abscess severities and decreased CFU densities compared to those in naive controls. Interestingly, protection was greater on the previously infected flank than on the naive flank for wild-type and rag1-/- mice. For wild-type mice, protective efficacy corresponded to increased infiltration of neutrophils (polymorphonuclear leukocytes [PMN]), macrophages (MΦ), Langerin+ dendritic cells (LDC), and natural killer (NK) cells. Protection was associated with the induction of interleukin-17A (IL-17A), IL-22, and gamma interferon (IFN-γ) as well as the antimicrobial peptides CRAMP and mßD-3. Priming also protected rag1-/- mice against recurring SSSI, with increased MΦ and LDC infiltration and induction of IL-22, CRAMP, and mßD-3. These findings suggest that innate immune memory, mediated by specific cellular and molecular programs, likely contributes to the localized host defense in recurrent MRSA SSSI. These insights support the development of targeted immunotherapeutic strategies to address the challenge of MRSA infection.

The GraS Sensor in Staphylococcus aureus Mediates Resistance to Host Defense Peptides Differing in Mechanisms of Action.

Staphylococcus aureus uses the two-component regulatory system GraRS to sense and respond to host defense peptides (HDPs). However, the mechanistic impact of GraS or its extracellular sensing loop (EL) on HDP resistance is essentially unexplored. Strains with null mutations in the GraS holoprotein (ΔgraS) or its EL (ΔEL) were compared for mechanisms of resistance to HDPs of relevant immune sources: neutrophil α-defensin (human neutrophil peptide 1 [hNP-1]), cutaneous ß-defensin (human ß-defensin 2 [hBD-2]), or the platelet kinocidin congener RP-1. Actions studied by flow cytometry included energetics (ENR); membrane permeabilization (PRM); annexin V binding (ANX), and cell death protease activation (CDP). Assay conditions simulated bloodstream (pH 7.5) or phagolysosomal (pH 5.5) pH contexts. S. aureus strains were more susceptible to HDPs at pH 7.5 than at pH 5.5, and each HDP exerted a distinct effect signature. The impacts of ΔgraS and ΔΕL on HDP resistance were peptide and pH dependent. Both mutants exhibited defects in ANX response to hNP-1 or hBD-2 at pH 7.5, but only hNP-1 did so at pH 5.5. Both mutants exhibited hyper-PRM, -ANX, and -CDP responses to RP-1 at both pHs and hypo-ENR at pH 5.5. The actions correlated with ΔgraS or ΔΕL hypersusceptibility to hNP-1 or RP-1 (but not hBD-2) at pH 7.5 and to all study HDPs at pH 5.5. An exogenous EL mimic protected mutant strains from hNP-1 and hBD-2 but not RP-1, indicating that GraS and its EL play nonredundant roles in S. aureus survival responses to specific HDPs. These findings suggest that GraS mediates specific resistance countermeasures to HDPs in immune contexts that are highly relevant to S. aureus pathogenesis in humans.

Nonredundant Roles of Interleukin-17A (IL-17A) and IL-22 in Murine Host Defense against Cutaneous and Hematogenous Infection Due to Methicillin-Resistant Staphylococcus aureus.

Staphylococcus aureus is the leading cause of skin and skin structure infections (SSSI) in humans. Moreover, the high frequency of recurring SSSI due to S. aureus, particularly methicillin-resistant S. aureus (MRSA) strains, suggests that infection induces suboptimal anamnestic defenses. The present study addresses the hypothesis that interleukin-17A (IL-17A) and IL-22 play distinct roles in immunity to cutaneous and invasive MRSA infection in a mouse model of SSSI. Mice were treated with specific neutralizing antibodies against IL-17A and/or IL-22 and infected with MRSA, after which the severity of infection and host immune response were determined. Neutralization of either IL-17A or IL-22 reduced T cell and neutrophil infiltration and host defense peptide elaboration in lesions. These events corresponded with increased abscess severity, MRSA viability, and CFU density in skin. Interestingly, combined inhibition of IL-17A and IL-22 did not worsen abscesses but did increase gamma interferon (IFN-γ) expression at these sites. The inhibition of IL-22 led to a reduction in IL-17A expression, but not vice versa. These results suggest that the expression of IL-17A is at least partially dependent on IL-22 in this model. Inhibition of IL-17A but not IL-22 led to hematogenous dissemination to kidneys, which correlated with decreased T cell infiltration in renal tissue. Collectively, these findings indicate that IL-17A and IL-22 have complementary but nonredundant roles in host defense against cutaneous versus hematogenous infection. These insights may support targeted immune enhancement or other novel approaches to address the challenge of MRSA infection.

Mechanisms of NDV-3 vaccine efficacy in MRSA skin versus invasive infection.

Increasing rates of life-threatening infections and decreasing susceptibility to antibiotics urge development of an effective vaccine targeting Staphylococcus aureus. This study evaluated the efficacy and immunologic mechanisms of a vaccine containing a recombinant glycoprotein antigen (NDV-3) in mouse skin and skin structure infection (SSSI) due to methicillin-resistant S. aureus (MRSA). Compared with adjuvant alone, NDV-3 reduced abscess progression, severity, and MRSA density in skin, as well as hematogenous dissemination to kidney. NDV-3 induced increases in CD3+ T-cell and neutrophil infiltration and IL-17A, IL-22, and host defense peptide expression in local settings of SSSI abscesses. Vaccine induction of IL-22 was necessary for protective mitigation of cutaneous infection. By comparison, protection against hematogenous dissemination required the induction of IL-17A and IL-22 by NDV-3. These findings demonstrate that NDV-3 protective efficacy against MRSA in SSSI involves a robust and complementary response integrating innate and adaptive immune mechanisms. These results support further evaluation of the NDV-3 vaccine to address disease due to S. aureus in humans.