Limits...
Protective effect of Toll-like receptor 4 in pulmonary vaccinia infection.

Hutchens MA, Luker KE, Sonstein J, Núñez G, Curtis JL, Luker GD - PLoS Pathog. (2008)

Bottom Line: We then focused on TLR4, the other Toll-like receptor that signals through TRIF.The mechanism of TLR4-mediated protection was not due to increased release of proinflammatory cytokines or changes in total numbers of immune cells recruited to the lung.These data establish that TLR4 mediates a protective innate immune response against vaccinia virus, which informs development of new vaccines and therapeutic agents targeted against poxviruses.

View Article: PubMed Central - PubMed

Affiliation: Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.

ABSTRACT
Innate immune responses are essential for controlling poxvirus infection. The threat of a bioterrorist attack using Variola major, the smallpox virus, or zoonotic transmission of other poxviruses has renewed interest in understanding interactions between these viruses and their hosts. We recently determined that TLR3 regulates a detrimental innate immune response that enhances replication, morbidity, and mortality in mice in response to vaccinia virus, a model pathogen for studies of poxviruses. To further investigate Toll-like receptor signaling in vaccinia infection, we first focused on TRIF, the only known adapter protein for TLR3. Unexpectedly, bioluminescence imaging showed that mice lacking TRIF are more susceptible to vaccinia infection than wild-type mice. We then focused on TLR4, the other Toll-like receptor that signals through TRIF. Following respiratory infection with vaccinia, mice lacking TLR4 signaling had greater viral replication, hypothermia, and mortality than control animals. The mechanism of TLR4-mediated protection was not due to increased release of proinflammatory cytokines or changes in total numbers of immune cells recruited to the lung. Challenge of primary bone marrow macrophages isolated from TLR4 mutant and control mice suggested that TLR4 recognizes a viral ligand rather than an endogenous ligand. These data establish that TLR4 mediates a protective innate immune response against vaccinia virus, which informs development of new vaccines and therapeutic agents targeted against poxviruses.

Show MeSH

Related in: MedlinePlus

TRIF−/− mice are more susceptible to vaccinia infection than WT.TRIF−/− and WT BL/6 mice were infected with 1×104 pfu Vac-FL. (A) Weight loss, expressed as percent of initial weight. *p<0.05. (B) Chest luminescence, expressed as photon flux. Error bars denote SEM.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2529451&req=5

ppat-1000153-g001: TRIF−/− mice are more susceptible to vaccinia infection than WT.TRIF−/− and WT BL/6 mice were infected with 1×104 pfu Vac-FL. (A) Weight loss, expressed as percent of initial weight. *p<0.05. (B) Chest luminescence, expressed as photon flux. Error bars denote SEM.

Mentions: Unexpectedly, susceptibility of TRIF−/− mice to vaccinia infection was distinct from that of the TLR3−/− mice. TRIF−/− mice had less weight loss than wild-type mice on days 1–4 post-infection (p<0.05), which is similar to our published results for TLR3−/− versus wild-type mice, (Figure 1A). However, TRIF−/− mice differed from TLR3−/− animals in that replication of Vac-GFL was greater in mice lacking TRIF, as quantified by region of interest analysis of head, chest, and abdomen sites on bioluminescence images. By area under the curve (AUC) analysis, TRIF−/− mice had significantly greater luminescence in their chests (from lung infection) than wild-type mice (Figure 1B; p<0.01). These data indicate that a different and/or additional host molecule(s) controls responses to vaccinia in TRIF−/− mice relative to those mediated solely by TLR3. This experiment continued until day 7 post-infection, when the animals were euthanized to obtain plasma and bronchoalveolar (BAL) fluid for quantification of cytokines. Levels of IL-6, IL-4, IFN-γ, MCP-1, TNF-α, and TGF-β were measured in these samples, but no significant differences were seen between the TRIF−/− and WT mice (data not shown).


Protective effect of Toll-like receptor 4 in pulmonary vaccinia infection.

Hutchens MA, Luker KE, Sonstein J, Núñez G, Curtis JL, Luker GD - PLoS Pathog. (2008)

TRIF−/− mice are more susceptible to vaccinia infection than WT.TRIF−/− and WT BL/6 mice were infected with 1×104 pfu Vac-FL. (A) Weight loss, expressed as percent of initial weight. *p<0.05. (B) Chest luminescence, expressed as photon flux. Error bars denote SEM.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2529451&req=5

ppat-1000153-g001: TRIF−/− mice are more susceptible to vaccinia infection than WT.TRIF−/− and WT BL/6 mice were infected with 1×104 pfu Vac-FL. (A) Weight loss, expressed as percent of initial weight. *p<0.05. (B) Chest luminescence, expressed as photon flux. Error bars denote SEM.
Mentions: Unexpectedly, susceptibility of TRIF−/− mice to vaccinia infection was distinct from that of the TLR3−/− mice. TRIF−/− mice had less weight loss than wild-type mice on days 1–4 post-infection (p<0.05), which is similar to our published results for TLR3−/− versus wild-type mice, (Figure 1A). However, TRIF−/− mice differed from TLR3−/− animals in that replication of Vac-GFL was greater in mice lacking TRIF, as quantified by region of interest analysis of head, chest, and abdomen sites on bioluminescence images. By area under the curve (AUC) analysis, TRIF−/− mice had significantly greater luminescence in their chests (from lung infection) than wild-type mice (Figure 1B; p<0.01). These data indicate that a different and/or additional host molecule(s) controls responses to vaccinia in TRIF−/− mice relative to those mediated solely by TLR3. This experiment continued until day 7 post-infection, when the animals were euthanized to obtain plasma and bronchoalveolar (BAL) fluid for quantification of cytokines. Levels of IL-6, IL-4, IFN-γ, MCP-1, TNF-α, and TGF-β were measured in these samples, but no significant differences were seen between the TRIF−/− and WT mice (data not shown).

Bottom Line: We then focused on TLR4, the other Toll-like receptor that signals through TRIF.The mechanism of TLR4-mediated protection was not due to increased release of proinflammatory cytokines or changes in total numbers of immune cells recruited to the lung.These data establish that TLR4 mediates a protective innate immune response against vaccinia virus, which informs development of new vaccines and therapeutic agents targeted against poxviruses.

View Article: PubMed Central - PubMed

Affiliation: Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.

ABSTRACT
Innate immune responses are essential for controlling poxvirus infection. The threat of a bioterrorist attack using Variola major, the smallpox virus, or zoonotic transmission of other poxviruses has renewed interest in understanding interactions between these viruses and their hosts. We recently determined that TLR3 regulates a detrimental innate immune response that enhances replication, morbidity, and mortality in mice in response to vaccinia virus, a model pathogen for studies of poxviruses. To further investigate Toll-like receptor signaling in vaccinia infection, we first focused on TRIF, the only known adapter protein for TLR3. Unexpectedly, bioluminescence imaging showed that mice lacking TRIF are more susceptible to vaccinia infection than wild-type mice. We then focused on TLR4, the other Toll-like receptor that signals through TRIF. Following respiratory infection with vaccinia, mice lacking TLR4 signaling had greater viral replication, hypothermia, and mortality than control animals. The mechanism of TLR4-mediated protection was not due to increased release of proinflammatory cytokines or changes in total numbers of immune cells recruited to the lung. Challenge of primary bone marrow macrophages isolated from TLR4 mutant and control mice suggested that TLR4 recognizes a viral ligand rather than an endogenous ligand. These data establish that TLR4 mediates a protective innate immune response against vaccinia virus, which informs development of new vaccines and therapeutic agents targeted against poxviruses.

Show MeSH
Related in: MedlinePlus