The Toll-Like Receptor 4 Agonist Monophosphoryl Lipid A Augments Innate Host Resistance to Systemic Bacterial Infection

Abstract

Monophosphoryl lipid A (MPLA) is a Toll-like receptor 4 (TLR4) agonist that is currently used as a vaccine adjuvant in humans. In this study, we evaluated the effect of MPLA treatment on the innate immune response to systemic bacterial infections in mice. Mice treated with MPLA after burn injury showed improved survival and less local and systemic dissemination of bacteria in a model of Pseudomonas aeruginosa burn wound infection. Prophylactic treatment with MPLA significantly enhanced bacterial clearance at the site of infection and reduced systemic dissemination of bacteria despite causing attenuation of proinflammatory cytokine production during acute intra-abdominal infection caused by cecal ligation and puncture. Administration of MPLA at 1 h after CLP also improved bacterial clearance but did not alter cytokine production. MPLA treatment increased the numbers of granulocytes, double-positive myeloid cells, and macrophages at sites of infection and increased the percentage and total numbers of myeloid cells mediating phagocytosis of bacteria. Depletion of Ly6G؉ neutrophils, but not macrophages, eliminated the ability of MPLA treatment to improve bacterial clearance. The immunomodulatory effects of MPLA were absent in TLR4-deficient mice. In conclusion, these studies show that MPLA treatment significantly augments the innate immune response to bacterial infection by enhancing bacterial clearance despite the attenuation of proinflammatory cytokine production. The enhanced bacterial clearance is mediated, in part, by increased numbers of myeloid cells with effective phagocytic functions at sites of infection and is TLR4 dependent.

Lipopolysaccharide Clearance, Bacterial Clearance, and Systemic Inflammatory Responses Are Regulated by Cell Type–Specific Functions of TLR4 during Sepsis

“…It was shown that TLR4 stimulation leads to enhanced phagocytosis of bacteria by macrophages (15). Furthermore, other investigators showed that agonists of TLR4 (33,46) or other TLRs (46), given either as a pretreatment or early postinfection, enhance bacterial clearance and survival in models of sepsis. We confirm in our current work that LPS given 1 h after CLP improves bacterial clearance.…”

“…Inflammation, tissue damage, and lethality are diminished in the absence of TLR4 signaling (29). However, in the setting of infection with live bacteria, the contribution of TLR4 varies depending on the experimental model and type of organism used in the study (13)(14)(15)(30)(31)(32)(33)(34)(35)(36)(37). Most early studies used mouse strains with mutant forms of TLR4.…”

Assessment of immunogenicity and protective efficacy of Microsporum canis secreted components coupled to monophosphoryl lipid-A adjuvant in a vaccine study using guinea pigs

“…MPLA is a detoxified form of the endotoxin lipopolysaccharide recognised by TLR-4 (Johnson et al, 1987) and is used as a vaccine adjuvant in humans (Thoelen et al, 1998). The MPLA improves the innate immune response to bacterial infections by increasing the number of cells with phagocytic functions at the sites of infection, which in turn enhances the bacterial clearance (Romero et al, 2011). This adjuvant is also able to stimulate the adaptive immune response by promoting the differentiation of CD4+ T cells into IFNγ-producing Th1 cells in mice (Thompson et al, 2005).…”

Toll-Like Receptor 4 Agonistic Antibody Promotes Innate Immunity against Severe Pneumonia Induced by Coinfection with Influenza Virus and Streptococcus pneumoniae

“…TLR4 mediates LPS responsiveness and recognizes Gram-negative bacteria via the LPS moiety on the surface of these microorganisms. Some researchers have reported that MPL treatment promotes neutrophil recruitment to the infectious source and mediates protection against both lethal systemic bacterial infection and nasopharyngeal colonization (28,29); however, little is known about whether the induction of innate immunity via TLR4 contributes to the protective immune response against bacterial infection. Therefore, in the current study, we used UT12, a new TLR4 agonistic monoclonal antibody, to address whether the promotion of innate host resistance through TLR4 mediates protection against secondary pneumococcal pneumonia following influenza virus infection.…”