Role of Francisella Lipid A Phosphate Modification in Virulence and Long-Term Protective Immune Responses

被引:27
作者
Kanistanon, Duangjit [1 ,2 ]
Powell, Daniel A. [1 ]
Hajjar, Adeline M. [3 ]
Pelletier, Mark R. [1 ]
Cohen, Ilana E. [4 ]
Way, Sing Sing [6 ]
Skerrett, Shawn J. [5 ]
Wang, Xiaoyuan [7 ]
Raetz, Christian R. H. [8 ]
Ernst, Robert K. [1 ]
机构
[1] Univ Maryland, Dept Microbial Pathogenesis, Baltimore, MD 21201 USA
[2] Mahidol Univ, Fac Med, Dept Immunol, Siriraj Hosp, Bangkok 10700, Thailand
[3] Univ Washington, Dept Immunol, Seattle, WA 98195 USA
[4] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA
[5] Univ Washington, Harborview Med Ctr, Dept Med, Seattle, WA 98104 USA
[6] Univ Minnesota, Dept Pediat, Div Infect Dis, Minneapolis, MN 55455 USA
[7] Jiangnan Univ, State Key Lab Food Sci & Technol, Wuxi, Peoples R China
[8] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA
关键词
LIVE VACCINE STRAIN; IFN-GAMMA; BACTERIAL CLEARANCE; IN-VIVO; TULARENSIS; INFECTION; LIPOPOLYSACCHARIDE; INTERFERON; MUTANT; LPS;
D O I
10.1128/IAI.06109-11
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Lipopolysaccharide (LPS) structural modifications have been shown to specifically affect the pathogenesis of many Gram-negative pathogens. In Francisella, modification of the lipid A component of LPS resulted in a molecule with no to low endotoxic activity. The role of the terminal lipid A phosphates in host recognition and pathogenesis was determined using a Francisella novicida mutant that lacked the 4' phosphatase enzyme (LpxF). The lipid A of this strain retained the phosphate moiety at the 4' position and the N-linked fatty acid at the 3' position on the diglucosamine backbone. Studies were undertaken to determine the pathogenesis of this mutant strain via the pulmonary and subcutaneous routes of infection. Mice infected with the lpxF-null F. novicida mutant by either route survived primary infection and subsequently developed protective immunity against a lethal wild-type (WT) F. novicida challenge. To determine the mechanism(s) by which the host controlled primary infection by the lpxF-null mutant, the role of innate immune components, including Toll-like receptor 2 (TLR2), TLR4, caspase-1, MyD88, alpha interferon (IFN-alpha), and gamma interferon(IFN-gamma), was examined using knockout mice. Interestingly, only the IFN-gamma knockout mice succumbed to a primary lpxF-null F. novicida mutant infection, highlighting the importance of IFN-gamma production. To determine the role of components of the host adaptive immune system that elicit the long-term protective immune response, T- and B-cell deficient RAG1(-/-) mice were examined. All mice survived primary infection; however, RAG1(-/-) mice did not survive WT challenge, highlighting a role for T and B cells in the protective immune response.
引用
收藏
页码:943 / 951
页数:9
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