Leptospira is a genus of bacteria in the leptospiraceae family of the spirochaete phylum. The genus contains both pathogenic species and free living saprophytic species that do not infect animal hosts. Pathogenic Leptospira species are the causative agents of leptospirosis. The disease is a zoonosis that can infect several animals with its main reservoir in rats. Despite its significance (causing more than 500,000 cases of severe human disease worldwide in 1999) leptospirosis is considered a "neglected disease"  with relatively little increase in understanding it's pathogenesis since leptospira spp. were first implicated as the cause of infection in 1915.
Recent years however have shown a resurgence of interest in the disease as a result of several large outbreaks in Central and South America as well as emergence of the disease in groups, such as water sports practitioners , different from those traditionally affected.
This recent work using new genetic approaches as well as the publishing of genomes for three Leptospira species has begun to elucidate further the mechanisms by which the bacteria cause disease.
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Leptospira vary from around 0.25Âµm x 6Âµm in size to 0.25Âµm x 25Âµm and are comprised of a cylindrical cell body wound into a helix with either one or both of the ends of the bacterium are usually bent into a hook.
The cell membrane of Leptospira as with other spirochetes has features of both Gram positive and Gram negative membranes. The peptidoglycan layer of the membrane is associated with the inner membrane as with a Gram positive bacteria yet they also possess an LPS containing outer membrane as would be expected with a Gram negative bacterium.
Leptospira are highly motile organisms and this motility is conferred by 2 flagella extending from the inner membrane to the periplasmic space. In one model the rotation of these endoflagella causes rotation of the cell leading to screw like motion that can provide motility in both aqueous and viscous media.
Infection Cycle and Transmission
As mentioned above, Leptospira spp. are able to infect a variety of animals. These animals can be separated into maintenance hosts and incidental hosts. The maintenance hosts are those which continually circulate the pathogen amongst their population. Different maintenance hosts often carry different Leptospira serovars with some specific host-serovar relationships being particularly favoured. The most common maintenance hosts of Leptospira are rodents and this includes common host-serovar associations between rats and the Icterohaemorrhagiae serovar and also between mice and the Ballum serovar. Other maintenance hosts can include larger domestic animals such as dairy cattle which are associated with the hardjo, pomona and grippotyphosa serovars. The maintenance host will commonly not display the clinical signs of the disease and will develop chronic infections which result in the shedding of Leptospira over an extended period or life span.
Incidental hosts in contrast can become infected through contact with the maintenance host or environment contaminated by the maintenance host. Such infections can result in disease of varying severity including the severe acute diseases observed in humans and dogs and the symptomatic chronic infections observed in livestock.
Leptospira are transmitted to humans primarily through the urine of an infected animal carrier. Within the maintenance hosts the bacteria establish persistent infections within the renal tubules, in rats for example the Leptospira initially cause a systemic infection which is cleared by the immune system from everywhere but the renal tubules. Which are not cleared due to their status as an immunopriviliged site. This colonisation results in dense population of the renal tubules with bacteria and an associated high load of Leptospira in the rat urine of up to 107 organisms per ml. After excretion in the urine the bacteria are able to survive in the soil or water for weeks and even months by forming aggregates.
Transmission from this contaminated soil or water to humans can occur in several ways. The usual route is by penetrating abraded or cut skin that comes into contact with the contaminated material. Leptospira can also penetrate the mucous membranes of the respiratory and digestive tracts and this enables transmission via drinking or inhaling water or eating contaminated food. Once inside the body the bacteria rapidly cross tissue barriers and establish systemic infection.
Disease and Virulence
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Infection with Leptospira results in a wide spectrum of clinical features. Subclinical infection or symptoms so mild that no medical attention is sought seemingly occurs in a substantial proportion of cases. Symptoms of acute leptospirosis are typically fever, headache, nausea and vomiting.
The most severe cases of infection present as Weil's disease which is typified by jaundice, renal failure and haemorrhage. Fatality rates for Weil's diseases range from 5%-15%.
A further form of leptospirosis, Leptospirosis-associated pulmonary haemorrhage syndrome (LPHS) has emerging as a major cause of haemorrhagic fever in developing countries.
The factors important for the ability of Leptospira to cause disease are only beginning to be identified and described, largely with the aid of the sequencing of 3 Leptospira genomes. 1 saprophytic and 2 pathogenic species have been sequenced and this has allowed comparative genome analysis which has begun to identify genes and proteins of importance to virulence.
A common backbone of 2052 proteins has been identified among the species whilst 656 proteins have been found that only appear in the pathogenic species and not the free living Leptospira. Of these 656 pathogen specific proteins, 59% have unknown functions and thereby suggest unique pathogenic mechanisms in Leptospira spp.
One major difference between the two pathogenic species genomes has helped to explain the different modes of transmition they use. The L. Borgpetersenii species has a significantly smaller genome at 3.9MB than does the L.interrogans species with 4.6MB. Additionally L. Borgpetersenii has a higher proportion of its genome taken up by pseudogenes and transposons (20% as opposed to the 2% in L.interrogans). These observations may explain the poor survival of L. Borgpetersenii in the environment with its reduced genome not coding for genes required for efficient survival in water such as the reduced complement of signal transduction genes. With a reduced ability to survive in the environment the ability to transfer through water and contaminated soil is reduced and a greater dependence on direct host to host contact is the result.
In addition to such general features, specific genes and proteins of pathogenic Leptospira are being identified as factors contributing to their virulence.
An important step in the establishment of systemic leptospirosis in a host is the crossing of tissue barriers by the bacterium. Other spirochetes accomplish this by spreading through intracellular junctions however it has been demonstrated that this is not the case for Leptospira spp. which instead are thought to enter and traverse host cells. In order to accomplish this the Leptospira form an "intimate association" with the host cells before entering and rapidly crossing the cell layer. With such a host cell -Leptospira interaction it should be unsurprising that many putative virulence factors are leptospiral surface proteins with suspected roles as adhesins.
Loa22 - One such protein is Loa22 which, although it's function is unknown does possess some host-cell adhesion activity. Loa22 is the only gene so far identified as a putative virulence factor that fulfils Koch's molecular postulates for a virulence factor. The postulates state that the property under investigation should be associated with pathogenic strains of the organism. This is the case with Loa22 found to be conserved amongst Leptospira that cause disease but not found in saprophytic species (though an orthologue does exist).
The postlulates further state that specific inactivation of the gene should result in a reduction in pathogenicity and this too is shown to occur with Loa22- strains of pathogenic Leptospira(with the gene knocked out by transposon) are not able to cause any death in guinea pig models and show a 90% reduction in mortality in hamsters.
Finally, restoration of the mutated gene should restore pathogenicity and this was again shown to be the case with complementation restoring lethality in the animal models.
As mentioned above, the precise role that Loa22 plays in the pathogenesis of leptospirosis has not been determined. The Loa22 protein has an OmpA domain and OmpA has been shown to be an adhesin in Gram negative bacteria. Additionally Loa22 has been shown to show limited binding to the extracellular matrix and this may indeed be its role in determining pathogenicity.
Alternatively however, OmpA type proteins have been suggested as playing a role in envelope stabilisation and as Loa22 has a peptidoglycan binding motif it is thought that it may act as a bridge between the inner membrane associated peptidoglycan layer and the outer membrane sheath.
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Lig Proteins - Leptospiral immunoglobulin-like proteins (Lig proteins) are members of a wider group of proteins called the bacterial immunoglobulin-like proteins. Three Lig proteins have been identified in Leptospira and found to be exclusive to the outer membranes of pathogenic species. The Lig proteins (LigA, LigB and LigC) are able to bind to a variety of host extracellular matrix proteins especially fibronectin and fibrinogen. In addition, bacterial immunoglobulin-like proteins are known to be involved in host cell interactions in other pathogenic bacteria. An example would be the Escherichia Coli protein intimin which is known as a major virulence factor in enterohaemorrhagic strains where it is involved in adherence to host cells.
For these reasons the Lig proteins are considered to be putative virulence factors. Investigation of LigB using a LigB- strain of L. interrogans however, has failed to confirm the importance of the protein for virulence. No reduction in adherence was noticed in the LigB- mutants, nor was there any significant difference in the ability of the mutant to infect hamster or rat hosts. The significance of this result however is complicated by the possibility of redundancy within the bacterium. With several other putative adhesins recognised (including LigA) it is possible that the loss of LigB is compensated for by other proteins. Indeed, LigA is hypothesised to be derived from LigB by gene duplication and modification and they possess substantial identical sections possibly indicating a similar function. This introduces the possibility that the normal role of LigB as a contributing factor virulence was obscured in this experiment.
LipL32 - LipL32 is another surface exposed protein which makes up a significant portion of the proteins on the outer membranes of pathogenic Leptospira. The protein is highly conserved amongst pathogenic species and with no orthologues in saprophytes had long been thought to be a determinant of virulence. Further evidence suggested that LipL32 may play a role as an adhesin binding Leptospira to the extracellular matrix. The C-terminus of LipL32 was found to bind to a variety of host matrix components including type IV collagen and plasma fibronectin in addition to laminin and 2 further collagen types.
The LipL32 protein was shown not to fulfil Koch's molecular postulates however in that inactivation of the gene was not shown to produce a reduction in virulence. There was no observed reduction in adherence to the extracellular matrix in the mutant strain, and the progression of the infection both in hamsters (to acute clinical manifestations) and in rats (to colonisation of renal tubules) was indistinguishable from that of the wild type. As such the role of LipL32 in infection by Leptospira is not clear.
The issue is further clouded by the observation that LipL32 is able to induce a strong inflammatory response in the renal tubules of infected mice and potentially cause damage to the tubules in this way.
Endostatin-like Proteins - Leptospira Endostatin-like proteins (Len proteins) are a class of proteins identified as being present in the pathogenic L. Interrogans species but not possessing homologues in saprophytes. 6 such proteins have been currently identified, LenA (also called LfhA) through LenF. Though homologues of each other they have varying functions, one such function is adhesion to the extracellular matrix of the host. LenC, Len E and Len F in particular show a strong binding affinity for laminin, and LenB binds to both laminin and fibronectin. This suggests a potential role for these proteins in forming the association with host cells.
Additionally however, 2 of these proteins (LenA and LenB) may contribute to the ability of Leptospira to evade the host immune system during infection. Both proteins exhibit binding activity for Factor H which mediates the alternative complement pathway. Many other pathogenic bacteria including Neisseria meningitides produce outer surface proteins that bind Factor H. It is hypothesised therefore that in these species and in Leptospira the ability to bind Factor H confers resistance to complement-mediated killing and thus facilitates infection. Yet again however this has not been tested by mutating these genes.
Host Cell Penetration - In addition to close association through adhesion, the crossing of tissue barriers requires penetration of the host cells. Pathogenic Leptospira have been found to produce a range of proteins including various haemolysins and proteases which may accomplish this. One such protein, the haemolysin SphH has been found to form pores on the cells of the host. It is suggested that disruption of the epithelium by this protein could assist the bacteria in entering the bloodstream and beginning systemic infection. This protein is not found in the saprophytic Leptospira and may be important for establishing infection.
Additionally, analysis of the genome has shown that some pathogenic Leptospira possess genes coding for homologues of proteins involved in host cell invasion in other bacteria. These include the Mammalian Cell Entry (Mce) protein found in Mycobacterium tuberculosis and the InvA gene found in Rickettsia prowazeskii. These proteins are virulence factors in their respective bacteria and the homologues in Leptospira could potentially play a similarly important role.
Motility - Motility is common to both pathogenic and saprophytic species of Leptospira but is thought to still be a potentially important factor for virulence. Investigations into the ability of Leptospira to cross tissue barriers have suggested that the speed with which the barrier is crossed may play an important role in determining pathogenicity. It is suggested that the corkscrew motility of Leptospira which enables movement through viscous media may facilitate movement of the bacteria through host cell cytoplasm.
Some support for the importance of motility in virulence comes from the observation that freshly isolated pathogenic bacteria have display greater motility than passaged strains. Of the 50 genes found to be related to motility however, none have been tested to determine whether a loss of motility results in a loss of pathogenicity and as such the importance of motility for virulence remains unconfirmed.
Cleavage of Host Cell Proteins
Capsid Protein Maturation
Gag and Gag-Pro-Pol Processing
Env Expression and Processing
Cleavage of Host Cell Proteins
Release of Virus
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