PATHOGENESIS, PATHOLOGY AND IMMUNITY

Anaplasma, Ehrlichia and some Rickettsia species are known to exploit mammals as reservoir hosts, and they do so using strategies that best facilitate their transmission to arthropods.

Unlike Rickettsia species, Anaplasma and Ehrlichia species are unable to synthesize lipopolysaccharide or peptidogly­can. Both of these molecules are important pathogen/ microbe-associated molecular patterns, recognized by cells of the host innate immune system, so their absence is likely to help immune evasion by invading Anaplasma and Ehr­lichia species. In the absence of a conventional envelope, the integrity of the outer membrane of these species is maintained by incorporating cholesterol from the host cell. Endocytosis leads to cell entry and the creation of an intra­cellular inclusion, but this inclusion does not progress along the endocytic membrane transport pathway, and thus is not subjected to lysosomal fusion.

Little is known about the importance of specific bacte­rial proteins for intracellular survival, but one group of proteins that are likely to play a key role in granulocyte subversion are those that comprise a ‘type four secretion system’ that exports infection-mediating ‘effector’ pro­teins, including an ankyrin-repeat-domain-containing protein known as AnkA, directly into the host cell cyto­plasm. The function of this, or other effector proteins, may underlie the ability of A. phagocytophilum to inhibit neu­trophil apotosis, thereby prolonging the life span of its niche within a host. Another key mechanism by which A. phagocytophilum appears to prolong infection is through antigenic variation. The surface protein P44 has been found to be immunodominant, but it is now recognized that each bacterium has the ability to express one of about 100 different p44 pseudogenes in its genome, thereby creating antigenic diversity within an infecting A. phago- cytophilum population. Waves of sequentially expressed p44 loci have been documented in experimentally infected animals, and it is thought that the subsidence of waves follows specific host immunological response to them. This feature of A. phagocytophilum has led to it being dubbed a ‘microbial chameleon’, exploiting its ability to change its surface coating to facilitate its persistence within a reservoir host.

Anaplasma marginale, despite its tropism for erythro­cytes rather than neutrophils, shares some virulence traits with A. phagocytophilum. It too possesses a repertoire of p44 pseudogenes, which are expressed in a similar, con­certed, way. Unlike A. phagocytophilum, A. marginale has the capacity to generate genetic mosaics comprising frag­ments of different p 44 pseudogenes, a process that allows the generation of a vast array of antigenic variation within the P44 protein.

Ehrlichia canis is a parasite of monocytic cells and, like A. phagocytophilum, within their target cell E. canis resides within membrane-bound inclusions called morulae. How­ever, very little is known about the molecular mechanisms that mediate bacterial interaction with monocytic cells. Genomic analysis has revealed that E. canis, and other Ehrlichia species, possess a locus containing numerous copies of genes that encode for immunodominant 28 kDa outer membrane proteins. Expression studies suggest that some of these genes are preferentially expressed in macro­phages, but their role remains elusive.

Despite the benign nature of infections in reservoir host species, Rickettsia, Anaplasma and Ehrlichia species have the capacity to provoke overt disease, primarily in ‘acci­dental’ hosts (see animal and public health concern sec­tions below). No reports of the pathology associated with infections due to Rickettsia, Anaplasma or Ehrlichia species in European wildlife have been published; thus our knowl­edge of the pathology of these infections is drawn solely from observations in humans, companion animals or live­stock, which, for most species, are accidental hosts.

Infections by Rickettsia, Anaplasma and Ehrlichia species provoke an immune response in both reservoir hosts and accidentally infected hosts. Natural killer cell-derived inter­feron gamma and tumour necrosis factor are fundamental to the innate immune counter of infections through the activation of endothelial cells and macrophages, which are the major target cells for rickettsiae. In addition, as rickett­siae are inoculated through the dermis, resident dendritic cells (DC) play an important role in innate and acquired immunity by effectively presenting rickettsial antigens to T cells. T cells act against Rickettsia spp. in various ways, including the cytotoxic killing of infected target cells and cooperating with B cells in antibody production, which is an important defence against reinfection.