Haemolysin Ahh1 secreted from Aeromonas dhakensis activates the NLRP3 inflammasome in macrophages and mediates severe soft tissue infection.

Severe soft tissue infections caused by Aeromonas dhakensis, such as necrotizing fasciitis or cellulitis, are prevalent in southern Taiwan and around the world. However, the mechanism by which A. dhakensis causes tissue damage remains unclear. Here, we found that the haemolysin Ahh1, which is the major virulence factor of A. dhakensis, causes cellular damage and activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome signalling pathway. Deletion of ahh1 significantly downregulated caspase-1, the proinflammatory cytokine interleukin 1ß (IL-1ß) and gasdermin D (GSDMD) and further decreased the damage caused by A. dhakensis in THP-1 cells. In addition, we found that knockdown of the NLRP3 inflammasome confers resistance to A. dhakensis infection in both THP-1 NLRP3-/- cells and C57BL/6 NLRP3-/- mice. In addition, we demonstrated that severe soft-tissue infections treated with antibiotics combined with a neutralizing antibody targeting IL-1ß significantly increased the survival rate and alleviated the degree of tissue damage in model mice compared control mice. These findings show that antibiotics combined with therapies targeting IL-1ß are potential strategies to treat severe tissue infections caused by toxin-producing bacteria.

Are Vitamin D Levels Associated With Risk of Deep Neck Infection?

Deep neck infection (DNI) refers to infections in spaces created by superficial and deep cervical fascia around the muscles and organs in the neck. Vitamin D is highly important for an effective immune system. Vitamin D receptors (VDR) have been identified in immune system cells, and particularly in T and B lymphocytes, macrophages, and dendritic cells. Vitamin D deficiency is thought to result in impaired immune response, decreased leukocyte chemotaxis, and an increased disposition to infection. The purpose of this study was to investigate whether vitamin D deficiency is an underlying occult factor in the development of DNI. Sixty-five patients aged 6 to 90, diagnosed with DNI, and 70 healthy age- and sex-compatible cases were included in the study. Serum levels of calcium, phosphorus, parathyroid hormone, and 25-hydroxy vitamin D (25(OH)D) were determined in each case. 25-hydroxy vitamin D levels above 20 ng/mL were regarded as normal, 12 to 20 ng/mL as insufficient, 5 to 12 ng/mL as deficient, and less than 5 ng/mL as severely deficient. Mean serum 25(OH)D levels were 10.4 (6.2) ng/mL in the patient group and 15.5 (6.4) ng/mL in the control group (P < .01). This difference was statistically significant (P < .01). Vitamin D was within normal limits in 9.2% (n = 6) of cases in the study group, insufficient in 29.2% (n = 19), deficient in 35.3% (n = 23), and severely deficient in 26.2% (n = 17). The equivalent values in the control group were 21.4% (n = 15), 48.5% (n = 34), 30% (n = 21), and 0% (n = 0). Serum 25(OH)D levels were significantly lower in patients with DNI compared to the healthy cases; 25(OH)D levels may be a factor in the development of DNI.

Skin and Soft Tissue Infections in Non-Human Immunodeficiency Virus Immunocompromised Hosts.

Skin and soft tissue infections among the non-human immunodeficiency virus infected immunosuppressed population are a serious and growing concern. Many pathogens can cause cutaneous infections in these patients owing to the highly varied and profound immune deficits. Although patients can be infected by typical organisms, the diversity and antimicrobial-resistant nature of the organisms causing these infections result in significant morbidity and mortality. The diagnostic approach to these infections in immunocompromised hosts can differ dramatically depending on the potential causative organisms. An understanding of new immunosuppressive treatments and evolving antimicrobial resistance patterns are required to optimally manage these difficult cases.

Infections and diabetes: Risks and mitigation with reference to India.

BACKGROUND AND AIMS: The link between diabetes and increased risk of infectious disease has long been recognized, but has re-entered sharp focus following the COVID-19 pandemic. METHODS: A literature search was conducted in PubMed for articles in English on diabetes and infection. RESULTS: Diabetes predisposes to infections through alterations in innate and acquired immune defenses. Outcomes of infection are worse in people with uncontrolled diabetes, and infection can worsen hyperglycemia in hitherto well controlled diabetes (bidirectional relationship). Diabetes does not increase the risk of infection with COVID-19 per se, but predisposes to severe disease and poor outcomes. COVID-19 has also been linked to deterioration of glycemic control as well as new-onset diabetes. CONCLUSIONS: Clinicians caring for people with diabetes should be aware of the increased risk of infections in this population, as well as the possibility of worsening hyperglycemia. A holistic approach with frequent monitoring of blood glucose levels and appropriate titration of medications, along with close attention to nutritional status, is essential to ensure the best possible outcomes.

Complement Activation Is Associated With Mortality in Patients With Necrotizing Soft-Tissue Infections-A Prospective Observational Study.

Aim: We assessed whether different complement factors and complement activation products were associated with poor outcome in patients with necrotizing soft-tissue infection (NSTI). Methods: We conducted a prospective, observational study in an intensive care unit where treatment of NSTI is centralized at a national level. In 135 NSTI patients and 65 control patients, admission levels of MASP-1, MASP-2, MASP-3, C4, C3, complement activation products C4c, C3bc, and terminal complement complex (TCC) were assessed. Results: The 90-day mortality was 23%. In a Cox regression model adjusted for sex, and SAPS II, a higher than median MASP-1 (HR 0.378, CI 95% [0.164-0.872], p = 0.0226) and C4 (HR 0.162, 95% CI [0.060-0.438], p = 0.0003), C4c/C4 ratio (HR 2.290 95% CI [1.078-4.867], p = 0.0312), C3bc (HR 2.664 95% CI [1.195-5.938], p = 0.0166), and C3bc/C3 ratio (HR 4.041 95% CI [1.673-9.758], p = 0.0019) were associated with 90-day mortality, while MASP-2, C4c, C3, and TCC were not. C4 had the highest ROC-AUC (0.748, [95% CI 0.649-0.847]), which was comparable to the AUC for SOFA score (0.753, [95% CI 0.649-0.857]), and SAPS II (0.862 [95% CI 0.795-0.929]). Conclusion: In adjusted analyses, high admission levels of the C4c/C4 ratio, C3bc, and the C3bc/C3 ratio were significantly associated with a higher risk of death after 90 days while high admission levels of MASP-1 and C4 were associated with lower risk. In this cohort, these variables are better predictors of mortality in NSTI than C-reactive protein and Procalcitonin. C4's ability to predict mortality was comparable to the well-established scoring systems SAPS score II and SOFA on day 1.

A 72-Year-Old Man With a Violaceous Rash and Sepsis.

CASE PRESENTATION: A 72-year-old man presented to our ED less than 24 hours following the acute onset of nausea, vomiting, and diarrhea. Within 12 hours of symptom onset, he noted bilateral lower extremity pain and swelling. His pain was associated with a new violaceous irregular rash on the anterior aspect of both feet and legs. There was no history of inciting trauma or recent wounds. In addition, there was no history of consumption of raw or undercooked food (including seafood) or recent change in food source. There was accompanying fever and chills for the same duration and painful swelling of his left thumb. His comorbidities included stage IIIb classical Hodgkin lymphoma diagnosed 4 months prior. His last dose of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy was 4 days before presentation. He had previously failed anti-CD30 monoclonal therapy resulting from attributed pancolitis.

Periocular necrotizing soft tissue infection in Greater Copenhagen.

PURPOSE: Necrotizing soft tissue infection, also known as necrotizing fasciitis (NF), is a fast-spreading life-threatening infection that most commonly affects the lower limbs, groin, or abdomen. Periocular necrotizing fasciitis (PNF) is rare. Limited data exist on PNF immune cell subset; hence, this study aims to determine the representation of immune cell subsets in patients diagnosed with PNF using immunohistochemical stainings. METHODS: All patients diagnosed with PNF at Copenhagen University Hospital from 2008 to 2018 were included. Their electronic medical records and pathology reports were assessed, and available tissue specimens were reviewed and stained with monoclonal antibodies for CD1a+ Langerhans' cells, CD3+ T lymphocytes, CD15+ granulocytes, CD44+ lymphohematopoietic cells, CD68+ histiocytes, CD79α+ B lymphocytes, and FXIIIa+ dendritic macrophages and Langerhans' cells. The number of positive cells was counted, and an average score was calculated. The location of immune cells and bacteria was assessed. RESULTS: The specimens were characterized by acute inflammation and necrosis of the fascia, while striated muscle involvement was less frequent. Haemolytic group A streptococci and Staphylococcus aureus were identified and mainly located in the deep dermis and subcutis in close relation to the fascia. Only few areas harboured both bacteria and inflammatory cells. Granulocytes, histiocytes and CD44+ lymphohematopoietic cells were demonstrated to be abundant in all patients, while B and T lymphocytes, dendritic macrophages and Langerhans' cells were less frequent. CONCLUSION: The immune cell subsets found in this study of PNF were consistent with those identified in the literature on NF in other anatomical locations. This study concludes that immune cells are abundant and exhibit a typical pattern in PNF.

Laboratory diagnostics, phylogenetic analysis and clinical outcome of a subcutaneous Mycoleptodiscus indicus infection in an immunocompetent cat.

BACKGROUND: Mycoleptodiscus indicus is a dematiaceous hyphomycete fungus found on plant leaves. It has been rarely reported as a cause of human or animal disease, possibly because it is difficult to culture and identify from clinical specimens. Infections are presumably acquired by traumatic implantation. CASE PRESENTATION: An 8-year-old non-immunosuppressed cat from Georgia, USA, presented with a left front leg swelling without lameness. Cytology from a fine needle aspirate revealed pyogranulomatous inflammation with both cytoplasmic and extracellular fungal elements. There were septate hyphae with irregularly sized segments, non-staining uneven walls, and rounded yeast-like forms from which longer hyphae arose in a hub-and-spoke pattern. A mold was isolated on agar from a fine needle aspirate collected 1 week later and identified as M. indicus by morphology, DNA sequencing and phylogenetic analysis. The cat recovered completely and uneventfully with antifungal treatment. CONCLUSIONS: We report a previously undescribed presentation of M. indicus causing a subcutaneous infection in a cat with successful antifungal treatment. In this study we highlight the potential of M. indicus to infect immunocompetent animals, and the veterinary medical community should be aware of its unusual but characteristic clinical, microbiological and cytologic presentation.

The good side of inflammation: Staphylococcus aureus proteins SpA and Sbi contribute to proper abscess formation and wound healing during skin and soft tissue infections.

Staphylococcus aureus is the most prominent cause of skin and soft tissue infections (SSTI) worldwide. Mortality associated with invasive SSTI is a major threat to public health considering the incidence of antibiotic resistant isolates in particular methicillin resistant S. aureus both in the hospital (HA-MRSA) and in the community (CA-MRSA). To overcome the increasing difficulties in the clinical management of SSTI due to MRSA, new prophylactic and therapeutic approaches are urgently needed and a preventive vaccine would be welcome. The rational design of an anti-S. aureus vaccine requires a deep knowledge of the role that the different bacterial virulence factors play according to the type of infection. In the present study, using a set of isogenic deficient mutants and their complemented strains we determined that the staphylococcal surface proteins SpA and Sbi play an important role in the induction of inflammatory cytokines and chemokines in the skin during SSTI. SpA and Sbi initiate signaling cascades that lead to the early recruitment of neutrophils, modulate their lifespan in the skin milieu and contribute to proper abscess formation and bacterial eradication. Moreover, the expression of SpA and Sbi appear critical for skin repair and wound healing. Thus, these results indicate that SpA and Sbi can promote immune responses in the skin that are beneficial for the host and therefore, should not be neutralized with vaccine formulations designed to prevent SSTI.

Skin and Soft Tissue Infections Caused by Mycobacterium chelonae: More Common Than Expected?

Mycobacterium chelonae is a rapidly growing non-tuberculous mycobacterium, which causes infections of the human skin and soft tissue. Despite an increasing incidence of such infections, patients are often misdiagnosed. We report here 5 patients with cutaneous and/or soft tissue infection due to M. chelonae who were diagnosed and treated at our centre. Two of the 5 patients were on immunosuppressive treatment. While clinical presentations differed in each patient, all had a long history of skin lesions. In addition to careful history-taking, tissue biopsies were obtained for mycobacterial culture and histopathological examination. Culture-directed antibiotic therapy was initiated, which resulted in a slow, but continuous, healing of the lesions. In summary, M. chelonae infections are still relatively rare, but should be considered in both immunocompromised and immunocompetent patients with prolonged skin lesions resistant to standard antibiotic treatment. For diagnosis, tissue analysis for mycobacterial culture and histopathological examination, and once diagnosed, adequate antibiotic treatment, is needed.

Retrospective Identification of a Broad IgG Repertoire Differentiating Patients With S. aureus Skin and Soft Tissue Infections From Controls.

Background: Although the relevance of humoral immunity for protection against S. aureus skin and soft tissue infections (SSTIs) has been suggested by several animal and human studies, the question of which human antibodies may be protective has so far impeded the development of a safe and effective vaccine. Because most adults have developed certain anti-S. aureus antibodies due to S. aureus colonization or infection, we hypothesized that the titers of antibodies to S. aureus in uninfected controls would differ from those in infected patients and would also differ in infected patients from the time of acute infection to a 40-day convalescent serum. Methods: To test these hypotheses, we measured human antibody levels against a panel of 134 unique antigens comprising the S. aureus surfome and secretome in subjects with active culture-confirmed S. aureus SSTIs (cases) and in controls with no infection, using a novel S. aureus protein microarray. Results: Most S. aureus SSTI patients (n = 60) and controls (n = 142) had antibodies to many of the tested S. aureus antigens. Univariate analysis showed statistically weak differences in the IgG levels to some antigens in the SSTI patient (case) sera compared with controls. Antibody levels to most tested antigens did not increase comparing acute with 40-day serum. Multiple logistic regression identified a rich subset of antigens that, by their antibody levels, together correctly differentiated all cases from all controls. Conclusions: Antibodies directed against S. aureus antigens were present both in patients with S. aureus SSTIs and in uninfected control patients. We found that SSTI patients and controls could be distinguished only based on differences in antibody levels to many staphylococcal surface and secreted antigens. Our results demonstrate that in the studied population, the levels of anti-S. aureus antibodies appear largely fixed, suggesting that there may be some level of unresponsiveness to natural infection.

Protection against Staphylococcus aureus Colonization and Infection by B- and T-Cell-Mediated Mechanisms.

Staphylococcus aureus is a major cause of morbidity and mortality worldwide. S. aureus colonizes 20 to 80% of humans at any one time and causes a variety of illnesses. Strains that are resistant to common antibiotics further complicate management. S. aureus vaccine development has been unsuccessful so far, largely due to the incomplete understanding of the mechanisms of protection against this pathogen. Here, we studied the role of different aspects of adaptive immunity induced by an S. aureus vaccine in protection against S. aureus bacteremia, dermonecrosis, skin abscess, and gastrointestinal (GI) colonization. We show that, depending on the challenge model, the contributions of vaccine-induced S. aureus-specific antibody and Th1 and Th17 responses to protection are different: antibodies play a major role in reducing mortality during S. aureus bacteremia, whereas Th1 or Th17 responses are essential for prevention of S. aureus skin abscesses and the clearance of bacteria from the GI tract. Both antibody- and T-cell-mediated mechanisms contribute to prevention of S. aureus dermonecrosis. Engagement of all three immune pathways results in the most robust protection under each pathological condition. Therefore, our results suggest that eliciting multipronged humoral and cellular responses to S. aureus antigens may be critical to achieve effective and comprehensive immune defense against this pathogen.IMPORTANCES. aureus is a leading cause of healthcare- and community-associated bacterial infections. S. aureus causes various illnesses, including bacteremia, meningitis, endocarditis, pneumonia, osteomyelitis, sepsis, and skin and soft tissue infections. S. aureus colonizes between 20 and 80% of humans; carriers are at increased risk for infection and transmission to others. The spread of multidrug-resistant strains limits antibiotic treatment options. Vaccine development against S. aureus has been unsuccessful to date, likely due to an inadequate understanding about the mechanisms of immune defense against this pathogen. The significance of our work is in illustrating the necessity of generating multipronged B-cell, Th1-, and Th17-mediated responses to S. aureus antigens in conferring enhanced and broad protection against S. aureus invasive infection, skin and soft tissue infection, and mucosal colonization. Our work thus, provides important insights for future vaccine development against this pathogen.

Heterogeneity in FoxP3- and GARP/LAP-Expressing T Regulatory Cells in an HLA Class II Transgenic Murine Model of Necrotizing Soft Tissue Infections by Group A Streptococcus.

Invasive group A streptococcus (GAS) infections include necrotizing soft tissue infections (NSTI) and streptococcal toxic shock syndrome (STSS). We have previously shown that host HLA class II allelic variations determine the risk for necrotizing fasciitis (NF), a dominant subgroup of NSTI, and STSS by modulating responses to GAS superantigens (SAgs). SAgs are pivotal mediators of uncontrolled T-cell activation, triggering a proinflammatory cytokine storm in the host. FoxP3-expressing CD4+ CD25+ T regulatory cells (Tregs) comprise phenotypically and functionally heterogeneous subsets with a profound ability to suppress inflammatory responses. Specifically, activated Tregs, which express glycoprotein A repetitions predominant (GARP) and display latent transforming growth factor ß1 (TGF-ß1) complexes (latency-associated peptide [LAP]), exhibit strong immunosuppressive functions. The significance of Tregs that may participate in suppressing inflammatory responses during NSTI is unknown. Here, we phenotypically characterized FoxP3/GARP/LAP-expressing Tregs in GAS-infected or SAg (SmeZ)-stimulated splenocytes from transgenic (tg) mice expressing human HLA-II DRB1*15 (DR15 allele associated with nonsevere NF/STSS-protective responses) or DRB1*0402/DQB1*0302 (DR4/DQ8 alleles associated with neutral risk for combined NF/STSS). We demonstrated both in vivo and in vitro that the neutral-risk allele upregulates expression of CD4+ CD25+ activated effector T cells, with a significantly lower frequency of Foxp3+/GARP+ LAP- but higher frequency of Foxp3- LAP+ Tregs than seen with the protective allele. Additional in vitro studies revealed that the presentation of SmeZ by the neutral-risk allele significantly increases proliferation and expression of effector cytokines gamma interferon (IFN-γ) and interleukin-2 (IL-2) and upregulates CD4+ CD25+ T cell receptors (TCRs) carrying specific Vß 11 chain (TCRVß11+) T cells and Th1 transcription factor Tbx21 mRNA levels. Our data suggest that neutral-risk alleles may drive Th1 differentiation while attenuating the induction of Tregs associated with suppressive function.

Hierarchy of human IgG recognition within the Staphylococcus aureus immunome.

Staphylococcus aureus is an opportunistic pathogen that causes a range of serious infections associated with significant morbidity, by strains increasingly resistant to antibiotics. However, to date all candidate vaccines have failed to induce protective immune responses in humans. We need a more comprehensive understanding of the antigenic targets important in the context of human infection. To investigate infection-associated immune responses, patients were sampled at initial presentation and during convalescence from three types of clinical infection; skin and soft tissue infection (SSTI), prosthetic joint infection (PJI) and pediatric hematogenous osteomyelitis (PHO). Reactivity of serum IgG was tested with an array of recombinant proteins, representing over 2,652 in-vitro-translated open reading frames (ORFs) from a community-acquired methicillin-resistant S. aureus USA300 strain. High-level reactivity was demonstrated for 104 proteins with serum IgG in all patient samples. Overall, high-level IgG-reactivity was most commonly directed against a subset of secreted proteins. Although based on limited surveys, we found subsets of S. aureus proteins with differential reactivity with serum samples from patients with different clinical syndromes. Together, our studies have revealed a hierarchy within the diverse proteins of the S. aureus "immunome", which will help to advance efforts to develop protective immunotherapeutic agents.

Coagulase-Negative Staphylococcus Skin and Soft Tissue Infections.

Coagulase-negative staphylococcus organisms may be normal flora of human skin, however these bacteria can also be pathogens in skin and soft tissue infections. A summary of skin and soft tissue infections caused by coagulase-negative staphylococcus species is provided in this review. We conducted a search of the PubMed database using the following terms: abscess, auricularis, biofilm, capitis, cellulitis, coagulase, contaminant, cyst, draining, epidermidis, felon, folliculitis, furuncle, haemolyticus, hominis, indolent, infection, lugdunensis, mecA, microbiome, negative, osteomyelitis, paronychia, saprophyticus, skin, simulans, sinus, soft, staphylococcus, systemic, tissue, virulence, virulent, and vulvar. The relevant papers, and their references, generated by the search were reviewed. Skin and soft tissue infections have been observed to be caused by many coagulase-negative staphylococcus organisms: Staphylococcus auricularis, Staphylococcus capitis, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus lugdunensis, Staphylococcus saprophyticus, and Staphylococcus simulans. Coagulase-negative staphylococcus skin infections predominantly present as abscesses and paronychia. They are most common in elderly patients or those individuals who are immunosuppressed, and tend to be broadly susceptible to antibiotic treatment. In conclusion, albeit less common, coagulase-negative staphylococcus organisms can result in skin and soft tissue infections, particularly in older and/or immunocompromised individuals. A review of the literature found that coagulase-negative staphylococcus organisms are most commonly grown in cultures of abscesses and paronychia. Therefore, coagulase-negative staphylococcal organisms should not always be considered as contaminants or normal flora, but rather as causative pathogens. They are usually susceptible to antibiotics used to treat methicillin-sensitive Staphylococcus aureus.

Human Memory B Cells Targeting Staphylococcus aureus Exotoxins Are Prevalent with Skin and Soft Tissue Infection.

Staphylococcus aureus is a Gram-positive opportunistic pathogen that causes superficial and invasive infections in the hospital and community. High mortality from infection emphasizes the need for improved methods for prevention and treatment. Although S. aureus possesses an arsenal of virulence factors that contribute to evasion of host defenses, few studies have examined long-term humoral and B-cell responses. Adults with acute-phase skin and soft tissue infections were recruited; blood samples were obtained; and S. aureus isolates, including methicillin-resistant strains, were subjected to genomic sequence analysis. In comparisons of acute-phase sera with convalescent-phase sera, a minority (37.5%) of patients displayed 2-fold or greater increases in antibody titers against three or more S. aureus antigens, whereas nearly half exhibited no changes, despite the presence of toxin genes in most infecting strains. Moreover, enhanced antibody responses waned over time, which could reflect a defect in B-cell memory or long-lived plasma cells. However, memory B cells reactive with a range of S. aureus antigens were prevalent at both acute-phase and convalescent-phase time points. While some memory B cells exhibited toxin-specific binding, those cross-reactive with structurally related leucocidin subunits were dominant across patients, suggesting the targeting of conserved epitopes. Memory B-cell reactivity correlated with serum antibody levels for selected S. aureus exotoxins, suggesting a relationship between the cellular and humoral compartments. Overall, although there was no global defect in the representation of anti-S. aureus memory B cells, there was evidence of restrictions in the range of epitopes recognized, which may suggest potential therapeutic approaches for augmenting host defenses.IMPORTANCE The contribution of B-cell memory and long-term antibody responses to host defenses against S. aureus exotoxins remains poorly understood. Our studies confirmed that infection did not commonly lead to enhanced long-term humoral responses. Whereas circulating memory B cells against S. aureus secreted exotoxins were prevalent, they were dominated by cross-reactivity with structurally related leucocidin subunits, consistent with recognition of conserved epitopes. These findings also provide the first evidence of a relationship between the reactivity of antistaphylococcal circulating memory B cells and serum antibody levels. In general, infection was not associated with a global defect in B-cell memory for S. aureus secreted factors, and responses were highly dominated by cross-reactivity to structurally related exotoxins, which arguably may alone be suboptimal in providing host defenses. Our studies illuminate aspects of the S. aureus-host relationship that may better inform strategies for the development of an effective protective vaccine.

Comparison of the immune response during acute and chronic Staphylococcus aureus infection.

Staphylococcus aureus bacteria are able to grow in a planktonic state that is associated with acute infections and in biofilms that are associated with chronic infections. Acute infections, such as skin infections, are often self-limiting. However, chronic infections, such as implant infections, can be difficult to clear and may require surgical intervention. The host immune response may contribute to the different outcomes often associated with these two disease types. We used proteomic arrays and two murine models for an initial, descriptive characterization of the contribution of the host immune response to outcomes of acute versus chronic S. aureus disease. We compared the immune responses between a model of self-limiting skin and soft tissue infection caused by the planktonic form of S. aureus versus a model of surgical mesh implant infection, which we show to be caused by a bacterial biofilm. The significantly altered host cytokines and chemokines were largely different in the two models, with responses diminished by 21 days post-implantation in surgical mesh infection. Because bacterial levels remained constant during the 21 days that the surgical mesh infection was followed, those cytokines that are significantly increased during chronic infection are not likely effective in eradicating biofilm. Comparison of the levels of cytokines and chemokines in acute versus chronic S. aureus infection can provide a starting point for evaluation of the role of specific immune factors that are present in one disease manifestation but not the other.

Protein SIC Secreted from Streptococcus pyogenes Forms Complexes with Extracellular Histones That Boost Cytokine Production.

Innate immunity relies on an effective recognition of the pathogenic microorganism as well as on endogenous danger signals. While bacteria in concert with their secreted virulence factors can cause a number of inflammatory reactions, danger signals released at the site of infection may in addition determine the amplitude of such responses and influence the outcome of the disease. Here, we report that protein SIC, Streptococcal Inhibitor of Complement, an abundant secreted protein from Streptococcus pyogenes, binds to extracellular histones, a group of danger signals released during necrotizing tissue damage. This interaction leads to the formation of large aggregates in vitro. Extracellular histones and SIC are abundantly expressed and seen colocalized in biopsies from patients with necrotizing soft-tissue infections caused by S. pyogenes. In addition, binding of SIC to histones neutralized their antimicrobial activity. Likewise, the ability of histones to induce hemolysis was inhibited in the presence of SIC. However, when added to whole blood, SIC was not able to block the pro-inflammatory effect of histones. Instead SIC boosted the histone-triggered release of a broad range of cytokines and chemokines, including IL-6, TNF-α, IL-8, IL-1ß, IL-1ra, G-CSF, and IFN-γ. These results demonstrate that the interaction between SIC and histones has multiple effects on the host response to S. pyogenes infection.

Prolonged Allograft Survival in a Patient With Chronic Immunosuppression: A Case Report and Systematic Review.

A 41-year-old man with past medical history of kidney-liver transplantation requiring chronic immunosuppression presented 2 years posttransplant with a necrotizing soft tissue infection of his right thigh. Serial debridement to remove necrotic tissue was performed, and a Matrix HD Allograft Fenestrated (RTI Surgical, Alachua, FL) was applied. At 5-months post grafting, the patient demonstrated fully vascularized and intact skin. Under normal circumstances, a cadaveric allograft sloughs over several weeks and is not usually considered a permanent solution for wound closure. A systematic review of transplant patients on chronic immunosuppression with skin allografts demonstrates the potential for the indefinite survival of an allograft. Necrotizing soft tissue infections can definitively be treated using serial debridement and allograft transplantation in the chronically immunosuppressed.

Effect of underlying immune compromise on the manifestations and outcomes of group A streptococcal bacteremia.

BACKGROUND: Group A streptococcal bloodstream infection is the most common presentation of invasive group A streptococcal disease. We sought to determine the impact of immunosuppression on severity of disease and clinical outcomes. METHODS: This retrospective review of 148 patients with at least one positive blood culture for Streptococcus pyogenes from 1/2003 to 3/2013 compared immunocompromised patients with those with no immunocompromise in regards to development of severe complications and mortality. RESULTS: Twenty-five patients (17%) were immunocompromised; 123 were not. Skin and soft tissue infection occurred in 60% of immunocompromised vs. 38% of non-immunocompromised patients, p = .04. Necrotizing fasciitis and septic shock were significantly more common in immunocompromised patients, p < .0001 and .028, respectively. Mortality at 30 days was 32% in immunocompromised patients vs. 16% in non-immunocompromised patients, p = .05. CONCLUSION: Patients who are immunocompromised are more likely to develop necrotizing fasciitis and septic shock as complications of group A streptococcal bacteremia and have a higher mortality rate than patients who are not immunocompromised.