Legionella Feeleii: Pneumonia Or Pontiac Fever? Bacterial Virulence Traits and Host Immune Response

Medical Microbiology and Immunology (2019) 208:25–32 https://doi.org/10.1007/s00430-018-0571-0 REVIEW Legionella feeleii: pneumonia or Pontiac fever? Bacterial virulence traits and host immune response Changle Wang1 · Xia Chuai1 · Mei Liang2 Received: 17 July 2018 / Accepted: 27 October 2018 / Published online: 1 November 2018 © Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract Gram-negative bacterium Legionella is able to proliferate intracellularly in mammalian host cells and amoeba, which became known in 1976 since they caused a large outbreak of pneumonia. It had been reported that different strains of Legionella pneumophila, Legionella micdadei, Legionella longbeachae, and Legionella feeleii caused human respiratory diseases, which were known as Pontiac fever or Legionnaires’ disease. However, the differences of the virulence traits among the strains of the single species and the pathogenesis of the two diseases that were due to the bacterial virulence factors had not been well elucidated. L. feeleii is an important pathogenic organism in Legionellae, which attracted attention due to cause an outbreak of Pontiac fever in 1981 in Canada. In published researches, it has been found that L. feeleii serogroup 2 (ATCC 35849, LfLD) possess mono-polar flagellum, and L. feeleii serogroup 1 (ATCC 35072, WRLf) could secrete some exopolysaccharide (EPS) materials to the surrounding. Although the virulence of the L. feeleii strain was evidenced that could be promoted, the EPS might be dispensable for the bacteria that caused Pontiac fever. Based on the current knowledge, we focused on bacterial infection in human and murine host cells, intracellular growth, cytopathogenicity, stimulatory capacity of cytokines secretion, and pathogenic effects of the EPS ofL. feeleii in this review. Keywords Legionella feeleii · Pontiac fever · Legionnaires’ disease · Flagellum · Exopolysaccharide · Bacterial infection Introduction Legionella, they will cause respiratory diseases by the air- borne agent [4]. Legionellae are gram-negative intracellular pathogenic bacteria that are capable of living ubiquitously in natural or artificial aquatic environments, such as rivers, lakes, streams, Intracellular growth and Legionella feeleii fountains, air conditioning cooling towers, humidifiers, and whirlpool spas. The organisms live and grow in water Legionella can form a commensal relationship with freshwa- systems at temperatures of 20–50 °C, with the optimum at ter or soil amoebae [5, 6]. The bacteria can be provided with 35 °C [1]. The exception of Legionella living in the natural a niche for multiplication, and the resistance to disadvanta- environment is Legionella longbeachae, which was primar- geous environmental factors can be promoted [7–9]. Differ- ily isolated from the soil [2]. Until now, more than 60 species ent species of Legionella exhibited proliferation capacity in of Legionella have been identified, and at least 20 of them mammalian macrophages and epithelial cells [10–14]. After have been associated with the diseases [3]. Once humans entering the cytoplasm of the eukaryotes, the bacteria estab- inhale aerosolized water droplets that are contaminated by lish Legionella-containing vacuoles (LCVs) to avoid fusion with lysosomes and replicate inside the LCVs. The organisms rupture the vacuole membrane and lyse the host cells * Changle Wang [15]. Neighboring cells can be infected with the released [email protected] bacteria for sequential infection [16, 17]. During proliferation, different species of Legionella can even form different 1 Department of Pathogenic Biology, Hebei Medical intracellular colony morphologies in mammalian cells [18]. University, Shijiazhuang 050017, People’s Republic of China Legionella feeleii serogroup 1 (ATCC 35072, hereinaf- 2 School of Basic Medical Science, Hebei Medical University, ter referred to as LfPF) was reported for the first time in Shijiazhuang 050017, People’s Republic of China Vol.:(0123456789)1 3 26 Medical Microbiology and Immunology (2019) 208:25–32 1984, since the bacteria caused an outbreak of Pontiac fever adherence to human epithelial cells [29, 30] and invasion in Canada [19]. The same serogroup bacterium was also of Acanthamoeba atronyxis [31]. A variety of non-flagellar reported that caused pneumonia in two immunosuppressed toxins or effectors and flagellar proteins were demonstrated patients [20]. In 1985 in America, L. feeleii serogroup 2 that could be delivered to the extracellular milieu by the type (ATCC 35849, hereinafter referred to as LfLD) was iso- III-like protein secretion apparatus [32, 33]. lated from a Legionnaires’ disease patient [21]. However, Most of the Legionella species are flagellated pathogenic the pathogenesis of L. feeleii that caused Pontiac fever or organisms [34]. In previous researches, it is identified that Legionnaires’ disease has not been elucidated. L. feeleii flaA was one of the virulence factors that could affect bacte- could proliferate in human macrophages and amoeba at rial virulence in Legionella [35–37]. The flaA mutant strain 37 °C environment [22]. The bacteria can maintain the com- significantly reduced the infectious capacity to the eukaryote position of the cellular fatty acid in a stable status during the cells [38]. LfLD was observed that showed smooth-waved stationary growth phase. Due to the differences of bacterial mono-polar flagellum at 25 and 30 °C; however, LfPF did physiological age, L. feeleii could not grow as rapidly as L. not possess the flagellum [14]. Heuner et al. had reported pneumophila [23]. This organism showed lethal ability to that Western blot analysis for FlaA was positive in L. fee- guinea pigs at the bacterial concentration of 109/ml. How- leii ATCC 35849 (LfLD), but negative in L. feeleii ATCC ever, there were no death in guinea pigs after the bacteria 35072 (LfPF). They also found that L. feeleii ATCC 35849 were exposed to a series of disadvantageous factors, which (LfLD) was a flagellated bacterium by electron microscopy caused the bacterial toxic activity to be attenuated [24]. [39]. Based on these distinctions, LfLD was found that have enhanced invasion capacity to human epithelial cells and have promoted internalization by human and murine Characteristics and virulence traits macrophages (Fig. 1). While the key role of the flagellum of flagellum in Legionella feeleii for promoting bacterial entry to the host cells has been evidenced in LfLD, the same flagellar morphology cannot be Flagellum is an appendage of the bacterium whose structure found after the bacteria were cultured between 25 °C and is mainly comprised of three parts, such as a basal body, a 37 °C [14]. The flagellum of L. pneumophila JR32 showed hook structure, and a filament [25, 26]. In the process of the same smooth-waved morphology at 25, 30, and 37 °C assembling the flagellum, a type III-like secretion system (Wang et al., unpublished data). It is hypothesized that there plays a key role in exporting the hook and the filament-form- may be some differences in flagellin arrangement of flagel- ing proteins out of the bacterial cells [27]. In general, the lar production of LfLD at higher temperature. Ott et al. had flagellum can help the bacterium to evade adverse environ- reported that the flagellum of L. pneumophila expressed in a mental conditions, mediate chemotaxis toward favorable and temperature-dependent manner [40]. Actually, the numbers rich nutrimental areas, and promote bacterial virulence [28]. of the flagellated LfLD and L. pneumophila JR32 were the The flagellum was evidenced that it was connected with bac- most at 25 °C of the bacterial culture, moderate at 30 °C, and terial virulence traits, since it could contribute to bacterial less at 37 °C under the electron microscope [14]. Fig. 1 Simple illustration of entry into cytoplasm, intracellular proliferation and stimu- lated cytokines secretion of Legionella feeleii LfPF (WRLf anf BTLf) and LFLD. In bacterial entry, both flagellum and exopolysaccharide (EPS) play an important role in promoting internalization of bacteria by the host cells. LfLD could induce a great amount of cytokines secretion (direct arrow), while LfPF induced less (indirect arrow). Whether L. feeleii could form Legionella-containing vacuole (LCV, grey color) and Utilize Type 4 Secretion Syatem (T4SS) for proliferation in the cytoplasm, and the pathway of inducing cytokines production should be demonstrated 1 3 Medical Microbiology and Immunology (2019) 208:25–32 27 The virulence of the flagellum also affected cytopatho- [55]. Proinflammatory cytokines secretion is considered genicity and cytokines secretion, such as the flagellin which as a double-edged sword for the pulmonary cells and tis- were purified from two species of the motile wild type sue. It can contribute to playing a role in host defense when Legionella that triggered host cells death and induced IL-1β produced moderately [56]. Once excess of proinflammatory secretion, while the bacteria failed [41]. In L. pneumoph- cytokines are triggered to secrete, it may play as a patho- ila, the flaA mutant strain expressed deficiency in trigger- genic factor that could exacerbate the damage of the host ing murine bone marrow-derived macrophages death [42]. tissue and develop into pulmonary inflammation. In addi- Similar results were also found in L. feeleii. LfLD exhibited tion, the direct injury of the host pulmonary epithelial tissue stronger cytopathogenicity than LfPF, which killed approxi- that is caused by the intracellular

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