Streptococcal protein SIC activates monocytes and induces inflammation

Neumann, Ariane; Happonen, Lotta; Karlsson, Christofer; Bahnan, Wael; Frick, Inga Maria; Björck, Lars

doi:10.1016/j.isci.2021.102339

Cited by 7 publications

(6 citation statements)

References 66 publications

(74 reference statements)

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“…Monocytes and dendritic cells were increased in the blood of participants who developed pharyngitis. Activation of monocytes to induce proinflammatory responses occurs following binding of TLR2 to the Streptococcal Inhibitor of Complement (SIC) protein secreted by S. pyogenes which may explain the elevated intermediate monocyte frequency 30 . In addition, the elevation of monocytes and dendritic cells was associated with increased levels of IL-1Ra, IL-18 and IP-10, produced in response to infection [31][32][33] .…”

Section: Discussionmentioning

confidence: 99%

Immune signature of acute pharyngitis in a Streptococcus pyogenes human challenge trial

et al. 2022

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Streptococcus pyogenes causes at least 750 million infections and more than 500,000 deaths each year. No vaccine is currently available for S. pyogenes and the use of human challenge models offer unique and exciting opportunities to interrogate the immune response to infectious diseases. Here, we use high-dimensional flow cytometric analysis and multiplex cytokine and chemokine assays to study serial blood and saliva samples collected during the early immune response in human participants following challenge with S. pyogenes. We find an immune signature of experimental human pharyngitis characterised by: 1) elevation of serum IL-1Ra, IL-6, IFN-γ, IP-10 and IL-18; 2) increases in peripheral blood innate dendritic cell and monocyte populations; 3) reduced circulation of B cells and CD4+ T cell subsets (Th1, Th17, Treg, TFH) during the acute phase; and 4) activation of unconventional T cell subsets, γδTCR + Vδ2+ T cells and MAIT cells. These findings demonstrate that S. pyogenes infection generates a robust early immune response, which may be important for host protection. Together, these data will help advance research to establish correlates of immune protection and focus the evaluation of vaccines.

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Section: Discussionmentioning

confidence: 99%

Immune signature of acute pharyngitis in a Streptococcus pyogenes human challenge trial

et al. 2022

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“…CEF might also have additional yet undiscovered binding partners apart from complement proteins similar to SIC which also inhibits the antibacterial activity of a wide range of antimicrobial peptides and proteins, including lysozyme, LL-37 and human beta-defensins [ 52 ]. SIC also interacts with both human thrombin and plasminogen to inhibit fibrinolysis [ 53 ] and with Toll-like receptor 2 (TLR-2) and CD14 on monocytes to induce pro-inflammatory cytokines [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

Complement evasion factor (CEF), a novel immune evasion factor of Streptococcus pyogenes

et al. 2022

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Streptococcus pyogenes , a leading human pathogen, is responsible for a wide range of diseases, including skin and soft tissue infections and severe invasive diseases. S. pyogenes produces a large arsenal of virulence factors, including several immune evasion factors. We have identified an open reading frame ( spy0136 ) in the S. pyogenes SF370 genome encoding a protein of unknown function. Using recombinant Spy0136 in a pull-down assay with human plasma and ELISA, we have identified four complement proteins (C1r, C1s, C3, and C5) as binding partners. Treatment of the complement proteins with PNGase F abrogated binding to C1s, C3, and C5, indicating glycan-dependent interactions. rSpy0136 inhibited complement-mediated hemolysis and interfered with all three complement pathways in a Wieslab complement assay. Furthermore, rSpy0136 inhibited deposition of the C3b opsonin and the membrane attack complex (MAC) on the surface of S. pyogenes . We therefore named the previously unknown protein ‘complement evasion factor’ (CEF). An S. pyogenes Δspy0136/cef deletion mutant showed decreased virulence in an in-vitro whole blood killing assay and a Galleria mellonella (wax moth) infection model. Furthermore, an L. lactis spy0136/cef gain-of-function mutant showed increased survival during growth in whole human blood. Analysis of serum samples from patients with invasive S. pyogenes revealed Spy0136/CEF sero-conversion indicating expression during disease. In summary, we have identified a novel S. pyogenes immune evasion factor that binds to several complement proteins to interfere with complement function. This is the first example of a S. pyogenes virulence factor binding to several different target proteins via glycan-dependent interactions.

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“…Sic has several different mechanisms of actions, interference with complement and other host defences, and has been proposed to play a significant role in streptococcal infections [ 57 ]. It was recently shown that the Sic protein from M1 S. pyogenes , a type over-represented among severe invasive cases of NSTI [ 20 ], interacts with TLR2 resulting in release of pro-inflammatory cytokines [ 58 ]. A study by Kachroo et al [ 59 ] revealed a positive correlation between sic and genes involved in the host immune response and inflammation when they examined the dual RNA-seq transcriptomes of S. pyogenes and host skeletal muscle from infected non-human primates.…”

Section: Discussionmentioning

confidence: 99%

Analysis of host-pathogen gene association networks reveals patient-specific response to streptococcal and polymicrobial necrotising soft tissue infections

Jahagirdar

Morris

Benis

et al. 2022

BMC Med

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Abstract Background Necrotising soft tissue infections (NSTIs) are rapidly progressing bacterial infections usually caused by either several pathogens in unison (polymicrobial infections) or Streptococcus pyogenes (mono-microbial infection). These infections are rare and are associated with high mortality rates. However, the underlying pathogenic mechanisms in this heterogeneous group remain elusive. Methods In this study, we built interactomes at both the population and individual levels consisting of host-pathogen interactions inferred from dual RNA-Seq gene transcriptomic profiles of the biopsies from NSTI patients. Results NSTI type-specific responses in the host were uncovered. The S. pyogenes mono-microbial subnetwork was enriched with host genes annotated with involved in cytokine production and regulation of response to stress. The polymicrobial network consisted of several significant associations between different species (S. pyogenes, Porphyromonas asaccharolytica and Escherichia coli) and host genes. The host genes associated with S. pyogenes in this subnetwork were characterised by cellular response to cytokines. We further found several virulence factors including hyaluronan synthase, Sic1, Isp, SagF, SagG, ScfAB-operon, Fba and genes upstream and downstream of EndoS along with bacterial housekeeping genes interacting with the human stress and immune response in various subnetworks between host and pathogen. Conclusions At the population level, we found aetiology-dependent responses showing the potential modes of entry and immune evasion strategies employed by S. pyogenes, congruent with general cellular processes such as differentiation and proliferation. After stratifying the patients based on the subject-specific networks to study the patient-specific response, we observed different patient groups with different collagens, cytoskeleton and actin monomers in association with virulence factors, immunogenic proteins and housekeeping genes which we utilised to postulate differing modes of entry and immune evasion for different bacteria in relationship to the patients’ phenotype.

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Streptococcal protein SIC activates monocytes and induces inflammation

Cited by 7 publications

References 66 publications

Immune signature of acute pharyngitis in a Streptococcus pyogenes human challenge trial

Immune signature of acute pharyngitis in a Streptococcus pyogenes human challenge trial

Complement evasion factor (CEF), a novel immune evasion factor of Streptococcus pyogenes

Analysis of host-pathogen gene association networks reveals patient-specific response to streptococcal and polymicrobial necrotising soft tissue infections

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