Immune pathways distinct evolutionary patterns in sequential phases of immune responses

Using the established framework, the immune repertoires can be dissected into several different phases. Commencing with molecular recognition of microbial patterns, the immune signals produced subsequently pass through a modulation phase, followed by signal transduction and activation of effector responses (Table 6.1). Signalling through the Toll or Imd pathways is known to be triggered by members of the recognition receptor families: Gram-negative-bacteria-binding proteins (GNBPs) or peptidoglycan-recognition proteins (PGRPs) (see Chapter 2). The repertoire of recognition receptors for universally encountered micro-bial groups such as bacteria and fungi appears to have evolved through species- and lineage-specific duplication events, of genes and domains, leading to expanded sets of related genes. These data, in conjunction with the sequence similarity between members of the recognition families, indicate that insects employ a conservative evolutionary strategy for the recognition of bacterial and fungal molecular patterns, complemented with species-specific fine-tuning via gene duplications and minimal sequence divergence.

Each of the genes encoding the Gram-negative peptidoglycan recognizing DmPGRP-LC and its Anopheles orthologue have three PGRP domains capable of alternative splicing. However, their domains apparently arose through phylogenetic-ally independent duplications: they are more similar within each species than between species. In Drosophila, a separate duplication of two adjacent PGRP-LC domains has generated the PGRP-LF gene, which is not found in mosquitoes. PGRP-SD is fruit fly-specific and recognizes Gram-positive bacteria to activate the Toll pathway. The same activation is served by DmPGRP-SA, which has mosquito orthologues and functions together with GNBP1 to process polymeric peptidoglycan, making it accessible to PGRP-SA (Wang et al., 2006). A large mosquito-specific expansion has generated a group of B-type GNBPs, distinct from the two A-type orthologous pairs that more closely resemble the three fruit fly GNBPs. DmGNBP3

recognizes fungi, possibly through binding ß-1,3-glucans, suggesting that mosquito A-type GNBPs may serve a similar function; the B-type receptors may facilitate novel recognition interactions (Warr et al, 2008).

Triggering of signalling through fungal and Gram-positive recognition in Drosophila activates an extracellular cascade of serine proteases and their serpin inhibitors, all of which lack mosquito orthologues. The cascade culminates in proteolytic cleavage of a cytokine precursor, Spätzle, releasing an active factor that binds to the Toll receptor (DmToll-1) and leads to intracellular Toll pathway signal transduction. No clear orthologues of this DmToll-1 have been identified in mosquitoes; instead, gene duplications have created a clade of mosquito genes related to both DmToll-1 and DmToll-5 (Figure 6.2). Toll pathway cytoplas-mic signal transduction occurs through a chain of interacting partners—MyD88, Tube, Pelle, TRAF6, and CACT—which are strictly maintained as single-copy orthologues, but evolve extensively in sequence. The same is true for the components of the Imd pathway: Imd, FADD, Dredd (CASPL1), IAP2, TAK1, and IKKy and ß. This observed pattern of persistent orthology coupled with high sequence divergence also applies to the signal transducers Dome and Hop in the immune-signalling JAK/STAT pathway, which is activated in Drosophila by viral infections (Dostert et al., 2005). These observations lead to the hypothesis that the requirement to interact productively with others in the same chain may drive escalating sequence divergence among these factors: mutations may be mutually acceptable between interacting partners, leading to coherent evolution rather than stasis. These characteristics highlight that the serially interacting signal transducers evolve in concert: strong selective pressure on pathway maintenance is combined with parallel diversification of their sequences.

The final stage of signal transduction leads to nuclear translocation of NF-kB transcription factors and activation of transcriptional responses; for example, the upregulation of immune effector genes. Several quite different effector mechanisms provide collective defence through the immune responses of lysis, melanization, encapsulation, or phagocytosis. Understanding the evolutionary patterns exhibited by these effector families requires an understanding of their modes of action. AMPs such as defensins and cecropins exhibit species- and lineage-specific duplications, while others such as gambicin appear as novelties, only in mosquitoes. Enzyme families implicated in oxidative defence, such as peroxidases show several expansions, but exhibit low sequence divergence, suggestive of constraints to preserve ubiquitous catalytic activities. Thus, effectors acting directly on microbes diversify rapidly or are species- specific, whereas enzymes that produce chemical cues to attack invaders remain conserved, but expand independently in each species.

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