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Novel aspects on the pathogenesis of Mycoplasma pneumoniae pneumonia and therapeutic implications.

Saraya T, Kurai D, Nakagaki K, Sasaki Y, Niwa S, Tsukagoshi H, Nunokawa H, Ohkuma K, Tsujimoto N, Hirao S, Wada H, Ishii H, Nakata K, Kimura H, Kozawa K, Takizawa H, Goto H - Front Microbiol (2014)

Bottom Line: Mycoplasma pneumoniae (Mp) is a leading cause of community acquired pneumonia.Accumulated expertise concerning this critical issue has been hard to apply clinically, and potential problems may remain undiscovered.It is our hope that this might lead to new insights into this common respiratory disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Respiratory Medicine, Kyorin University School of Medicine Mitaka, Japan.

ABSTRACT
Mycoplasma pneumoniae (Mp) is a leading cause of community acquired pneumonia. Knowledge regarding Mp pneumonia obtained from animal models or human subjects has been discussed in many different reports. Accumulated expertise concerning this critical issue has been hard to apply clinically, and potential problems may remain undiscovered. Therefore, our multidisciplinary team extensively reviewed the literature regarding Mp pneumonia, and compared findings from animal models with those from human subjects. In human beings, the characteristic pathological features of Mp pneumonia have been reported as alveolar infiltration with neutrophils and lymphocytes and lymphocyte/plasma cell infiltrates in the peri-bronchovascular area. Herein, we demonstrated the novel aspects of Mp pneumonia that the severity of the Mp pneumonia seemed to depend on the host innate immunity to the Mp, which might be accelerated by antecedent Mp exposure (re-exposure or latent respiratory infection) through up-regulation of Toll-like receptor 2 expression on bronchial epithelial cells and alveolar macrophages. The macrolides therapy might be beneficial for the patients with macrolide-resistant Mp pneumonia via not bacteriological but immunomodulative effects. This exhaustive review focuses on pathogenesis and extends to some therapeutic implications such as clarithromycin, and discusses the various diverse aspects of Mp pneumonia. It is our hope that this might lead to new insights into this common respiratory disease.

No MeSH data available.


Related in: MedlinePlus

Female BALB/c (7-week-old) mice were inoculated intratracheally with Mp antigen with or without pre-immunization. Pre-immunization was carried out by intraperitoneal injection at 7 and 14 days prior to the intratracheal (IT) challenge. Model A: IT without pre-immunization. Model B: IT after twice pre-immunizing with Mp antigen alone. Model C: IT after twice pre-immunizing with Mp antigen plus CpG. Model D: IT after twice pre-immunizing with alum alone. Model E: IT after twice pre-immunizing with Mp antigen plus alum. One week following the last immunization, mice underwent IT with 50 μg of Mp antigen. Bronchoalveolar lavage fluid (BALF) and lung specimens were obtained before this process and 8, 24, 48, 96, and 168 h after IT. Mp: mycoplasma.
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Figure 1: Female BALB/c (7-week-old) mice were inoculated intratracheally with Mp antigen with or without pre-immunization. Pre-immunization was carried out by intraperitoneal injection at 7 and 14 days prior to the intratracheal (IT) challenge. Model A: IT without pre-immunization. Model B: IT after twice pre-immunizing with Mp antigen alone. Model C: IT after twice pre-immunizing with Mp antigen plus CpG. Model D: IT after twice pre-immunizing with alum alone. Model E: IT after twice pre-immunizing with Mp antigen plus alum. One week following the last immunization, mice underwent IT with 50 μg of Mp antigen. Bronchoalveolar lavage fluid (BALF) and lung specimens were obtained before this process and 8, 24, 48, 96, and 168 h after IT. Mp: mycoplasma.

Mentions: We designed five different mouse models for Mp pneumonia (Figure 1) to examine the resulting pathology in animals having various immune status (Saraya et al., 2007b, 2011; Saraya, 2013). Animals were peritoneally immunized with various regimens (one per model) once a week (on days −14 and −7), then 1 week after the last immunization the animals were intratracheally (IT) challenged with sonicated Mp antigen, as previously reported (Saraya et al., 2011). Among those models, only groups immunized with Mp antigen and alum adjuvant (Figure 1E) or CpG (Figure 1C) developed severe lymphocytic infiltration into PBVAs at 96 h after IT (Figures 2C,E) while, no inflammatory cells were seen on models A and B (Figures 2A,B). However, the pathognomonic feature for human Mp pneumonia was reconstructed only in models D and E, in which lymphoplasmacytic infiltration into PBVAs occurred 96 h post-IT (Figures 2D,E). Those results suggest that enhanced host immune responses, as occurred in models C and E, against Mp antigen are required for persistent inflammation in the lung, as well as Th2 characteristics (produced by use of Th2 adjuvant, as in models D and E) causing plasma cell infiltration into the PBVAs, but not Th1 characteristics (produced by use of the Th1 adjuvant, CPG, as in the model depicted in Figure 1C). Aluminum hydroxide adjuvant, named alum, is well-known for initiating strong antigen-specific Th2 responses in the absence of interleukin(IL)-4- or IL-13-mediated signaling (Brewer et al., 1999); Th2 predominant characteristics might be required to generate typical Mp pneumonia, even in humans. Previous studies showed that the histopathological score of Mp pneumonia is significantly higher in infected BALB/c mice (Th2 predominant) than in C57BL/6 mice (Th1 predominant) through the late phase, suggesting differences in host reactions against intranasally-inoculated live Mp (Fonseca-Aten et al., 2005). Tanaka et al. (1996) describe the different pathological findings in an M. pulmonis–infected mouse model for treatment with IL-2 (Th1 up-regulated) vs. cyclosporine A (Th1 down-regulated).


Novel aspects on the pathogenesis of Mycoplasma pneumoniae pneumonia and therapeutic implications.

Saraya T, Kurai D, Nakagaki K, Sasaki Y, Niwa S, Tsukagoshi H, Nunokawa H, Ohkuma K, Tsujimoto N, Hirao S, Wada H, Ishii H, Nakata K, Kimura H, Kozawa K, Takizawa H, Goto H - Front Microbiol (2014)

Female BALB/c (7-week-old) mice were inoculated intratracheally with Mp antigen with or without pre-immunization. Pre-immunization was carried out by intraperitoneal injection at 7 and 14 days prior to the intratracheal (IT) challenge. Model A: IT without pre-immunization. Model B: IT after twice pre-immunizing with Mp antigen alone. Model C: IT after twice pre-immunizing with Mp antigen plus CpG. Model D: IT after twice pre-immunizing with alum alone. Model E: IT after twice pre-immunizing with Mp antigen plus alum. One week following the last immunization, mice underwent IT with 50 μg of Mp antigen. Bronchoalveolar lavage fluid (BALF) and lung specimens were obtained before this process and 8, 24, 48, 96, and 168 h after IT. Mp: mycoplasma.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4127663&req=5

Figure 1: Female BALB/c (7-week-old) mice were inoculated intratracheally with Mp antigen with or without pre-immunization. Pre-immunization was carried out by intraperitoneal injection at 7 and 14 days prior to the intratracheal (IT) challenge. Model A: IT without pre-immunization. Model B: IT after twice pre-immunizing with Mp antigen alone. Model C: IT after twice pre-immunizing with Mp antigen plus CpG. Model D: IT after twice pre-immunizing with alum alone. Model E: IT after twice pre-immunizing with Mp antigen plus alum. One week following the last immunization, mice underwent IT with 50 μg of Mp antigen. Bronchoalveolar lavage fluid (BALF) and lung specimens were obtained before this process and 8, 24, 48, 96, and 168 h after IT. Mp: mycoplasma.
Mentions: We designed five different mouse models for Mp pneumonia (Figure 1) to examine the resulting pathology in animals having various immune status (Saraya et al., 2007b, 2011; Saraya, 2013). Animals were peritoneally immunized with various regimens (one per model) once a week (on days −14 and −7), then 1 week after the last immunization the animals were intratracheally (IT) challenged with sonicated Mp antigen, as previously reported (Saraya et al., 2011). Among those models, only groups immunized with Mp antigen and alum adjuvant (Figure 1E) or CpG (Figure 1C) developed severe lymphocytic infiltration into PBVAs at 96 h after IT (Figures 2C,E) while, no inflammatory cells were seen on models A and B (Figures 2A,B). However, the pathognomonic feature for human Mp pneumonia was reconstructed only in models D and E, in which lymphoplasmacytic infiltration into PBVAs occurred 96 h post-IT (Figures 2D,E). Those results suggest that enhanced host immune responses, as occurred in models C and E, against Mp antigen are required for persistent inflammation in the lung, as well as Th2 characteristics (produced by use of Th2 adjuvant, as in models D and E) causing plasma cell infiltration into the PBVAs, but not Th1 characteristics (produced by use of the Th1 adjuvant, CPG, as in the model depicted in Figure 1C). Aluminum hydroxide adjuvant, named alum, is well-known for initiating strong antigen-specific Th2 responses in the absence of interleukin(IL)-4- or IL-13-mediated signaling (Brewer et al., 1999); Th2 predominant characteristics might be required to generate typical Mp pneumonia, even in humans. Previous studies showed that the histopathological score of Mp pneumonia is significantly higher in infected BALB/c mice (Th2 predominant) than in C57BL/6 mice (Th1 predominant) through the late phase, suggesting differences in host reactions against intranasally-inoculated live Mp (Fonseca-Aten et al., 2005). Tanaka et al. (1996) describe the different pathological findings in an M. pulmonis–infected mouse model for treatment with IL-2 (Th1 up-regulated) vs. cyclosporine A (Th1 down-regulated).

Bottom Line: Mycoplasma pneumoniae (Mp) is a leading cause of community acquired pneumonia.Accumulated expertise concerning this critical issue has been hard to apply clinically, and potential problems may remain undiscovered.It is our hope that this might lead to new insights into this common respiratory disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Respiratory Medicine, Kyorin University School of Medicine Mitaka, Japan.

ABSTRACT
Mycoplasma pneumoniae (Mp) is a leading cause of community acquired pneumonia. Knowledge regarding Mp pneumonia obtained from animal models or human subjects has been discussed in many different reports. Accumulated expertise concerning this critical issue has been hard to apply clinically, and potential problems may remain undiscovered. Therefore, our multidisciplinary team extensively reviewed the literature regarding Mp pneumonia, and compared findings from animal models with those from human subjects. In human beings, the characteristic pathological features of Mp pneumonia have been reported as alveolar infiltration with neutrophils and lymphocytes and lymphocyte/plasma cell infiltrates in the peri-bronchovascular area. Herein, we demonstrated the novel aspects of Mp pneumonia that the severity of the Mp pneumonia seemed to depend on the host innate immunity to the Mp, which might be accelerated by antecedent Mp exposure (re-exposure or latent respiratory infection) through up-regulation of Toll-like receptor 2 expression on bronchial epithelial cells and alveolar macrophages. The macrolides therapy might be beneficial for the patients with macrolide-resistant Mp pneumonia via not bacteriological but immunomodulative effects. This exhaustive review focuses on pathogenesis and extends to some therapeutic implications such as clarithromycin, and discusses the various diverse aspects of Mp pneumonia. It is our hope that this might lead to new insights into this common respiratory disease.

No MeSH data available.


Related in: MedlinePlus