Role of Francisella lipid A phosphate modification in virulence and long-term protective immune responses.
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-α), and gamma interferon(IFN-γ), was examined using knockout mice. Interestingly, only the IFN-γ knockout mice succumbed to a primary lpxF-null F. novicida mutant infection, highlighting the importance of IFN-γ 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.
Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Duangjit
D
Kanistanon
Daniel A
DA
Powell
Adeline M
AM
Hajjar
Mark R
MR
Pelletier
Ilana E
IE
Cohen
Sing Sing
SS
Way
Shawn J
SJ
Skerrett
Xiaoyuan
X
Wang
Christian R H
CR
Raetz
Robert K
RK
Ernst
D000818:Animals; D016207:Cytokines / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005603:Francisella / Q000276:immunology* / Q000378:metabolism / Q000472:pathogenicity*; D055786:Gene Knockout Techniques; D016905:Gram-Negative Bacterial Infections / Q000276:immunology / Q000382:microbiology / Q000401:mortality / Q000473:pathology; D007113:Immunity, Innate; D008050:Lipid A / Q000276:immunology / Q000378:metabolism* / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010710:Phosphates / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics; D016019:Survival Analysis; D014774:Virulence
D016207:Cytokines; D008050:Lipid A; D010710:Phosphates; D011971:Receptors, Immunologic; C095015:lipid A 4'-phosphatase; D010744:Phosphoric Monoester Hydrolases