Burkholderia pseudomallei (Bp) is the causative agent of melioidosis, a disease of the tropics with high clinical mortality rates. To date, no vaccines are approved for melioidosis and current treatment relies on antibiotics. Conversely, common misdiagnosis and high pathogenicity of Bp hamper efforts to fight melioidosis. This bacterium can be isolated from a wide range of niches such as waterlogged fields, stagnant water bodies, salt water bodies and from human and animal clinical specimens. Although extensive studies have been undertaken to elucidate pathogenesis mechanisms of Bp, little is known about how a harmless soil bacterium adapts to different environmental conditions, in particular, the shift to a human host to become a highly virulent pathogen. The bacterium has a large genome encoding an armory of factors that assist the pathogen in surviving under stressful conditions and assuming its role as a deadly intracellular pathogen. This review presents an overview of what is currently known about how the pathogen adapts to different environments. With in-depth understanding of Bp adaptation and survival, more effective therapies for melioidosis can be developed by targeting related genes or proteins that play a major role in the bacteria's survival.

Introduction

Melioidosis is a life-threatening disease caused by the highly pathogenic Burkholderia pseudomallei [1]-a Gram-negative β-proteobacterium environmental saprophyte that dwells in soil, streams, groundwater and rice paddies [2]. In Southeast Asia and northern Australia, infection by B. pseudomallei (Bp) is endemic [1] and the mortality rate for melioidosis remains high. This pathogen is responsible for 20–30% of septicemic cases and 40% of sepsis-related mortality [3]. Recently, reports of endemic melioidosis have been increasingly reported in southern China [4], Hong Kong [5], Taiwan [6], Papua New Guinea [7], South Asia [8,9], Middle East [10], and Africa [11,12]. Additionally, sporadic cases have been reported in Brazil [13], the Americas [14,15], New Caledonia [16], Mauritius [17], and Madagascar [18]. Imported melioidosis cases were also reported in Europe [19], South Korea [20], and Japan [21]. It is estimated that annually about 165 000 human melioidosis cases are reported worldwide with a mortality rate projected at 50% [10] in resource-limited countries.

The bacteria is acquired through direct contact with contaminated water or soil and transmission of Bp occurs through percutaneous inoculation and ingestion [22] while the possibility of infection is low through inhalation [23]. The clinical manifestations of melioidosis are extremely diverse as reviewed by Lee and Nathan [24] and Bp infection can be acute, chronic or latent [25]. Up to 85% of reported melioidosis cases are acute infections with death recorded within 24–48 h after bacterial exposure [26] usually a result of sepsis with or without pneumonia or localised abscesses. Chronic melioidosis is the most common presentation of this disease and remains undiagnosed until activated by traumatic events or post-mortem examination of tissues [27]. Once activated, chronic melioidosis often mimics tuberculosis [28]. As melioidosis is a manifestation of non-specific symptoms, it is often referred to by its nickname, ‘the great mimicker’ [25] which inadvertently can delay accurate diagnosis of melioidosis, resulting in high fatality rates [19,29]. Relapse melioidosis cases from latency are possible, albeit uncommon [22].

Treatment of melioidosis is currently limited to β-lactam antibiotics such as ceftazidime, imipenem, meropenem, trimethoprim-sulfamethoxazole and amoxicillin-clavulanate [22,30]. To date, no approved vaccine is available for melioidosis as the vaccine candidates that provide partial protection in Bp infected mice fail to completely achieve sterilising immunity and none have progressed to nonhuman primates or human trials. However, more recently, a ΔtonB Δhcp1 mutant that successfully activated a robust immune response and offered full protection against a Bp aerosol infection looks promising as a potential vaccine [31].

Pathogenesis of B. pseudomallei

The genome of Bp is 7.24 Mb and unevenly distributed across two chromosomes of 4.07 Mb and 3.17 Mb. The large chromosome encodes proteins involved in cell growth and core metabolism whereas the smaller chromosome carries genes associated with adaptation and survival. Approximately 6.1% of the Bp genome is made up of genomic islands that are associated with in vivo survival of Bp [32]. The initial prediction of 16 genomic islands in the Bp K96243 strain varies in other strains and may account for potential differences in virulence between Bp isolates [33].

A mammalian host can be infected by soil or water contaminated with Bp through skin abrasions or mucosal surfaces. Bp can infect both epithelial and phagocytic (macrophages and neutrophils) cells [34]. Bp can adhere to different cell types such as endothelial cells, platelets and monocytes that express protease-activated receptor-1 (PAR-1) [35]. Upon close contact with the host cells, Bp deploys the injectisome Type III Secretion System (T3SS) and exports toxins (effectors) from the bacterial cytosol into the host cytosol, as reviewed by Galán et al. [36]. There are three types of T3SS (T3SS-1 to -3) [37] but only T3SS-3 is required for animal pathogenesis [38]. BipC is one of the many effectors secreted by T3SS-3 that facilitates cell invasion by rearranging the host actin cytoskeleton [39].

Cyclic diguanylic acid (c-di-GMP), an intracellular signaling molecule is known to assist in Bp cell invasion by biofilm formation [40]. It was shown that a low intracellular concentration of c-di-GMP inhibited biofilm formation in Bp [41]. Bp biofilm promotes host cell attachment and invasion, triggering host cell apoptosis and proinflammatory responses [40]. Adherence of Bp to host cells was also dependent on the presence of extracellular DNA (eDNA) [42], an essential component in the initial development of biofilm and subsequent maturation of bacteria [43,44]. Reducing eDNA in the biofilm matrix has been proposed as a strategy to reduce Bp attachment to host cells [42]. We previously proposed that Bp biofilm is both a virulence factor as well as a contributory factor in the occurrence of persistent infection in the host as biofilm attenuated the cytokine response in Bp infected mice [45]. Bp also expresses adhesion factors such as PilA (type IV pilin) [46], BoaA and BoaB [47], and BapA [48] to facilitate bacterial adherence to epithelial cells. Bacterial flagella were also reported to help penetrate the mucosal linings of the epithelial cells [49].

Survival of Bp in different environments

Despite extensive studies on Bp pathogenesis, not much is known about the emergence of a harmless soil bacterium into a highly virulent pathogen that causes a life-threatening disease in humans and animals. Soil bacteria are often exposed to extreme and unpredictable biotic and abiotic challenges, which include variable soil temperature and humidity as well as the need to compete for nutrients and survive the presence of soil-living predators. It has been proposed that the bacterium's ability to survive the harsh conditions of the soil may indirectly contribute to its clinical pathogenicity. Hence, the key to understanding the complete molecular mechanisms underlying Bp pathogenesis is knowing how a pathogen responds to different environments.

As a soil-dwelling bacterium, Bp is usually isolated from environmental soil [50] and groundwater [51]. High prevalence of Bp is found in soil with depths of >30 cm with high water content, low organic matter, carbon and nitrogen sources [52] but low soil phosphorus, iron, calcium, magnesium and potassium content [53]. Hence, rice paddy fields are a favoured reservoir for Bp where the nutritional content of the soil is usually low [53]. Interestingly, Bp can also survive in distilled water at 25°C for up to 16 years, in rain water and in the absence of any carbon source for several years [54]. Bp’s ablity to thrive in saline conditions provides an ecological advantage over other soil-dwelling microbes. Pumirat et al. [55] reported that T3SS secreted proteins BipD and BopE were overexpressed in the presence of 170 mM NaCl which may explain the frequent occurrence of melioidosis in northeastern Thailand where the salt content of soil and water is high. Furthermore, Bp is resistant to the presence of herbicides in soil and sigma factor E has been implicated in the regulation of polyamine spermidine to protect the bacteria from oxidative stress [56].

Bp can also be isolated from plants and insects, making it a versatile pathogen [57]. Bp was shown to colonise and form biofilm on the root structures of rice paddy, Oryza sativa [58]. It was previously thought that the survival of this pathogen was enhanced by free-living soil amoeba such as Acanthamoeba astronyxis in treated potable water, proposing that amoeba could act as potential hosts for Bp [59]. However, a recent study showed that soil amoeba such as Acanthamoeba spp., Paravahlkampfia ustiana and isolate A-ST39-E1 could be predators of rather than environmental reservoirs for Bp [60]. The bacteria can also survive in soil-dwelling nematodes such as Caenorhabditis elegans and thus, the C. elegans-Bp model has been extensively used in host-pathogen interaction studies [61–63] All in all, the ability of Bp to adapt to and survive in different niches is remarkable.

Once in the infected host, Bp expresses pathogen associated molecular patterns (PAMPs) such as pathogen-specific carbohydrates and nucleic acids as part of the pathogen life cycle [64]. Infected mammalian host cells respond to PAMPs by triggering toll-like-receptor (TLR)-dependent killing mechanisms. Within the infected host milieu, Bp lipopolysaccharide (LPS) [65] and flagellin [66] attach to TLR2, TLR4 and TLR5 of infected host cells triggering the production of proinflammatory and anti-inflammatory cytokines [67,68] via a cascade of activated eukaryotic pathways such as myeloid differentiation primary response protein 88 (MyD88) [69], Toll-interleukin receptor (TIR)-domain-containing adapter-inducing interferon-β (TRIF) [70], and mitogen activated protein kinase (MAPK) [71].

Upon uptake by host cells, Bp is enveloped in either endocytic vesicles (epithelial cells) or phagosomes (phagocytic cells) [72]. To escape, Bp uses T3SS-3 components such as BopA [73], BopC [74], BsaM [37], BsaQ [75], and BsaZ [76]. Moreover, Bp also secretes phospholipase C to cleave the phosphodiester bond of the endocytic vesicle phospholipids bilayer to escape [77]. In infected cells, reactive oxygen species (ROS) such as superoxides (O2), hydrogen peroxides (H2O2) and hydroxyl radicals (OH) [78] denature bacterial enzymes, fatty acids and DNA [34]. In response to oxidative stress, Bp RpoE [56] and RpoS [79] act as transcriptional factors to regulate the expression of many proteins for intracellular survival. To avoid killing by ROS, particularly O2, Bp secretes superoxide dismutases (Sod) that catalyse the conversion of O2 into H2O2 [80]. Three bacterial Sod, SodA, SodB and SodC, have been reported [81]. However, only SodB [82] and SodC [83] are required for Bp intracellular survival. Bp RpoS suppresses inducible nitric oxide synthase (iNOS) induced by the activated TRIF pathway [84] to ensure its survival. T3SS-associated proteins, sigma factor E and Acyl Co-A dehydrogenase are also overexpressed under high salinity [85]. This is pertinent to Bp infection of the cystic fibrosis patients with high salt concentrations in their lung [55].

In enveloped vesicles, Bp secretes ecotin, a serine protease inhibitor, to degrade host proteases and facilitate its growth and virulence in infected cells [86]. Bp then uses the T3SS-3 to escape from endocytic vesicles or phagosomes [37,87] before phagolysosomal fusion occurs [34]. Host apoptosis-related proteins such as caspase-3, caspase-8, caspase-9, Bax, and Bcl-2 as well as caspase-1 dependent and independent pathways are induced following Bp infection in mouse models [88]. However, Bp T3SS secretes cycle inhibiting factors (Cifs) that activate the ERK pathway leading to phosphorylation and subsequent degradation of the proapoptotic protein, Bcl2-like protein 11 thereby inhibiting cell apoptosis [89]. Bp is also capable of evading autophagy by reducing the level of autophagy-related protein 10 in host cells [90]. Bp’s survivability in the host environment triggers a competition for essential micronutrients such as iron [91] and de novo fatty acids [92]. In the presence of low-iron concentrations in the host, Bp turns to nitrogen metabolism and electron transport to generate ATP and ensure its survival. Bp turns on the arginine deiminase (ADI) pathway to protect itself from harsh conditions such as acidic [93] and anoxic [94] environments. As the ADI pathway is a secondary energy-providing pathway in other bacteria [95,96], it is possible that Bp also utilises arginine as an alternative energy source in hostile environments. Ergothionine was also shown to be important in Bp survival in mice as inhibition of ergothionine synthesis delayed bacterial organ colonisation [97]. It was also reported that Bp secretes trehalase to catabolise trehalose, produced by eukaryotic cells, into glucose for bacterial assimilation [57].

Bp also suppresses the infected host immune response by interfering with host protein synthesis through the secretion of various effector proteins. A Bp infection of C. elegans down-regulated the nematode erythroid-like transcription factor-2 (ELT-2) [98], a homologue of the human GATA transcription factor with roles in host immunity [99,100]. A Bp effector protein enlisted the nematode ubiquitin-proteasome system to degrade ELT-2 thereby suppressing the host immune response towards the pathogen [98]. We also identified Bp bactobolin, a member of the polyketide-peptide family of molecules, as a toxin that disrupts host protein translation [62] and Burkholderia lethal factor 1 (BLF-1) that inhibits helicase activity of the host translation factor eIF4A thereby disrupting synthesis of host proteins [101]. Collectively, Bp has evolved the capacity to interfere with the host machinery thus dampening the host defense towards the bacteria.

Once pathogens have established themselves within the host cell milieu, the bacteria will shift its focus to intercellular spreading in an attempt to avoid direct confrontation with the extracellular host immune response [102]. Bp localises the autotransporter proteins, Burkholderia intracellular motility A (BimA), to one pole of the bacterium, facilitated by BimC for actin formation [103]. BimA then interacts with the host actin monomers and polymerisation occurs to form ‘comet’ actin tails that help cell-to-cell spread [104]. The Bp type VI secretion systems (T6SS) aids in cell fusion of infected and neighbouring cells [105,106] although the exact mechanism remains to be elucidated [107]. Hemolysin co-regulated protein 1 (Hcp1) [108] and valine-glycine repeat protein (VgrG5) are effectors secreted by the Bp T6SS-1 and T6SS-5 [105,106] respectively, to mediate cellular membrane fusion during intercellular motility. Eventually, the merging of multiple cells forms multinucleated giant cells (MNGC), a hallmark in melioidosis [105]. Formation of MNGCs can occur in both phagocytic and non-phagocytic cells [109] as well as tissues isolated from melioidosis patients [110]. Lysis of MNGCs releases intracellular Bp and creates plaques in vitro [107]. Bp proteins and their roles in bacterial adaptation and survival are summarised in Table 1.

Table 1
B. pseudomallei proteins required for adaptation and survival to establish successful infection
Virulence factorFunctionReference(s)
Host cell invasion 
c-di-GMP Intracellular signaling molecule involved in biofilm formation Kunyanee et al. [40
Biofilm Cell attachment and invasion  
PilA Cell adherence Essex-Lopresti et al. [46
BoaA Putative autotransporter Balder et al. [47
BoaB   
BapA Trimeric autotransporter adhesin Lazar Adler et al. [48
T3SS-3 Injection of bacterial effectors into host cytoplasm Teh et al. [37
BipC Effector secreted by T3SS-3 to rearrange host cytoskeleton for cell invasion Kang et al. [39
BipD Host cell invasion in high salinity condition Pumirat et al. [55
BopE   
Flagella Facilitate cell invasion within mucosal linings Chuaygud et al. [49
Endocytic vesicle escape 
BopA Effector secreted by T3SS-3 to facilitate escape from endocytic vesicle Gong et al. [73
BopC T3SS-3 effector protein in aiding endocytic vesicle escape Srinon et al. [74
BsaM Structural components of T3SS-3 and help in the escape from endocytic vesicle Teh et al. [37
BsaQ  Muangsombut et al. [75
BsaZ  Burtnick et al. [76
Phospholipase C Cleaves the phosphodiester bond of the endocytic vesicle phospholipids bilayer to escape Liew et al. [77
Intracellular survival 
RpoE Transcriptional regulator in response to harsh conditions Jitprasutwit et al. [56
RpoS Transcriptional regulator in response to oxidative stress Sanongkiet et al. [79
Superoxide  dismutases Resist oxidative stress by converting O2- to H2O2 Moule et al. [82
  Vanaporn et al. [83
Ecotin Degrade host proteases Ireland et al. [86
T3SS-3 Facilitate bacterial escape from enveloped vesicle Teh et al. [37
Cifs Cell apoptosis inhibition to enable intracellular bacterial survival Ng et al. [89
Ferric siderophores Scavenge iron from the host cell environment Mathew et al. [91
Arginine deiminase Bacteria protection in harsh environments Chantratita et al. [93
  Hamad et al. [94
Ergothioneine A Bp sulfoxide synthase with role in bacterial pathogenesis in mammalian hosts Gamage et al. [97
Trehalase Catabolise host trehalose into glucose for bacterial assimilation Vanaporn et al. [57
BLF-1 Disruption of host protein translation Cruz-Migoni et al. [101
Bactobolin  Wong et al. [62
Intracellular motility and multinucleated giant cell formation 
BimA ‘Comet’ actin tail formation Lu et al. [103
BimC   
T6SS Cell fusion of infected and neighbouring cells to form multinucleated giant cells Toesca et al. [105
Hcp1 Secreted by T6SS as an effector to facilitate cell fusion Burtnick et al. [108
VgrG5 Bacterial effector secreted by T6SS required for MNGC formation and virulence Schwarz et al. [106
Virulence factorFunctionReference(s)
Host cell invasion 
c-di-GMP Intracellular signaling molecule involved in biofilm formation Kunyanee et al. [40
Biofilm Cell attachment and invasion  
PilA Cell adherence Essex-Lopresti et al. [46
BoaA Putative autotransporter Balder et al. [47
BoaB   
BapA Trimeric autotransporter adhesin Lazar Adler et al. [48
T3SS-3 Injection of bacterial effectors into host cytoplasm Teh et al. [37
BipC Effector secreted by T3SS-3 to rearrange host cytoskeleton for cell invasion Kang et al. [39
BipD Host cell invasion in high salinity condition Pumirat et al. [55
BopE   
Flagella Facilitate cell invasion within mucosal linings Chuaygud et al. [49
Endocytic vesicle escape 
BopA Effector secreted by T3SS-3 to facilitate escape from endocytic vesicle Gong et al. [73
BopC T3SS-3 effector protein in aiding endocytic vesicle escape Srinon et al. [74
BsaM Structural components of T3SS-3 and help in the escape from endocytic vesicle Teh et al. [37
BsaQ  Muangsombut et al. [75
BsaZ  Burtnick et al. [76
Phospholipase C Cleaves the phosphodiester bond of the endocytic vesicle phospholipids bilayer to escape Liew et al. [77
Intracellular survival 
RpoE Transcriptional regulator in response to harsh conditions Jitprasutwit et al. [56
RpoS Transcriptional regulator in response to oxidative stress Sanongkiet et al. [79
Superoxide  dismutases Resist oxidative stress by converting O2- to H2O2 Moule et al. [82
  Vanaporn et al. [83
Ecotin Degrade host proteases Ireland et al. [86
T3SS-3 Facilitate bacterial escape from enveloped vesicle Teh et al. [37
Cifs Cell apoptosis inhibition to enable intracellular bacterial survival Ng et al. [89
Ferric siderophores Scavenge iron from the host cell environment Mathew et al. [91
Arginine deiminase Bacteria protection in harsh environments Chantratita et al. [93
  Hamad et al. [94
Ergothioneine A Bp sulfoxide synthase with role in bacterial pathogenesis in mammalian hosts Gamage et al. [97
Trehalase Catabolise host trehalose into glucose for bacterial assimilation Vanaporn et al. [57
BLF-1 Disruption of host protein translation Cruz-Migoni et al. [101
Bactobolin  Wong et al. [62
Intracellular motility and multinucleated giant cell formation 
BimA ‘Comet’ actin tail formation Lu et al. [103
BimC   
T6SS Cell fusion of infected and neighbouring cells to form multinucleated giant cells Toesca et al. [105
Hcp1 Secreted by T6SS as an effector to facilitate cell fusion Burtnick et al. [108
VgrG5 Bacterial effector secreted by T6SS required for MNGC formation and virulence Schwarz et al. [106

The adaptive survival mechanisms of this pathogen mainly involve changes in bacterial gene and protein expression which could alter the bacteria's cell membrane, metabolism and virulence [85]. Previously, comparative transcriptional profiles of environmental and clinical isolates of Vibrio vulnificus provided new knowledge on bacterial genes required for the emergence of a soil bacterium into a human pathogen [111]. Comparative transcriptomics of Burkholderia cenocepacia under conditions mimicking soil versus cystic fibrosis sputum revealed the up-regulation of eight genes in the cystic fibrosis condition [112]. To survive in nutrient-depleted media, B. cenocepacia also utilised a subset of genes involved in the biosynthesis of aromatic amino acids [113] that mediate the regulation of quorum sensing signal molecules and virulence factors [114].

Understanding how Bp adapts to different environments will provide important insights into the survival and pathogenesis of Bp and assist in the development of novel strategies for control, prevention and treatment of melioidosis. Ooi et al. [115] assessed the transcriptional landscape of Bp in over 80 different environmental and genetic conditions and reported several key physiological processes and genes involved in in vivo infection and quorum sensing pathways. They also proposed important roles for small RNAs (sRNA or ncRNA) that regulate the expression of proteins required for host cell invasion, environmental adaptation and pathogenicity. Mohd-Padil et al. [116] showed that cis-encoded Bp RNA were differentially expressed in nutrient-depleted conditions. Recently, a comparative transcriptome profile of Bp isolated from five cystic fibrosis patients showed differential patterns of virulence factors and antibiotic resistance [117]. Our group also previously reported that during infection of U937 macrophage cells, Bp made rapid metabolic adjustments by down-regulating genes associated with catabolism and housekeeping genes due to lower energy requirements and inhibition of bacterial growth. Of note, flagella synthesis was down-regulated to avoid recognition by TLR-5, hence, dampening the activation of the host innate immune response. Concurrently, anabolism-related genes and T6SS were up-regulated to ensure bacterial survival and virulence [87].

To understand changes in gene expression that govern bacterial adaptation when transitioning from soil to mammals, we performed comparative RNA-seq on Bp grown in human blood plasma and conditions mimicking soil. Our preliminary data showed that Bp up-regulated its ADI and cytochrome ubiquinol oxidase pathways as well as biofilm, flagella, capsular polysaccharide and T3SS encoding genes in plasma-grown bacteria relative to bacteria grown in the soil environment (Figure 1). We suggest that when Bp shifts between its environmental niches to the infected host, it protects itself from host defense mechanisms and other antimicrobial treatments by forming biofilm as well as rerouting its focus to the secretion of virulence factors and secondary energy sourcing [118]. In conclusion, Bp is a highly adaptive microbe and this versatility may be attributed to the genome plasticity of Bp and a complex multifactorial route that enables survival under hostile environments as well as promoting pathogenesis.

Heat-map showing the gene expression profile of selected Bp genes in conditions mimicking soil versus human plasma.

Figure 1.
Heat-map showing the gene expression profile of selected Bp genes in conditions mimicking soil versus human plasma.

Coloured scales represent log2 fold change values with green and red for down-regulated and up-regulated genes, respectively.

Figure 1.
Heat-map showing the gene expression profile of selected Bp genes in conditions mimicking soil versus human plasma.

Coloured scales represent log2 fold change values with green and red for down-regulated and up-regulated genes, respectively.

Perspectives

  • Importance to the field: Melioidosis remains a global disease with high mortality rates due to misdiagnosis and high virulence of Bp. Although the bacterial pathogenesis mechanism is an area of active study, our knowledge of the genetic adaptations employed by the bacteria under different environments, is limited. Understanding how Bp regulates its gene expression under different environments, particularly when interacting with the host, would aid in identifying key bacterial proteins as targets for the development of more effective therapeutics for melioidosis.

  • Current thinking: The traditional approaches to assess host and pathogen transcriptomes do not allow concurrent transcriptome profiling of both host and pathogen [119] as unfavourable host-pathogen ratios hamper efforts to profile host-pathogen transcriptomes [120]. However, the establishment of dual RNA-seq allows synchronous transcriptome profiling of both host and pathogen under a given condition [121] enabling functional annotation of poorly characterised genes and pathways [122].

  • Future directions: New insights into the transcriptional adaptation of a pathogen during host-pathogen interaction will contribute new knowledge on pathogenic mechanisms, virulence factors and host responses. Contribution of the host microbiome is also key to understand the interaction between Bp and the infected host and whether modulating the microbiota can confer resistance to Bp infection in highly endemic areas. Taken together with the current understanding on Bp pathogenesis, the melioidosis research community will be a step closer to developing more effective treatments for melioidosis.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Acknowledgements

The authors acknowledge funding from Universiti Kebangsaan Malaysia (DIP-2015-015) and Ministry of Education Malaysia (FRGS/1/2016/SKK11/UKM/01/1) for supporting our research findings presented in this review.

Abbreviations

     
  • ADI

    Arginine deiminase

  •  
  • Bim

    Burkholderia intracellular motility

  •  
  • BLF-1

    Burkholderia lethal factor 1

  •  
  • c-di-GMP

    cyclic diguanylic acid

  •  
  • Cifs

    cycle inhibiting factors

  •  
  • eDNA

    extracellular DNA

  •  
  • ELT-2

    erythroid-like transcription factor-2

  •  
  • ERK

    extracellular receptor kinase

  •  
  • Hcp1

    Hemolysin co-regulated protein 1

  •  
  • iNOS

    inducible nitric oxide synthase

  •  
  • LPS

    lipopolysaccharide

  •  
  • MAPK

    mitogen-activated protein kinase

  •  
  • MNGC

    multinucleated giant cell

  •  
  • MyD88

    myeloid differentiation primary response protein 88

  •  
  • PAMP

    pathogen-associated molecular patterns

  •  
  • PAR-1

    protease-activated receptor-1

  •  
  • ROS

    reactive oxygen species

  •  
  • SOD

    superoxide dismutase

  •  
  • sRNA

    small RNAs

  •  
  • T3SS

    type III secretion system

  •  
  • T6SS

    type VI secretion system

  •  
  • TIR

    Toll-interleukin receptor

  •  
  • TLR

    Toll-like receptor

  •  
  • TRIF

    TIR-domain-containing adapter-inducing interferon-β

  •  
  • VgrG

    valine-glycine repeat protein

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