Abstract
Pulmonary hemorrhage has been recognized as a major, often lethal, manifestation of severe leptospirosis albeit the pathogenesis remains unclear. The Leptospira interrogans virulent serogroup Icterohaemorrhagiae serovar Lai encodes a protein (LA2144), which exhibited the platelet-activating factor acetylhydrolase (PAF-AH) activity in vitro similar to that of human serum with respect to its substrate affinity and specificity and thus designated L-PAF-AH. On the other hand, the primary amino acid sequence of L-PAF-AH is homologous to the α1-subunit of the bovine brain PAF-AH isoform I. The L-PAF-AH was proven to be an intracellular protein, which was encoded unanimously and expressed similarly in either pathogenic or saprophytic leptospires. Mongolian gerbil is an appropriate experimental model to study the PAF-AH level in serum with its basal activity level comparable to that of human while elevated directly associated with the course of pulmonary hemorrhage during severe leptospirosis. Mortality occurred around the peak of pulmonary hemorrhage, along with the transition of the PAF-AH activity level in serum, from the increasing phase to the final decreasing phase. Limited clinical data indicated that the serum activity of PAF-AH was likely to be elevated in the patients infected by L. interrogans serogroup Icterohaemorrhagiae, but not in those infected by other less severe serogroups. Although L-PAF-AH might be released into the micro-environment via cell lysis, its PAF-AH activity apparently contributed little to this elevation. Therefore, the change of PAF-AH in serum not only may be influential for pulmonary hemorrhage, but also seems suitable for disease monitoring to ensure prompt clinical treatment, which is critical for reducing the mortality of severe leptospirosis.
Highlights
Leptospirosis continues to be a leading zoonotic infection throughout the world [1]
Other two essential His224 and Asp227 residues were conserved in LA2144, which may form a catalytic triad with Ser80 as in a1 (Figure 1)
It suggested that LA2144 might have an ‘‘a1-subunit-like’’ function despite its unique N-terminal 22 residues (Figure 1) and the gene encoding LA2144 was tentatively designated l-paf-ah for leptospiral platelet-activating factor acetylhydrolase [14]
Summary
Pathogenic leptospires infection caused a diverse array of clinical manifestations ranging from subclinical infection to undifferentiated febrile illness to jaundice, renal failure, and potentially lethal pulmonary hemorrhage [2,3]. Pulmonary hemorrhage is the most frequent cause of death of leptospirosis [4,5,6]. Little is known about the substances and mechanisms responsible for the hemorrhage and hemoptysis involved in their pathogenicity. It is generally believed that neither thrombocytopenia nor diminution of hepatically synthesized clotting factors seen in human leptospirosis were sufficient to account for the bleeding diathesis observed per se [1,2,3]. In 2004, Nally et al reported that an autoimmune process may be involved in the etiology of fatal pulmonary hemorrhage in leptospirosis [13]
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