Outer Membrane Protein-Specific Monoclonal Antibodies Protect SCID Mice from Fatal Infection by the Obligate Intracellular Bacterial Pathogen Ehrlichia chaffeensis

Abstract

Previous studies of Ehrlichia chaffeensis infection in the mouse have demonstrated that passive transfer of polyclonal Abs from resistant immunocompetent mice to susceptible SCID mice ameliorated infection and disease, even when Abs were administered during established infection. To identify particular Abs that could mediate bacterial clearance in vivo, E. chaffeensis-specific mAbs were generated and administered to infected SCID mice. Bacterial infection in the livers was significantly lowered after administration of either of two Abs of different isotypes (IgG2a and IgG3). Moreover, repeated administration of one Ab (Ec56.5; IgG2a) rescued mice from an otherwise lethal infection for at least 5 wk. Both protective Abs recognized the E. chaffeensis major outer membrane protein (OMP)-1g. Further studies revealed that both Abs recognized closely related epitopes within the amino terminus of the first hypervariable region of OMP-1g. Analyses of human sera showed that E. chaffeensis-infected patients also generated serological responses to OMP-1g hypervariable region 1, indicating that humans and mice recognize identical or closely related epitopes. These studies demonstrate that OMP-specific mAbs can mediate bacterial elimination in SCID mice, and indicate that Abs, in the absence of cell-mediated immunity, can play a significant role in host defense during infection by this obligate intracellular bacterium.

Structure-Based Vaccines Provide Protection in a Mouse Model of Ehrlichiosis

“…Previous studies in our laboratory and elsewhere have demonstrated that P28-19 is the most efficient and protective P28 paralog which provides protection against Ehrlichia [18], [19].…”

“…Studies from our laboratory and others have previously demonstrated the importance of antibodies in protection against Ehrlichia . Passive transfer of polyclonal immune sera or mAbs confers protection in SCID mice against E. muris and E. chaffeensis , respectively [18], [32]. Prior studies in mouse models have demonstrated that vaccination with P28 leads to immunity and clearance of Ehrlichia infection.…”

“…A previous study showed that mice immunized with the recombinant E. chaffeensis P28-19 (rP28) enhanced the spontaneous clearance of the infection in BALB/c mice [35]. A study by Li et al [18] indicated that a mAb directed against the E. chaffeensis P28-19 (OMP-1g) reduced the bacterial burden in SCID mice. Though they reported that the region spanning amino acids 68–90 of P28-19 of E. chaffeensis contains a B cell eptiope, subsequent studies by the group [19] utilized the 77–92 amino acid sequence to generate peptides.…”

A re-evaluation of the role of B cells in protective immunity to Chlamydia infection

“…Interestingly, in an effort to find the protective mechanism mediated by a C. burnettii phase I vaccine (PI-V) strain, Zhang et al demonstrated that a switched IgG response to PI-V lipopolysaccharide (LPS) provided significant protection to the host to an extent comparable to PI-V vaccination against C. burnetii infection [68]. Similar observations have also been made in obligate intracellular Ehrlichia chaffeensis infections, where antibody recognizing the major outer membrane protein (OMP)-1g of E. chaffeensis protects SCID mice from ehrlichiosis, a vector-borne disease [69]. …”

CD11c+ T-bet+ memory B cells: Immune maintenance during chronic infection and inflammation?

“…Although E muris was originally described as a mouse pathogen, a closely related, if not identical pathogen, has been shown to infect humans (known as the E. muris -like agent, or EMLA; [4]). As an obligate intracellular pathogen, E. muris cannot replicate outside of host cells, although we have reported that the bacteria can be found extracellularly [5], a property that is presumably necessary to facilitate blood-borne transmission, and which at the same time may predispose the bacteria to clearance by antibodies [6]. E. muris infection, which is not fatal in immunocompetent mice and humans, nonetheless causes a number of clinical manifestations, including anemia, thrombocytopenia, splenomegaly, as well as hematological alterations, including myelopoiesis and perturbation of the hematopoietic stem cell niche [7].…”