Complement Susceptibility in Relation to Genome Sequence of Recent Klebsiella pneumoniae Isolates from Thai Hospitals

Loraine, Jessica; Heinz, Eva; Almeida, Jessica De Sousa; Milevskyy, Oleksandr; Voravuthikunchai, Supayang Piyawan; Srimanote, Potjanee; Kiratisin, Pattarachai; Thomson, Nicholas R.; Taylor, Peter W.

doi:10.1128/msphere.00537-18

Cited by 23 publications

(29 citation statements)

References 91 publications

(161 reference statements)

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“…complement-resistant bacteria may not only mask their cell surface from the initial recognition by the three complement pathways but may also inhibit later stages of the complement pathway by altering their surface configuration in response to envelope stress, preventing membrane insertion and MAC pore formation. Our findings that distinct K. pneumoniae strains can have distinct complement evasion mechanisms, underpinned by dramatically different gene sets, highlights the complexity associated with predicting serum resistance based on genome sequence or single virulence factors-an undertaking which is not yet possible for K. pneumoniae (27). A comprehensive understanding of the basis of complement resistance in Gramnegative bacteria will only be forthcoming when the behavior of such clinically relevant pathogens can be explained.…”

Section: Discussionmentioning

confidence: 93%

“…Resistance to killing by complement is an important yet incompletely understood feature of K. pneumoniae pathogenesis (4,8,27). The prominent polysaccharide capsule has been invoked as a key determinant of resistance by virtue of its capacity to limit C3b deposition or assembly of the membrane attack complex (8,26), but it is clear that other factors also contribute to the complement-resistant phenotype (27). Resistance to serum killing is associated with K. pneumoniae hypervirulence, and we therefore selected three well-studied hypervirulent strains, as well as a recently isolated clinical .…”

Section: Discussionmentioning

confidence: 99%

“…Multiple different factors can influence serum resistance in K. pneumoniae, including capsule type and amount, O-antigen type, and various surface proteins; capsules and O antigens have each been invoked as the main determinant of complement resistance (9,26). However, a recent study of Ͼ150 K. pneumoniae clinical isolates from Thailand with various complement susceptibilities concluded that susceptibility did not correlate with the presence of specific genes, particular capsule types, or even with the hypercapsulation phenotype of the isolates (27). This study highlighted the main limitation of collective studies on complement resistance in K. pneumoniae to date-that although many resistance factors are individually well characterized, there is very limited understanding of how their activities play out in different combinations or across diverse isolates of K. pneumoniae.…”

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confidence: 99%

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Genomic Profiling Reveals Distinct Routes To Complement Resistance in Klebsiella pneumoniae

et al. 2020

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The serum complement system is a first line of defense against bacterial invaders. Resistance to killing by serum enhances the capacity of Klebsiella pneumoniae to cause infection, but it is an incompletely understood virulence trait. Identifying and characterizing the factors responsible for preventing activation of, and killing by, serum complement could inform new approaches to treatment of K. pneumoniae infections. Here, we used functional genomic profiling to define the genetic basis of complement resistance in four diverse serum-resistant K. pneumoniae strains (NTUH-K2044, B5055, ATCC 43816, and RH201207), and explored their recognition by key complement components. More than 90 genes contributed to resistance in one or more strains, but only three, rfaH, lpp, and arnD, were common to all four strains. Deletion of the antiterminator rfaH, which controls the expression of capsule and O side chains, resulted in dramatic complement resistance reductions in all strains. The murein lipoprotein gene lpp promoted capsule retention through a mechanism dependent on its C-terminal lysine residue; its deletion led to modest reductions in complement resistance. Binding experiments with the complement components C3b and C5b-9 showed that the underlying mechanism of evasion varied in the four strains: B5055 and NTUH-K2044 appeared to bypass recognition by complement entirely, while ATCC 43816 and RH201207 were able to resist killing despite being associated with substantial levels of C5b-9. All rfaH and lpp mutants bound C3b and C5b-9 in large quantities. Our findings show that, even among this small selection of isolates, K. pneumoniae adopts differing mechanisms and utilizes distinct gene sets to avoid complement attack.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Genomic Profiling Reveals Distinct Routes To Complement Resistance in Klebsiella pneumoniae

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“…Commercial (MP Biomedicals, United Kingdom) pooled human serum was stored and used to determine susceptibility to C', essentially as previously described (Loraine et al, 2018). Early mid-logarithmic-phase Luria-Bertani (LB) broth cultures of A. baumannii were washed three times with 200 µl of gelatinveronal-buffered saline containing Mg 2+ and Ca 2+ (GVB ++ ; pH 7.35) and suspended in 400 µl of GVB ++ .…”

Section: C' Susceptibilitymentioning

confidence: 99%

Genomic and Phenotypic Analyses of Acinetobacter baumannii Isolates From Three Tertiary Care Hospitals in Thailand

et al. 2020

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Antibiotic resistant strains of Acinetobacter baumannii are responsible for a large and increasing burden of nosocomial infections in Thailand and other countries of Southeast Asia. New approaches to their control and treatment are urgently needed and an attractive strategy is to remove the bacterial polysaccharide capsule, and thus the protection from the host's immune system. To examine phylogenetic relationships, distribution of capsule chemotypes, acquired antibiotic resistance determinants, susceptibility to complement and other traits associated with systemic infection, we sequenced 191 isolates from three tertiary referral hospitals in Thailand and used phenotypic assays to characterize key aspects of infectivity. Several distinct lineages were circulating in three hospitals and the majority belonged to global clonal group 2 (GC2). Very high levels of resistance to carbapenems and other front-line antibiotics were found, as were a number of widespread plasmid replicons. A high diversity of capsule genotypes was encountered, with only three of these (KL6, KL10, and KL47) showing more than 10% frequency. Almost 90% of GC2 isolates belonged to the most common capsule genotypes and were fully resistant to the bactericidal action of human serum complement, most likely protected by their polysaccharide capsule, which represents a key determinant of virulence for systemic infection. Our study further highlights the importance to develop therapeutic strategies to remove the polysaccharide capsule from extensively drug-resistant A. baumanii during the course of systemic infection.

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“…The polysaccharide capsule (encoded by the capsular polysaccharide synthesis locus— cps gene) is another important virulence factor for the establishment of skin infections, since it prevents phagocytosis and complement-mediated killing [ 262 , 263 ]. For K. pneumoniae , 78 capsular serotypes have been reported.…”

Section: Eskape and Wound Infectionsmentioning

confidence: 99%

Interplay between ESKAPE Pathogens and Immunity in Skin Infections: An Overview of the Major Determinants of Virulence and Antibiotic Resistance

et al. 2021

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The skin is the largest organ in the human body, acting as a physical and immunological barrier against pathogenic microorganisms. The cutaneous lesions constitute a gateway for microbial contamination that can lead to chronic wounds and other invasive infections. Chronic wounds are considered as serious public health problems due the related social, psychological and economic consequences. The group of bacteria known as ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter sp.) are among the most prevalent bacteria in cutaneous infections. These pathogens have a high level of incidence in hospital environments and several strains present phenotypes of multidrug resistance. In this review, we discuss some important aspects of skin immunology and the involvement of ESKAPE in wound infections. First, we introduce some fundamental aspects of skin physiology and immunology related to cutaneous infections. Following this, the major virulence factors involved in colonization and tissue damage are highlighted, as well as the most frequently detected antimicrobial resistance genes. ESKAPE pathogens express several virulence determinants that overcome the skin’s physical and immunological barriers, enabling them to cause severe wound infections. The high ability these bacteria to acquire resistance is alarming, particularly in the hospital settings where immunocompromised individuals are exposed to these pathogens. Knowledge about the virulence and resistance markers of these species is important in order to develop new strategies to detect and treat their associated infections.

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Complement Susceptibility in Relation to Genome Sequence of Recent Klebsiella pneumoniae Isolates from Thai Hospitals

Cited by 23 publications

References 91 publications

Genomic Profiling Reveals Distinct Routes To Complement Resistance in Klebsiella pneumoniae

Genomic Profiling Reveals Distinct Routes To Complement Resistance in Klebsiella pneumoniae

Genomic and Phenotypic Analyses of Acinetobacter baumannii Isolates From Three Tertiary Care Hospitals in Thailand

Interplay between ESKAPE Pathogens and Immunity in Skin Infections: An Overview of the Major Determinants of Virulence and Antibiotic Resistance

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