High-Temperature Protein G Is an Essential Virulence Factor of Leptospira interrogans

Abstract

e Leptospira interrogans is a global zoonotic pathogen and is the causative agent of leptospirosis, an endemic disease of humans and animals worldwide. There is limited understanding of leptospiral pathogenesis; therefore, further elucidation of the mechanisms involved would aid in vaccine development and the prevention of infection. HtpG (high-temperature protein G) is the bacterial homolog to the highly conserved molecular chaperone Hsp90 and is important in the stress responses of many bacteria. The specific role of HtpG, especially in bacterial pathogenesis, remains largely unknown. Through the use of an L. interrogans htpG transposon insertion mutant, this study demonstrates that L. interrogans HtpG is essential for virulence in the hamster model of acute leptospirosis. Complementation of the htpG mutant completely restored virulence. Surprisingly, the htpG mutant did not appear to show sensitivity to heat or oxidative stress, phenotypes common in htpG mutants in other bacterial species. Furthermore, the mutant did not show increased sensitivity to serum complement, reduced survival within macrophages, or altered protein or lipopolysaccharide expression. The underlying cause for attenuation thus remains unknown, but HtpG is a novel leptospiral virulence factor and one of only a very small number identified to date.

Leptospira interrogans lpxD Homologue Is Required for Thermal Acclimatization and Virulence

“…Leptospira burdens in kidneys and liver were determined by qPCR, as previously described (35,44), with the following modifications. The Leptospira Manilae wild-type, lpxD1 mutant, and lpxD1 complemented mutant strains were injected intraperitoneally into groups of 4 gerbils (10 4 bacteria per animal).…”

A Putative Regulatory Genetic Locus Modulates Virulence in the Pathogen Leptospira interrogans

“…Previous studies have identified a number of biological processes that appear to be required for leptospiral virulence. These include genes involved in motility (30,36), heme utilization (18), lipopolysaccharide biosynthesis (40), stress resistance (25,41,42), and the host-pathogen interaction (43) and genes that are involved in a manner that has not yet been determined (44,45). However, previous research has also negated the requirement of putative virulence factors LipL32 (46), LipL41 (47), and LigB (48) in the animal infection model.…”

Pathogenic <i>Leptospira</i>: Advances in understanding the molecular pathogenesis and virulence

“…Binding of L. interrogans Mce was also observed with the human leukocyte cell receptors alphaLbeta2 [(CD11a/CD18)-LFA-1] and alphaMbeta2 [(CD11b/CD18)-Mac-1], suggesting the participation of these proteins in the induction of host immune response . These and other studies (Oliveira et al, 2010;Lehmann et al, 2013;King et al, 2014) suggest that virulence of pathogenic Leptospira is mediated by a combination of factors derived from both the pathogen and susceptible host.…”

“…Furthermore, a recent analysis of the binding receptors for LexA and transcript turnover following stress associated with genotypic toxicity in L. interrogans , suggest that potential shifts in gene expression occur following DNA damage, thereby downregulating genes involved in cell growth and virulence, but upregulating genes involved in generation of gene mutations and recombination . In addition, a previous study described the potential role of iron metabolism in Leptospira , and explained how the pathogen responds to oxidative stress (King et al, 2014). The results have collectively shown the potential of transcript analysis to determine the mechanisms utilized by Leptospira in causing disease.…”

“…Additional studies described the mechanisms for the pathogen adaptation to thermal conditions (Eshghi et al, 2015a,b) and tolerance (Petrosova and Picardeau, 2014) outside the mammalian host. In addition, the inflammatory cascades that cause clinical disease (Gasque and Jaffar-Bandjee, 2015;Volz et al, 2015), virulence related proteins factors (King et al, 2014), bacteria-host interactions (Lo et al, 2009;Vieira et al, 2012;Siqueira et al, 2013;Fernandes et al, 2015), organization of the cytoskeletal and cellular in the host protein (Schuller et al, 2015) and defense mechanisms by the host (Werts, 2010) by pathogenic Leptospira have been described. Recent studies also identified leucine-rich repeat proteins that are known to be epitopes mediating antigen interaction (Nitipan et al, 2013), immune response factors in lipoproteins on the outer membrane of L. interrogans (Lin et al, 2010), ion transport mechanisms (Wu et al, 2004) and amino acid metabolism (Krajewska et al, 2016).…”