CD46 Contributes to the Severity of Group A Streptococcal Infection

Lövkvist, Lena; Sjölinder, Hong; Wehelie, Rahma; Aro, Helena; Norrby‐Teglund, Anna; Plant, Laura; Jonsson, Ann‐Beth

doi:10.1128/iai.00109-08

Cited by 28 publications

(38 citation statements)

References 55 publications

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“…Compared to such models, the s.c. inoculation into both hind footpads in the present study was a simple procedure, and the obtained data showed a narrow dispersion of reproducibility. A recent study demonstrated that infection in epithelial cells with GAS led to the shedding of human CD46 at the same time as bacterium-induced apoptosis and cell death occurred (30). In the present study, the amount of bacterial load in the PLN of CD46 Tg mice was the same as that of non-Tg mice 48 h after s.c. infection (Fig.…”

Section: Discussionsupporting

confidence: 62%

“…It was demonstrated that during 6 h of incubation, the growth of GAS was enhanced in the cell culture medium mixed with an equal volume of mouse whole blood containing soluble human CD46 (30). Then, we examined the changes in expression of sagA (streptolysin S; SLS) of GAS472 during 6 h of incubation under the above experimental conditions.…”

Section: Matsui Et Al Infect Immunmentioning

confidence: 99%

“…Human CD46-expressing transgenic (Tg) mice are susceptible to streptococcal disease (30). When CD46 Tg and non-Tg mice were infected intravenously (i.v.)…”

mentioning

confidence: 99%

“…When CD46 Tg and non-Tg mice were infected intravenously (i.v.) with GAS, the bacteremia levels, frequency of arthritis, and mortality rate were higher in CD46 Tg mice than in non-Tg mice (30). Unfortunately, this animal model does not reflect the natural infection process in the human host.…”

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confidence: 99%

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CD46 Transgenic Mouse Model of Necrotizing Fasciitis Caused by Streptococcus pyogenes Infection

et al. 2009

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We developed a human CD46-expressing transgenic (Tg) mouse model of subcutaneous (s.c.) infection into both hind footpads with clinically isolated 11 group A streptococcus (GAS) serotype M1 strains. When the severity levels of foot lesions at 72 h and the mortality rates by 336 h were compared after s.c. infection with 1 ؋ 10 7 CFU of each GAS strain, the GAS472 strain, isolated from the blood of a patient suffering from streptococcal toxic shock syndrome (STSS), induced the highest severity levels and mortality rates. GAS472 led to a 100% mortality rate in CD46 Tg mice after only 168 h postinfection through the supervention of severe necrotizing fasciitis (NF) of the feet. In contrast, GAS472 led to a 10% mortality rate in non-Tg mice through the supervention of partial necrotizing cutaneous lesions of the feet. The footpad skin sections of CD46 Tg mice showed hemorrhaging and necrotic striated muscle layers in the dermis, along with the exfoliation of epidermis with intracellular edema until 48 h after s.c. infection with GAS472. Thereafter, the bacteria proliferated, reaching a 90-fold or 7-fold increase in the livers of CD46 Tg mice or non-Tg mice, respectively, for 24 h between 48 and 72 h after s.c. infection with GAS472. As a result, the infected CD46 Tg mice appeared to suffer severe liver injuries. These findings suggest that human CD46 enhanced the progression of NF in the feet and the exponential growth of bacteria in deep tissues, leading to death.Group A streptococci (GAS), which are among the most common human pathogens, can cause a variety of uncomplicated superficial skin infections such as impetigo/pyoderma or throat infections, including streptococcal pharyngitis (sore throat) and tonsillitis (3). In addition, patients suffering from acute and complicated GAS infections, in particular streptococcal toxic shock syndrome (STSS) associated with severe necrotizing fasciitis (NF), have high mortality rates (4). M proteins, which attach to the cell wall, are one of the important virulence factors that GAS possess (15). The various GAS strains have more than 100 different antigenically distinguishable M proteins (46), and GAS serotype M1 strains are regarded as a highly virulent group (3).Membrane cofactor protein (MCP; CD46), which is expressed in every cell type except erythrocytes, is implicated as a receptor for at least six human pathogens (four viruses and two bacteria), including measles virus (9, 31, 35), herpesvirus 6 (40), adenovirus groups B (17, 41) and D (48), pathogenic Neisseria (23), and GAS (37). Human CD46-expressing transgenic (Tg) mice are susceptible to streptococcal disease (30). When CD46 Tg and non-Tg mice were infected intravenously (i.v.) with GAS, the bacteremia levels, frequency of arthritis, and mortality rate were higher in CD46 Tg mice than in non-Tg mice (30). Unfortunately, this animal model does not reflect the natural infection process in the human host. Consequently, we have attempted to establish a CD46 Tg mouse model of skin and soft tissue infection with GAS that...

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Section: Discussionsupporting

confidence: 62%

Section: Matsui Et Al Infect Immunmentioning

confidence: 99%

“…Human CD46-expressing transgenic (Tg) mice are susceptible to streptococcal disease (30). When CD46 Tg and non-Tg mice were infected intravenously (i.v.)…”

mentioning

confidence: 99%

mentioning

confidence: 99%

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CD46 Transgenic Mouse Model of Necrotizing Fasciitis Caused by Streptococcus pyogenes Infection

et al. 2009

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“…CD46 interacts with adenovirus 18 , human herpes virus 6 19 , pathogenic Neisseria [20][21][22] , measles virus 23 and Streptococcus pyogenes. 24 Infection of epithelial cells by N. gonorrhoeae and S. pyogenes triggers shedding of CD46 25,26 . Although CD46 is expressed in human gastric epithelium 27 , the role of CD46 in H. pylori infection has not yet been elucidated.…”

Section: Introductionmentioning

confidence: 99%

The Complement Regulator CD46 Is Bactericidal to Helicobacter pylori and Blocks Urease Activity

et al. 2011

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CD46 accelerates macrophage‐mediated host susceptibility to meningococcal sepsis in a murine model

et al. 2016

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Eur. J. Immunol. 2017. 47: 119-130 Macrophages play an essential role in controlling bacterial infection, as they efficiently eliminate pathogens, provide a significant source of cytokines, and represent and link between innate and adaptive immunity [6]. Both the environmental milieu and cellular mitochondrial metabolism [7] can alter the functional polarization of macrophages, which can be broadly classified as classically activated (M1) and alternatively activated (M2) [8]. M1 macrophages triggered by IFN-γ alone or in combination with bacterial LPS are characterized by the production of type 1 inflammatory cytokines and bactericidal mediators such as nitric oxide and reactive oxygen intermediates. Thus, M1 macrophages play a dominant role in controlling acute infections, but also have the potential to induce a cytokine storm that is associated with tissue injury. In contrast, M2 macrophages triggered by IL-4/IL-13, glucocorticoids, IL-10, or immune complexes produce elevated amounts of anti-inflammatory cytokines and Th2-recruiting chemokines. M2 macrophages exhibit efficient phagocytic activity as well as increased expression of arginase 1, and therefore contribute to tissue healing and resolution of harmful inflammation. However, prolonged M2 polarization can generate a survival niche that leads to chronic microbial infection [9]. Initial overwhelming inflammatory responses, followed by macrophage dysfunction during the later stages of infection, have been widely observed in patients with severe sepsis. This probably occurs due to a switch in the macrophage phenotype from M1 to M2, implying a close association between macrophage phenotype and the progression of sepsis [10].The transmembrane protein CD46 was initially identified as a co-factor for complement factor I, which is involved in protecting host cells from autologous complement-mediated attack [11]. CD46 also serves as a receptor for several pathogens including measles virus [12] (Fig. 1A). Systemic meningococcal dissemination was well controlled in the WT mice, but not in the CD46 +/+ mice (Fig. 1B).To investigate whether this phenomenon was a general response to gram-negative bacterial infection, we repeated the experiments, challenging the mice with E. coli LPS. A non-lethal dose (20 mg/kg) for WT mice led to 67% mortality in CD46 +/+ mice within 4 days (Fig. 1C). A reduction in body weight, a common indicator of the severity of sepsis, was observed in the CD46 +/+ mice. Body weight was maintained in WT mice even though an initial decline was observed (Fig. 1D). The levels of circulatory cytokines IL-10, IL-6, and TNF, which are closely associated with sepsis severity and a fatal outcome [27], were significantly higher in the CD46 +/+ mice than in the WT mice upon meningococcal infection (Fig. 1E). Stronger cytokine responses were also observed in CD46 +/+ mice, compared to that in WT mice, following LPS challenge even though the effect was transient and lost after 24 h for IL-10 and TNF ( hand, LPS degradation in vivo might also contribute t...

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CD46 Contributes to the Severity of Group A Streptococcal Infection

Cited by 28 publications

References 55 publications

CD46 Transgenic Mouse Model of Necrotizing Fasciitis Caused by Streptococcus pyogenes Infection

CD46 Transgenic Mouse Model of Necrotizing Fasciitis Caused by Streptococcus pyogenes Infection

The Complement Regulator CD46 Is Bactericidal to Helicobacter pylori and Blocks Urease Activity

CD46 accelerates macrophage‐mediated host susceptibility to meningococcal sepsis in a murine model

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