Limits...
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.

Show MeSH

Related in: MedlinePlus

Extensive liver necrosis occurred in C3-deficient mice.Liver samples were taken from mice 7 days after infection with ∼700 pfu via ear pinna, fixed, sectioned, and stained with hematoxylin and eosin. Representative images show the range of differences between the strains. White lines border coalesced areas of necrosis. Arrowheads point to non-necrotic inflammatory foci. T, portal triad; V, central vein. (A) Wild-type—blood flows through the liver from zone 1 to 3, as indicated by the arrow. Zone 1 encircles the portal triad, zone 3 encircles the central vein, and zone 2 occurs between zones 1 and 3. There are small inflammatory foci adjacent to two portal triads. (B) Wild-type—there are inflammatory foci adjacent to portal triads, and one focus has a small area of confluent necrosis. (C) C3−/−—larger inflammatory foci with areas of confluent necrosis. (D) C3−/−—an inflammatory infiltrate borders the extensive necrosis that bridges across all three zones (T→V).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2597719&req=5

ppat-1000249-g003: Extensive liver necrosis occurred in C3-deficient mice.Liver samples were taken from mice 7 days after infection with ∼700 pfu via ear pinna, fixed, sectioned, and stained with hematoxylin and eosin. Representative images show the range of differences between the strains. White lines border coalesced areas of necrosis. Arrowheads point to non-necrotic inflammatory foci. T, portal triad; V, central vein. (A) Wild-type—blood flows through the liver from zone 1 to 3, as indicated by the arrow. Zone 1 encircles the portal triad, zone 3 encircles the central vein, and zone 2 occurs between zones 1 and 3. There are small inflammatory foci adjacent to two portal triads. (B) Wild-type—there are inflammatory foci adjacent to portal triads, and one focus has a small area of confluent necrosis. (C) C3−/−—larger inflammatory foci with areas of confluent necrosis. (D) C3−/−—an inflammatory infiltrate borders the extensive necrosis that bridges across all three zones (T→V).

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)

Extensive liver necrosis occurred in C3-deficient mice.Liver samples were taken from mice 7 days after infection with ∼700 pfu via ear pinna, fixed, sectioned, and stained with hematoxylin and eosin. Representative images show the range of differences between the strains. White lines border coalesced areas of necrosis. Arrowheads point to non-necrotic inflammatory foci. T, portal triad; V, central vein. (A) Wild-type—blood flows through the liver from zone 1 to 3, as indicated by the arrow. Zone 1 encircles the portal triad, zone 3 encircles the central vein, and zone 2 occurs between zones 1 and 3. There are small inflammatory foci adjacent to two portal triads. (B) Wild-type—there are inflammatory foci adjacent to portal triads, and one focus has a small area of confluent necrosis. (C) C3−/−—larger inflammatory foci with areas of confluent necrosis. (D) C3−/−—an inflammatory infiltrate borders the extensive necrosis that bridges across all three zones (T→V).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2597719&req=5

ppat-1000249-g003: Extensive liver necrosis occurred in C3-deficient mice.Liver samples were taken from mice 7 days after infection with ∼700 pfu via ear pinna, fixed, sectioned, and stained with hematoxylin and eosin. Representative images show the range of differences between the strains. White lines border coalesced areas of necrosis. Arrowheads point to non-necrotic inflammatory foci. T, portal triad; V, central vein. (A) Wild-type—blood flows through the liver from zone 1 to 3, as indicated by the arrow. Zone 1 encircles the portal triad, zone 3 encircles the central vein, and zone 2 occurs between zones 1 and 3. There are small inflammatory foci adjacent to two portal triads. (B) Wild-type—there are inflammatory foci adjacent to portal triads, and one focus has a small area of confluent necrosis. (C) C3−/−—larger inflammatory foci with areas of confluent necrosis. (D) C3−/−—an inflammatory infiltrate borders the extensive necrosis that bridges across all three zones (T→V).
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