Perspectives Series: Host/Pathogen Interactions

The threat posed to human health by arthropod-borne bacteria is most vividly demonstrated by the devastating epidemics caused by the plague. The diversity of pathogenic bacteria spread by arthropods is probably underestimated. Recently recognized infectious diseases such as Lyme disease and ehrlichiosis are caused by bacteria transmitted by arthropods. Bacteria which alternate between arthropods and mammals have to survive and thrive in diverse niches. Because of the desire to prevent diseases caused by these organisms, more emphasis had been placed on understanding their life in the vertebrate rather than in the vector. However, understanding how these pathogens develop within their vectors may lead to novel control strategies. The most extensive studies on the development of pathogenic bacteria within arthropods have been done with the agent of plague, Yersinia pestis , and its flea vector. Recent studies with Borrelia burgdorferi , the Lyme disease spirochete, have also revealed insight into vector-borne transmission of bacteria. The work on B. burgdorferi is reviewed here, and when appropriate, contrasted with Y. pestis . In the northeastern United States, the Lyme disease spirochete is maintained in a natural cycle involving rodents and Ixodes scapularis ticks. Larval ticks acquire B. burgdorferi when they feed on infected mice, and the spirochetes survive through the molts and are present in all subsequent stages (nymphal and adult) of the vector. Mice acquire B. burgdorferi from infected nymphs. Studies have focused on events that take place when infected ticks transmit spirochetes to mice. Infected nymphs have several hundred B. burgdorferi present extracellularly in the lumen of the gut. When nymphs attach and engorge on mice, the spirochetes multiply to reach densities of . 100,000 bacteria in each tick. The gut is the primary site of B. burgdorferi residence and growth. Approximately 48 h into the blood meal, a few bacteria cross the gut epithelium into the hemocoel, invade the salivary glands, and then infect the host (1). Thus, B. burgdorferi , which primarily resides in the tick gut, invades the salivary glands only for a brief period during transmission. Similarly, Y. pestis resides in the lumen of an arthropod’s gut. In the gut of the flea, the bacteria multiply and form a plug that occludes the foregut and prevents successful feeding by the vector. During repeated, futile attempts at feeding by occluded fleas, Y. pestis are regurgitated into the mammalian host. Thus, although both Y. pestis and B. burgdorferi inhabit the gut lumen of their respective vectors, the two organisms use different routes of transmission. Y. pestis alters the feeding habits of the vector to increase transmission and eventually kills the flea, while there is no evidence that B. burgdorferi alters the behavior or survival of ticks. How do arthropod-borne bacteria adjust to the different niches they occupy? Several groups have found evidence of B. burgdorferi proteins expressed only at certain stages of the life cycle. Outer surface proteins (Osps) 1 A and B are two antigens coded on a bicistronic operon and abundantly expressed on the surface of spirochetes within unfed (flat) ticks. When nymphs feed, the majority of B. burgdorferi clear OspA and OspB from their surface and instead express OspC, a protein which is not expressed on spirochetes before tick engorgement (2, 3). Spirochetes that enter the host appear to continue expressing OspC and not OspA or OspB, because mice infected by tick bite rarely develop antibodies to OspA or OspB, while they readily seroconvert to OspC. However, during persistent infection of humans, OspA and OspB must be expressed (at least to some degree) because OspA and OspB antibodies are detectable in some patients with late-stage Lyme disease. Nevertheless, in general OspA and OspB appear to be tick-specific antigens while OspC appears to be expressed in feeding nymphs and in the vertebrate host. Immunological screening strategies have been developed to identify spirochetal genes that are differentially expressed in the vertebrate host. A B. burgdorferi expression library was screened using sera from infected mice and mice immunized with killed cultured spirochetes. Infected serum reflects the antigens that are expressed in the infected host, while the immunized serum represents antigens that are expressed on cultured spirochetes (in vitro) and possibly flat ticks. Antigens that are only recognized by infected sera may reflect genes that are selectively expressed in the mammalian host. The first host-specific gene isolated with this approach was p21 (4). Messenger RNA for p21 was readily detected in infected mice and not in cultured spirochetes, confirming the immunologic screening suggestion of in vivo expression. Recently, laboratories have identified more genes ( eppa , pG , bbk2.10 , and bmpD ) that appear to be induced in the mammalian host. An interesting feature of many of these genes is that they have homology to ospE and ospF , two surface proteins of spirochetes coded for by a single operon: both bbk2.10 and pG are homologues of ospF while p21 is an homologue of ospE . The B. burgdorferi ospE/F homologues appear to comprise a family of genes whose members are expressed at distinct stages of the spirochete’s life cycle. The environmental cues that regulate the expression of B. burgdorferi genes are not well understood although recent Address correspondence to Erol Fikrig, M.D., Yale University School of Medicine, Section of Rheumatology, P.O. Box 208031, 333 Cedar Street, New Haven, CT 06520-8031. Phone: 203-785-2454; FAX: 203785-7053; E-mail: [email protected] Received for publication 11 December 1996.