When the tail wags the dog

Flagella are whip-like structures that power the movement of certain cells. Analysis of a single-cell parasite, the African trypanosome, reveals that flagella are also essential for viability in this organism.

Many cells can move from one position to another, by various means. One locomotive structure that emerged early in evolution is a whip-like appendage called the flagellum that propels the cell by a cyclical beating motion. Stationary cells also use flagella and their shorter relatives, cilia, to move liquid across their surface, as in the lining of air passages for example. In nucleated, or eukaryotic, cells, the flagellum is wrapped in cell membrane and encompasses a central, flexible rod — the axoneme — that generates the beating motion. The flagella from diverse organisms have a remarkably similar morphology for the axoneme, with a cylindrical array of nine filaments called microtubules surrounding two core microtubules, which hints that the building-blocks of these structures have been highly conserved during evolution.

On page 224 of this issue, however, Broadhead et al.¹ reveal a surprising diversity among organisms of the roughly 300 proteins that form the microscopic bricks and mortar of the axoneme. Nonetheless, they also discovered that molecular components of the axoneme in the unicellular African trypanosome parasite are conserved from these ancient protozoa to humans. In humans, abnormal forms of these proteins are linked with debilitating diseases. Perhaps most remarkably, the authors have uncovered a more fundamental role for flagella than cellular motility. Flagella are essential for trypanosome cell division, and thus viability — an observation that may help in developing therapies against African sleeping sickness, the fatal disease caused by these parasites.

Proteomic analysis has become an increasingly powerful tool for defining the structures of subcellular bodies, termed organelles, that perform specialized functions for cells. In this approach, a particular organelle (or sub-structure thereof) is purified and the constituent proteins are identified by sophisticated mass spectrometry. When Broadhead et al.¹ applied this proteomic analysis to isolated flagellar axonemes from the African trypanosome, they discovered that there were many proteins in the trypanosome organelle that could not be identified from the sequenced genomes of other organisms (with the exception of two other parasitic protozoa closely related to African trypanosomes). A similar analysis by these authors of recently published data on flagellar axonemes from two other unicellular eukaryotes^2,3 revealed similarly unique cohorts of axonemal proteins in all three organisms compared. So the apparently conserved morphology of the axoneme belies a hidden molecular diversity.

All the same, there are also axonemal proteins that are conserved between trypanosomes and humans. When the authors identified the human chromosomal regions encoding all these conserved axonemal proteins, they found 34 genes that mapped to 25 loci that had been implicated previously in a plethora of genetic diseases. The characteristics of these conditions are consistent with defects in flagella or cilia. These diseases cover a broad spectrum ranging from hydrocephalus and polycystic kidney disease to epilepsy. Although in each case a rough genetic locus had been associated with disease, the specific disease-associated genes had not been identified previously. So Broadhead and colleagues' examination of the ancient trypanosomes has done a significant service to human biology and medicine by identifying likely candidates for disease-causing genes. These results highlight the often-overlooked virtues of studying unusual or ‘primitive’ organisms.

But of course trypanosomes cause a serious disease in their own right. African sleeping sickness is a fatal infection that currently afflicts an estimated 300,000–500,000 people in sub-Saharan Africa⁴. How does the new work¹ help in understanding this devastating disease? This is perhaps the most intriguing part of the story. The authors examined the role of five trypanosome axonemal proteins using RNA interference, a powerful genetic method that allows the selective degradation of an individual messenger RNA, specifically reducing the encoded protein. In all five cases, the trypanosomes underwent a fatal meltdown when they could no longer make each axonemal protein. Although the parasites continued to replicate their DNA, divide their nuclei, and generate new flagella and other organelles, they were unable to divide into independent daughter cells. Instead, they formed spectacularly distorted ‘monster’ cells (Fig. 1) with multiple nuclei and flagella, and rapidly died.

Figure 1: Failed flail.

S. GRIFFITHS/K. GULL

a, A scanning electron micrograph of the bloodstream form of a normal African trypanosome. b, A parasite in which expression of one of the flagellar axoneme proteins has been destroyed by RNA interference of the corresponding messenger RNA. Broadhead et al.¹ found that the contorted ‘monster’ parasite has multiple nuclei and flagella, and cannot divide. Scale bar, 1 µm. Another example is shown on the cover of this issue.

These results were initially astonishing, but they are consistent with observations from the same laboratory that trypanosomes use their flagella to determine cell polarity during division⁵. These previous revelations hinted at what the current paper now confirms, that flagella are indispensable for telling parasites how to divide — especially in the stage of their life cycle when they are in the bloodstream, causing the human and animal disease. Indeed, the flagellum seems to be the tail that wags the dog. These results raise the intriguing possibility of developing drugs that act selectively against the trypanosome-specific axonemal proteins. It may be possible to identify compounds that cripple the parasite flagellum while leaving the distinct proteins of the human axoneme alone.