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Surviving mousepox infection requires the complement system.

Moulton EA, Atkinson JP, Buller RM - PLoS Pathog. (2008)

Bottom Line: Poxviruses subvert the host immune response by producing immunomodulatory proteins, including a complement regulatory protein.Sera deficient in classical or alternative pathway components or antibody had reduced ability to neutralize viral particles, which likely contributed to increased viral dissemination and disease severity in vivo.In summary, the complement system acts in the first few minutes, hours, and days to control this poxviral infection until the adaptive immune response can react, and loss of this system results in lethal infection.

View Article: PubMed Central - PubMed

Affiliation: Rheumatology Division, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA.

ABSTRACT
Poxviruses subvert the host immune response by producing immunomodulatory proteins, including a complement regulatory protein. Ectromelia virus provides a mouse model for smallpox where the virus and the host's immune response have co-evolved. Using this model, our study investigated the role of the complement system during a poxvirus infection. By multiple inoculation routes, ectromelia virus caused increased mortality by 7 to 10 days post-infection in C57BL/6 mice that lack C3, the central component of the complement cascade. In C3(-/-) mice, ectromelia virus disseminated earlier to target organs and generated higher peak titers compared to the congenic controls. Also, increased hepatic inflammation and necrosis correlated with these higher tissue titers and likely contributed to the morbidity in the C3(-/-) mice. In vitro, the complement system in naïve C57BL/6 mouse sera neutralized ectromelia virus, primarily through the recognition of the virion by natural antibody and activation of the classical and alternative pathways. Sera deficient in classical or alternative pathway components or antibody had reduced ability to neutralize viral particles, which likely contributed to increased viral dissemination and disease severity in vivo. The increased mortality of C4(-/-) or Factor B(-/-) mice also indicates that these two pathways of complement activation are required for survival. In summary, the complement system acts in the first few minutes, hours, and days to control this poxviral infection until the adaptive immune response can react, and loss of this system results in lethal infection.

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C3-deficient mice had a greater number of inflammatory foci with more extensive necrosis.(A–F) Wild-type (WT, black, ▴) and C3−/− (red, •) mice were compared, and P values are above the bracket. Error bars are SEM. (A) The number of inflammatory foci/visual field was counted. Each point represents the mean from ∼7 fields for an individual mouse. The graph plots the mean number of foci for each animal. (B) The number of inflammatory foci containing necrosis was counted and displayed as described in (A). (C) The percentage of foci that contained areas of necrosis. (D) The severity of the necrosis was quantitated using a 0–4 scale: 0, none; 1, piecemeal necrosis; 2, confluent areas of necrosis; 3, confluent areas of necrosis that extend beyond a single zone; and 4, bridging necrosis. (E) The zones of the liver (1, 2, and 3) where necrosis occurred. Zones are described in Figure 3A. (F) The serum levels of the liver enzymes in uninfected mice were <100 for AST and <50 for ALT. (G) AST (blue) and ALT (black) levels positively correlate with liver viral titer (r2 = 0.54 and 0.69, respectively). The log of these parameters for both C3−/− and wild-type mice was used for linear regression.
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ppat-1000249-g004: C3-deficient mice had a greater number of inflammatory foci with more extensive necrosis.(A–F) Wild-type (WT, black, ▴) and C3−/− (red, •) mice were compared, and P values are above the bracket. Error bars are SEM. (A) The number of inflammatory foci/visual field was counted. Each point represents the mean from ∼7 fields for an individual mouse. The graph plots the mean number of foci for each animal. (B) The number of inflammatory foci containing necrosis was counted and displayed as described in (A). (C) The percentage of foci that contained areas of necrosis. (D) The severity of the necrosis was quantitated using a 0–4 scale: 0, none; 1, piecemeal necrosis; 2, confluent areas of necrosis; 3, confluent areas of necrosis that extend beyond a single zone; and 4, bridging necrosis. (E) The zones of the liver (1, 2, and 3) where necrosis occurred. Zones are described in Figure 3A. (F) The serum levels of the liver enzymes in uninfected mice were <100 for AST and <50 for ALT. (G) AST (blue) and ALT (black) levels positively correlate with liver viral titer (r2 = 0.54 and 0.69, respectively). The log of these parameters for both C3−/− and wild-type mice was used for linear regression.

Mentions: On day 4, the liver histopathology appeared normal in 4 of 5 wild-type and 3 of 4 C3−/− mice (data not shown). By day 7, all animals had a diffuse lymphocytic infiltrate in addition to discrete inflammatory foci (Figure 3). These lesions varied in size and were smaller and less frequent in the wild-type (Figure 3A and 3B) compared to the C3−/− mice (Figure 3C and 3D). They often occurred near the portal triad, and some contained areas of coagulative necrosis. An inflammatory infiltrate encircled the discrete necrotic foci (Figure 3B and 3C) and bordered the areas of bridging necrosis (Figure 3D). In contrast to the liver, no major differences were observed in the spleen at this time (data not shown). Using blinded samples, we counted the necrotic and non-necrotic foci and evaluated the location and severity of the necrosis in the liver (Figure 4).


Surviving mousepox infection requires the complement system.

Moulton EA, Atkinson JP, Buller RM - PLoS Pathog. (2008)

C3-deficient mice had a greater number of inflammatory foci with more extensive necrosis.(A–F) Wild-type (WT, black, ▴) and C3−/− (red, •) mice were compared, and P values are above the bracket. Error bars are SEM. (A) The number of inflammatory foci/visual field was counted. Each point represents the mean from ∼7 fields for an individual mouse. The graph plots the mean number of foci for each animal. (B) The number of inflammatory foci containing necrosis was counted and displayed as described in (A). (C) The percentage of foci that contained areas of necrosis. (D) The severity of the necrosis was quantitated using a 0–4 scale: 0, none; 1, piecemeal necrosis; 2, confluent areas of necrosis; 3, confluent areas of necrosis that extend beyond a single zone; and 4, bridging necrosis. (E) The zones of the liver (1, 2, and 3) where necrosis occurred. Zones are described in Figure 3A. (F) The serum levels of the liver enzymes in uninfected mice were <100 for AST and <50 for ALT. (G) AST (blue) and ALT (black) levels positively correlate with liver viral titer (r2 = 0.54 and 0.69, respectively). The log of these parameters for both C3−/− and wild-type mice was used for linear regression.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2597719&req=5

ppat-1000249-g004: C3-deficient mice had a greater number of inflammatory foci with more extensive necrosis.(A–F) Wild-type (WT, black, ▴) and C3−/− (red, •) mice were compared, and P values are above the bracket. Error bars are SEM. (A) The number of inflammatory foci/visual field was counted. Each point represents the mean from ∼7 fields for an individual mouse. The graph plots the mean number of foci for each animal. (B) The number of inflammatory foci containing necrosis was counted and displayed as described in (A). (C) The percentage of foci that contained areas of necrosis. (D) The severity of the necrosis was quantitated using a 0–4 scale: 0, none; 1, piecemeal necrosis; 2, confluent areas of necrosis; 3, confluent areas of necrosis that extend beyond a single zone; and 4, bridging necrosis. (E) The zones of the liver (1, 2, and 3) where necrosis occurred. Zones are described in Figure 3A. (F) The serum levels of the liver enzymes in uninfected mice were <100 for AST and <50 for ALT. (G) AST (blue) and ALT (black) levels positively correlate with liver viral titer (r2 = 0.54 and 0.69, respectively). The log of these parameters for both C3−/− and wild-type mice was used for linear regression.
Mentions: On day 4, the liver histopathology appeared normal in 4 of 5 wild-type and 3 of 4 C3−/− mice (data not shown). By day 7, all animals had a diffuse lymphocytic infiltrate in addition to discrete inflammatory foci (Figure 3). These lesions varied in size and were smaller and less frequent in the wild-type (Figure 3A and 3B) compared to the C3−/− mice (Figure 3C and 3D). They often occurred near the portal triad, and some contained areas of coagulative necrosis. An inflammatory infiltrate encircled the discrete necrotic foci (Figure 3B and 3C) and bordered the areas of bridging necrosis (Figure 3D). In contrast to the liver, no major differences were observed in the spleen at this time (data not shown). Using blinded samples, we counted the necrotic and non-necrotic foci and evaluated the location and severity of the necrosis in the liver (Figure 4).

Bottom Line: Poxviruses subvert the host immune response by producing immunomodulatory proteins, including a complement regulatory protein.Sera deficient in classical or alternative pathway components or antibody had reduced ability to neutralize viral particles, which likely contributed to increased viral dissemination and disease severity in vivo.In summary, the complement system acts in the first few minutes, hours, and days to control this poxviral infection until the adaptive immune response can react, and loss of this system results in lethal infection.

View Article: PubMed Central - PubMed

Affiliation: Rheumatology Division, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA.

ABSTRACT
Poxviruses subvert the host immune response by producing immunomodulatory proteins, including a complement regulatory protein. Ectromelia virus provides a mouse model for smallpox where the virus and the host's immune response have co-evolved. Using this model, our study investigated the role of the complement system during a poxvirus infection. By multiple inoculation routes, ectromelia virus caused increased mortality by 7 to 10 days post-infection in C57BL/6 mice that lack C3, the central component of the complement cascade. In C3(-/-) mice, ectromelia virus disseminated earlier to target organs and generated higher peak titers compared to the congenic controls. Also, increased hepatic inflammation and necrosis correlated with these higher tissue titers and likely contributed to the morbidity in the C3(-/-) mice. In vitro, the complement system in naïve C57BL/6 mouse sera neutralized ectromelia virus, primarily through the recognition of the virion by natural antibody and activation of the classical and alternative pathways. Sera deficient in classical or alternative pathway components or antibody had reduced ability to neutralize viral particles, which likely contributed to increased viral dissemination and disease severity in vivo. The increased mortality of C4(-/-) or Factor B(-/-) mice also indicates that these two pathways of complement activation are required for survival. In summary, the complement system acts in the first few minutes, hours, and days to control this poxviral infection until the adaptive immune response can react, and loss of this system results in lethal infection.

Show MeSH
Related in: MedlinePlus