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

• Published in: PLoS pathogens Vol. 4; no. 9; p. e1000153
• Main Authors: Hutchens, Martha A, Luker, Kathryn E, Sonstein, Joanne, Núñez, Gabriel, Curtis, Jeffrey L, Luker, Gary D
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.09.2008; Public Library of Science (PLoS)
• Subjects: Adaptor Proteins, Vesicular Transport - deficiency; Adaptor Proteins, Vesicular Transport - immunology; Animals; Biotechnology; Care and treatment; Cell receptors; Cells, Cultured; Chickenpox; Development and progression; Immune response; Immune system; Immunity, Innate; Immunology/Immunity to Infections; Infections; Lung Diseases - immunology; Lung Diseases - virology; Macrophages - immunology; Macrophages - virology; Mice; Mice, Knockout; Mortality; Physiological aspects; Poxvirus; Rodents; Smallpox; Toll-Like Receptor 4 - deficiency; Toll-Like Receptor 4 - immunology; Vaccines; Vaccinia; Vaccinia - immunology; Vaccinia virus; Vaccinia virus - immunology; Variola; Virology/Animal Models of Infection; United States
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1000153

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.